WO2025155607A1 - Méthodes de traitement du carcinome urothélial avec un antagoniste de liaison à l'axe pd-1 et un vaccin à arn - Google Patents

Méthodes de traitement du carcinome urothélial avec un antagoniste de liaison à l'axe pd-1 et un vaccin à arn

Info

Publication number
WO2025155607A1
WO2025155607A1 PCT/US2025/011687 US2025011687W WO2025155607A1 WO 2025155607 A1 WO2025155607 A1 WO 2025155607A1 US 2025011687 W US2025011687 W US 2025011687W WO 2025155607 A1 WO2025155607 A1 WO 2025155607A1
Authority
WO
WIPO (PCT)
Prior art keywords
rna vaccine
patient
weeks
binding antagonist
axis binding
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/011687
Other languages
English (en)
Inventor
Mahesh YADAV
Corey Allan CARTER
Viraj Vinay DEGAONKAR
Erik Todd GOLUBOFF
Irina IANCULESCU
Michael Robert MANCUSO
Ina Park RHEE
Ugur Sahin
Özlem TÜRECI
Liane Monika PREUSSNER
Luisa Marie Anna MANNING
Felicitas MÜLLER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biontech SE
Genentech Inc
Original Assignee
Biontech SE
Genentech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biontech SE, Genentech Inc filed Critical Biontech SE
Publication of WO2025155607A1 publication Critical patent/WO2025155607A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152

Definitions

  • Urothelial carcinoma is the most common cancer of the urinary system worldwide, with the majority of cases originating in the bladder (Leow et al. (2017) Upper tract urothelial carcinoma: a different disease entity in terms of management. ESMO Open 2017;l :e000126). Approximately 1 in 3 new cases of urothelial carcinoma are diagnosed as muscle invasive disease (cT2-T4aNxM0) (Kaufman et al. (2009) Bladder cancer. Lancet 2009;374:239-49).
  • MIUC muscle invasive urothelial carcinoma
  • MIBC muscle invasive bladder cancer
  • UTUC muscle invasive upper tract urothelial cancer
  • transitional cell carcinoma (TCC; also called UC) being the most common histologic subtype.
  • TCC transitional cell carcinoma
  • Patients with MIBC often undergo bladder resection (cystectomy).
  • Patients with UTUC often undergo kidney and/or ureter resection (nephroureterectomy).
  • Transitional cell carcinoma accounts for 90% of all MIBC cases in the industrialized world (Chalasani et al. (2009) Histologic variants of urothelial bladder cancer and nonurothelial histology in bladder cancer.
  • MIBC Despite radical cystectomy, MIBC recurs in many patients, who subsequently present with pain or constitutional symptoms such as fatigue, weight loss, anorexia, and failure to thrive. Approximately half of the patients with MIBC will develop a local and/or metastatic recurrence of their disease within 2 years of cystectomy and will eventually die from their disease (Raghavan et al. (1990) Biology and management of bladder cancer. N Engl J Med 1990;322: 1129-38; Stein et al. 2001; Stenzl et al. (2009) The updated EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol 2009;55:815-25).
  • Neoadjuvant and Adjuvant Treatments have been utilized in conjunction with radical cystectomy for MIBC.
  • the rationale for perioperative chemotherapy is based on the response in patients with metastatic UC, in which cisplatin-based chemotherapy has demonstrated efficacy with a median survival of approximately 15 months with responses in 40%-60% of patients (von der Maase et al. (2005) Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005;23:4602-8).
  • Neoadjuvant chemotherapy has provided a modest survival benefit of 5% in MIBC (Advanced Bladder Cancer Meta-Analysis Collaboration 2003).
  • the disadvantage of NAC is that it potentially delays definitive surgical management with radical cystectomy.
  • 60% of patients still have muscle-invasive disease at time of cystectomy (Rosenblatt et al. (2012) Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer.
  • Ur Urol 2012;61 : 1229-38 is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer.
  • the PD-1 axis binding antagonist is administered every four weeks starting in week 2 and every four weeks thereafter for up to one year, timing starting with week 1 of the priming phase.
  • the method comprises administration of 13 doses of the PD-1 axis binding antagonist, wherein one dose of the PD-1 axis binding antagonist is administered every 28 days over approximately 1 year.
  • the PD-1 axis binding antagonist is administered on day 2 of week 2 and on day 1 of weeks 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50, timing starting with week 1 of the priming phase.
  • the booster phase begins in week 14, timing starting with week 1 of the priming phase. In some embodiments, the booster phase begins on day 1 of week 14, timing starting with day 1 week 1 of the priming phase.
  • the booster phase comprises administering 6, 7, 8, 9, or 10 doses of the PD-1 axis binding antagonist. In some embodiments, the booster phase comprises administering 10 doses of the PD-1 axis binding antagonist. In some embodiments, the booster phase comprises administering 10 doses of the PD-1 axis binding antagonist and 4 doses of the RNA vaccine. In some embodiments, the booster phase comprises administering the PD-1 axis binding antagonist once every four weeks for up to 10 administrations. In some embodiments, the booster phase comprises administering the PD-1 axis binding antagonist on day 1 of week 1 of the booster phase and every four weeks thereafter. In some embodiments, the booster phase comprises administering the PD-1 axis binding antagonist on day 1 of week 1 of the booster phase and every four weeks thereafter for up to one year after the first administration of the PD-1 axis binding antagonist.
  • the booster phase begins in week 14 on day 8 of Cycle 4 and comprises days 8-28 of Cycle 4 and at least the nine 28-day Cycles thereafter, and the booster phase comprises administering the RNA vaccine on day 8 of Cycles 4 and 10 and administering the PD-1 axis binding antagonist on day 8 of Cycles 4-13, timing starting with Cycle 1 beginning on week 1 day 1 of the priming phase.
  • one or more doses of the RNA vaccine in the booster phase and/or the priming phase are missed, and/or one or more doses of the PD-1 axis binding antagonist in the booster phase and/or the priming phase are missed, due to treatment delay due to toxicity.
  • one or more make-up doses of the RNA vaccine are administered to make up for a missed booster dose or missed priming dose of the RNA vaccine.
  • one or more make-up priming dose of the RNA vaccine are administered.
  • one or more make-up priming dose of the RNA vaccine are administered no more frequently than weekly, ⁇ 2 days.
  • the priming phase comprises administering the RNA vaccine on day 1 of weeks 1, 2, 3, 4, 5, 6, 7, and 9 of the priming phase, and administering the PD-1 axis binding antagonist on day 2 of week 2 and on day 1 of week 6 of the priming phase;
  • a third dose of the PD-1 axis binding antagonist is administered on day 1 of week ten;
  • the booster phase comprises administering (i) a first booster dose of the RNA vaccine on day 1 of week 14, a second booster dose of the RNA vaccine on day 1 of week 38, a third booster dose of the RNA vaccine approximately 15 months after the first priming phase administration of the PD-1 axis binding antagonist, and a fourth booster dose of the RNA vaccine in approximately 21 months after the first priming phase administration of the PD-1 axis binding antagonist; and (ii) the PD-1 axis binding antagonist on day 1 of weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50; wherein timing starts with week 1 day 1 day 1
  • the priming phase begins between about 4 weeks and about 18 weeks after resection of the UC from the patient.
  • the anti-PD-Ll antibody comprises: (a) a heavy chain variable region (VH) that comprises an HVR-H1 comprising an amino acid sequence GFTFSDSWIH (SEQ ID NO: 1), an HVR-H2 comprising an amino acid sequence AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-H3 comprising an amino acid sequence RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (VL) that comprises an HVR-L1 comprising an amino acid sequence RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence QQYLYHPAT (SEQ ID NO:6).
  • VH heavy chain variable region
  • the anti-PD-Ll antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO:7 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO:8.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-PD-Ll antibody is atezolizumab.
  • the overall charge ratio of positive charges to negative charges of the lipid nanoparticle or lipoplex is 1.3:2 (0.65).
  • the one or more polynucleotides of the RNA vaccine are RNA molecules, optionally messenger RNA molecules.
  • the RNA vaccine comprises an RNA molecule comprising, in the 5’->3’ direction: (1) a 5’ cap; (2) a 5’ untranslated region (UTR); (3) a polynucleotide sequence encoding a secretory signal peptide; (4) a polynucleotide sequence encoding the one or more neoepitopes resulting from cancer-specific somatic mutations present in the tumor specimen; (5) a polynucleotide sequence encoding at least a portion of a transmembrane and cytoplasmic domain of a major histocompatibility complex (MHC) molecule; (6) a 3’ UTR comprising: (a) a 3’ untranslated region of an Amino-Terminal Enhancer of Split (AES) mRNA or a fragment thereof; and (b) non-coding RNA of a mitochondrially encoded 12S RNA or a fragment thereof; and (7) a poly(A) sequence.
  • AES Amino-Term
  • the amino acid linker comprises the sequence GGSGGGGSGG (SEQ ID NO: 39). In some embodiments, the polynucleotide sequence encoding the amino acid linker comprises the sequence GGCGGCUCUGGAGGAGGCGGCUCCGGAGGC (SEQ ID NO:37).
  • the RNA molecule comprises 5 linker-neoepitope modules, and the 5 linker-neoepitope modules each encode a different neoepitope. In some embodiments, the RNA molecule comprises 10 linker-neoepitope modules, and the 10 linker- neoepitope modules each encode a different neoepitope. In some embodiments, the RNA molecule comprises 20 linker-neoepitope modules, and the 20 linker-neoepitope modules each encode a different neoepitope.
  • the RNA molecule further comprises a second polynucleotide sequence encoding an amino acid linker, wherein the second polynucleotide sequence encoding the amino acid linker is between the polynucleotide sequence encoding the neoepitope that is most distal in the 3’ direction and the polynucleotide sequence encoding the at least portion of the transmembrane and cytoplasmic domain of the MHC molecule.
  • the polynucleotide sequence encoding the at least portion of the transmembrane and cytoplasmic domain of the MHC molecule comprises the sequence AUCGUGGGAAUUGUGGCAGGACUGGCAGUGCUGGCCGUGGUGGUGAUCGGAG CCGUGGUGGCUACCGUGAUGUGCAGACGGAAGUCCAGCGGAGGCAAGGGCGGC AGCUACAGCCAGGCCGCCAGCUCUGAUAGCGCCCAGGGCAGCGACGUGUCACU GACAGCC (SEQ ID NO:28).
  • the 3’ untranslated region of the AES mRNA comprises the sequence CUGGUACUGCAUGCACGCAAUGCUAGCUGCCCCUUUCCCGUCCUGGGUACCCC GAGUCUCCCCCGACCUCGGGUCCCAGGUAUGCUCCCACCUCCACCUGCCCCACU CACCACCUCUGCUAGUUCCAGACACCUCC (SEQ ID NO:33).
  • the UC is a resectable UTUC with pathological staging of (y)pT3-4 or (y)pN+ and M0 prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the UC prior to administration of the RNA vaccine and the PD-1 axis binding antagonist, is a resectable MIUC comprising one or more characteristics selected from the group consisting of: having been histologically confirmed as muscle-invasive UC of the bladder or upper urinary tract, wherein patients with mixed or variant histologies have a dominant urothelial pattern; a TNM classification at pathological examination of surgical resection specimen as tumor stage of (y)pT3-4a or (y)pN+ and M0; a TNM classification at pathological examination of surgical UTUC resection specimen as tumor stage of (y)pT3-4 or (y)pN+ and M0; PD-L1 expression per PD-L1 IHC 28-8 pharmD
  • the patient prior to administration of the RNA vaccine and the PD-1 axis binding antagonist, the patient comprises one or more characteristics selected from the group consisting of: impaired renal function; hearing loss; Grade 2 or greater peripheral neuropathy; recovery from cystectomy or nephroureterectomy within 120 days following surgery; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; ECOG performance status of 2, wherein the patient has not received cisplatin based neoadjuvant chemotherapy and is ineligible for cisplatin adjuvant chemotherapy agreement to remain abstinent or use contraception, wherein the patient is female; agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm, wherein the patient is female; and age 18 years or older.
  • ECOG Eastern Cooperative Oncology Group
  • a tumor specimen is prepared from a pretreatment tumor biopsy or surgical resection, wherein the tumor specimen comprises at least 5 identified cancer-specific neoepitopes.
  • the pretreatment tumor biopsy is a TURBT or wherein the surgical resection is a cystectomy or a nephroureterectomy.
  • the surgical resection is a radical cystectomy or a radical nephroureterectomy.
  • the method further comprises preparing one or more additional tissue samples taken at one or more additional times or anatomical sites.
  • the UC is MIBC, and wherein imaging of the upper urinary tracts is completed no more than about four weeks prior to administration of the RNA vaccine and includes intravenous pyelogram (IVP), CT urography, renal ultrasound with retrograde pyelogram, ureteroscopy, and/or MRI urogram.
  • the UC is UTUC, wherein cystoscopy and urine cytology are completed no more than about four weeks prior to administration of the RNA vaccine and include upper tract imaging, wherein absence of contralateral disease is confirmed.
  • the UC is both primary MIBC and primary UTUC, wherein upper tract imaging and urine cytology are completed no more than about four weeks prior to administration of the RNA vaccine and include upper tract imaging, wherein absence of contralateral disease is confirmed.
  • At least five neoepitopes resulting from cancer-specific somatic mutations are present in the tumor specimen obtained from the patient prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the patient is not pregnant, breastfeeding, or intending to become pregnant during the administration or within 28 days after the final dose of the RNA vaccine or within 5 months after the final dose of the PD-1 axis binding antagonist.
  • the patient is female and has a negative serum pregnancy test result within 14 days prior to administration of the RNA vaccine.
  • the patient does not have a partial cystectomy in the setting of a bladder cancer primary tumor or a partial nephrectomy in the setting of a renal pelvis primary tumor.
  • the patient does not have any approved anti -cancer therapy, including chemotherapy, or hormonal therapy, excluding hormone-replacement therapy and oral contraceptives, within 3 weeks prior to administration of the RNA vaccine.
  • the patient does not have any neoadjuvant immunotherapy prior to administration of the RNA vaccine.
  • the patient does not have adjuvant chemotherapy or radiation therapy for UC following surgical resection prior to administration of the RNA vaccine.
  • the patient received primary chemoradiation for bladder preservation before cystectomy or before nephroureterectomy.
  • the patient has UTUC and does not have antegrade or retrograde instillation of chemotherapy or BCG prior to administration of the RNA vaccine.
  • the patient has a single dose of intravesical chemotherapy post nephroureterectomy prior to administration of the RNA vaccine.
  • the patient is not treated with an investigational agent that is not an individualized RNA vaccine and/or a PD-1 axis binding antagonist within about one month or five half-lives of the investigational agent, whichever is longer, prior to administration of the RNA vaccine.
  • the patient is diagnosed with one or more malignancies of a negligible risk of metastasis or death, wherein the malignancy is treated with expected curative intent, and wherein there is no evidence of recurrence or metastasis by follow-up imaging and any disease-specific tumor markers, within 5 years prior to administration of the RNA vaccine.
  • the negligible risk of metastasis or death comprises risk of metastasis or death ⁇ 5% at 5 years.
  • the malignancy comprises carcinoma in situ of the cervix, basal or squamous cell skin cancer, and/or ductal carcinoma, and wherein treatment with expected curative intent comprises surgical treatment.
  • the patient does not have a major surgical procedure, other than for diagnosis or for resection of UC, within ⁇ 6 weeks prior to prior to administration of the RNA vaccine. In some embodiments, the patient does not have an anticipated need for a major surgical procedure for about 6 years following initiation of the priming phase. In some embodiments, the patient has a central venous access catheter placed within about 5 years prior to administration of the RNA vaccine. In some embodiments, the patient does not have significant cardiovascular disease within 3 months prior to administration of the RNA vaccine. In some embodiments, the significant cardiovascular disease is a New York Heart Association Class II or greater cardiac disease, a myocardial infarction, or a cerebrovascular accident.
  • the autoimmune disease or immune deficiency comprises myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, granulomatosis with polyangiitis, Sjogren syndrome, Guillain-Barre syndrome, and/or multiple sclerosis.
  • the patient has a history of autoimmune-related hypothyroidism and is on thyroid replacement hormone.
  • the patient has controlled Type 1 diabetes mellitus and is on an insulin regimen.
  • the patient does not have psoriatic arthritis.
  • the patient has been diagnosed with a disease selected from the group consisting of eczema, psoriasis, lichen simplex chronicus, and vitiligo; wherein the disease has only dermatologic manifestations; wherein the patient does not have a rash covering >10% of body surface area; wherein the disease is well-controlled upon initiation of the priming phase and requires only low-potency topical corticosteroids; and wherein the disease is not treated with psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, and/or high potency or oral corticosteroids within 12 months prior to administration of the RNA vaccine.
  • a disease selected from the group consisting of eczema, psoriasis, lichen simplex chronicus, and vitiligo; wherein the disease has only dermatologic manifestations; wherein the patient does not have a rash covering >10% of body surface area; wherein the disease is well-controlled
  • the patient does not have ongoing treatment with monoamine oxidase inhibitors (MAOIs). In some embodiments, the patient is not treated with monoamine oxidase inhibitors (MAOIs) within 3 weeks prior to administration of the RNA vaccine. In some embodiments, the patient is not treated with a systemic immunostimulatory agent within 4 weeks or 5 drug-elimination half-lives, whichever is longer, prior to administration of the RNA vaccine. In some embodiments, the systemic immunostimulatory agent comprises interferon and/or IL-2.
  • the patient is not treated with a systemic immunosuppressive medication within 2 weeks prior to administration of the first priming dose of the RNA vaccine, or wherein the patient does not have anticipated need for systemic immunosuppressive medication for about 6 years following initiation of the priming phase.
  • the systemic immunosuppressive medication comprises a corticosteroid, a cyclophosphamide, an azathioprine, a methotrexate, a thalidomide, and/or an anti-TNF agent.
  • the patient receives acute, low-dose systemic immunosuppressant medication and/or a one-time pulse dose of systemic immunosuppressant medication within 2 weeks prior to administration of the first priming dose of the RNA vaccine.
  • the one-time pulse dose of systemic immunosuppressant medication comprises 48 hours of corticosteroids for a contrast allergy.
  • the patient receives one or more of a mineralocorticoid, an inhaled or low dose corticosteroid for chronic obstructive pulmonary disease or asthma, and/or a low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency, within 2 weeks prior to administration of the first priming dose of the RNA vaccine.
  • the mineralocorticoid comprises fludrocortisone, and/or wherein the inhaled or low dose corticosteroid comprises ⁇ 10 mg oral prednisone per day or daily equivalent.
  • the patient does not have one or more of a characteristic selected from the group consisting of: a history of idiopathic pulmonary fibrosis; a history of organizing pneumonia; a history of drug-induced pneumonitis; a history of idiopathic pneumonitis; a history of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins; a known hypersensitivity to Chinese hamster ovary cell products; a known hypersensitivity or allergy to a component of a product comprising the RNA vaccine; a known hypersensitivity or allergy to a component of a product comprising the PD-1 axis binding antagonist; evidence of active pneumonitis by chest CT scan within about 1 month prior to administration of the first priming dose of the RNA vaccine; known active or latent tuberculosis; severe infection within 4 weeks prior to administration of the first priming dose of the RNA vaccine; prior allogeneic stem cell or solid organ transplantation; any other disease, metabolic dysfunction, physical examination finding, or clinical
  • the organizing pneumonia comprises bronchiolitis obliterans.
  • the severe infection comprises hospitalization for complications of infection, hospitalization for complications of bacteremia, hospitalization for complications of severe pneumonia, and/or any active infection that could impact patient safety.
  • the patient has a known increased risk for infection with Mycobacterium tuberculosis within about 20 weeks prior to administration of the first priming dose of the RNA vaccine, and wherein latent tuberculosis diagnostic procedures are followed prior to administration of the first priming dose of the RNA vaccine.
  • the patient has a spleen prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the patient has not had loss of spleen due to splenectomy, splenic injury/infarction, or functional asplenia prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • administration of the RNA vaccine and the PD-1 axis binding antagonist results in an improvement in the one or more clinical assessments as compared to the one or more clinical assessments in the patient prior to administration of the RNA vaccine and the PD-1 axis binding antagonist, and/or as compared to the one or more clinical assessments in a corresponding patient not administered the RNA vaccine and the PD-1 axis binding antagonist.
  • administration of the RNA vaccine and the PD-1 axis binding antagonist treatment results in an improved and/or altered relationship between biomarkers, level of biomarkers of blood and/or tumor tissue, level of ctDNA, symptom assessed by EORTC QLQ-C30, VAS score of an EQ-5D-5L questionnaire, plasma concentration of DOTMA, serum concentration of the PD-1 axis binding antagonist, prevalence of AD As to the PD-1 axis binding antagonist, and/or antigen- and/or tumorspecific T-cell responses in the patient as compared to prior to administration of the RNA vaccine and the PD-1 axis binding antagonist, and/or as compared to a corresponding patient not administered the RNA vaccine and the PD-1 axis binding antagonist.
  • the corresponding patient is a patient with a corresponding UC, optionally wherein the UC is a MIUC and the corresponding patient has MIUC, and optionally wherein the UC is a UTUC and the corresponding patient has UTUC.
  • the corresponding patient was treated with a standard of care treatment for UC, MIUC, UTUC, or resectable or resected UC, MIUC, UTUC.
  • the standard of care treatment comprises a cystectomy, a nephroureterectomy and/or adjuvant nivolumab.
  • the UC is MIUC, and wherein cystectomy comprises bilateral pelvic ly mphadenectomy .
  • the RNA vaccine dose is administered to the patient in two equal half-doses.
  • the two equal half-doses are administered sequentially, optionally with an observation period between the administered equal half- doses.
  • the dose of about 25 pg is split into two equal half-doses of about 12.5 pg, each administered over 1 minute, optionally with a 5-minute observation period between the administered equal half-doses.
  • an individualized RNA vaccine for use in a method for treating a urothelial carcinoma (UC) in a human patient in need thereof, wherein the RNA vaccine is to be administered in combination with a PD-1 axis binding antagonist according to the method of any one of the preceding embodiments, wherein the RNA vaccine comprises one or more polynucleotides encoding one or more neoepitopes resulting from cancerspecific somatic mutations present in a UC specimen obtained from the patient.
  • UC urothelial carcinoma
  • RNA vaccine in the manufacture of a medicament for treating a UC in a human patient in need thereof, wherein the RNA vaccine is to be administered in combination with a PD-1 axis binding antagonist according to the method of any one of the preceding embodiments, and wherein the RNA vaccine comprises one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a UC specimen obtained from the patient.
  • a PD-1 axis binding antagonist in the manufacture of a medicament for treating a UC in a human patient in need thereof, wherein the PD-1 axis binding antagonist is to be administered in combination with an individualized RNA vaccine according to the method of any one of the preceding embodiments, and wherein the RNA vaccine comprises one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a UC specimen obtained from the patient.
  • kits comprising an individualized RNA vaccine, for use in a method for treating a UC in a human patient in need thereof, wherein the RNA vaccine is to be administered in combination with a PD-1 axis binding antagonist according to the method of any one of the preceding embodiments, wherein the RNA vaccine comprises one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a UC specimen obtained from the patient.
  • kits comprising a PD-1 axis binding antagonist for use in a method for treating a UC in a human patient in need thereof, wherein the PD-1 axis binding antagonist is to be administered in combination with an individualized RNA vaccine according to the method of any one of the preceding embodiments, wherein the RNA vaccine comprises one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a UC specimen obtained from the patient.
  • the patient prior to the administering step, is selected by a method comprising: obtaining a tumor specimen from the patient and administering a radical surgical resection of the UC, and (a) administering a CT scan prior to the radical surgical resection and, from the CT scan, identifying the UC as having tumor stage cT3-T4 or N+; and/or (b) from the radical surgical resection, identifying the UC as having tumor stage of (y)pT3-4a or (y)pN+ and MO, wherein the UC is MIBC and wherein the radical surgical resection is a radical cystectomy; and/or (c) from the radical surgical resection, identifying the UC as having tumor stage of (y)pT3-4 or (y)pN+ and MO, wherein the UC is UTUC and wherein the radical surgical resection is an RNU; wherein the radical surgical resection is administered no more than about 120 days prior to administration of the RNA vaccine; and wherein the
  • the tumor specimen is a transurethral resection of the bladder tumor (TURBT) specimen.
  • the tumor specimen is a surgical resection specimen from cystectomy or from nephroureterectomy obtained no more than about 120 days prior to administration of the RNA vaccine.
  • the tumor specimen comprises a representative formalin-fixed paraffin-embedded (FFPE) tumor specimen from a pretreatment tumor biopsy prior to the administering step.
  • the pretreatment tumor biopsy comprises transurethral resection of the bladder tumor (TURBT).
  • the tumor specimen comprises a representative formalin-fixed paraffin-embedded (FFPE) surgical resection specimen prior to the administering step.
  • the method further comprises obtaining a post- TURBT or post-surgery matched blood sample from the patient prior to the administering step. In some embodiments, the method comprises identifying at least 5 neoepitopes resulting from cancer-specific somatic mutations in the tumor specimen obtained from the patient.
  • the UC exhibits a nodal stage of N+ within about a week, within about 5 days, within about 3 days, or less than 3 days before administration of the RNA vaccine. In some embodiments, the UC exhibits a nodal stage of NO within about a week, within about 5 days, within about 3 days, or less than 3 days before administration of the RNA vaccine. In some embodiments, the UC exhibits a PD-L1 IHC score of ⁇ 1% within about a week, within about 5 days, within about 3 days, or less than 3 days before administration of the RNA vaccine.
  • the UC exhibits a PD-L1 IHC score of ⁇ 1% within about a week, within about 5 days, within about 3 days, or less than 3 days before administration of the RNA vaccine. In some embodiments, the UC exhibits an indeterminate PD-L1 IHC score within about a week, within about 5 days, within about 3 days, or less than 3 days before administration of the RNA vaccine. In some embodiments, the patient has received neoadjuvant therapy for treatment of the UC prior to administration of the RNA vaccine. In some embodiments, the patient has not received neoadjuvant therapy for treatment of the UC prior to administration of the RNA vaccine.
  • FIG. 1 provides a non-limiting schematic of the design of the two-part screening period (Part A and Part B; shown in the top and bottom panels, respectively) and an overview of the treatment scheme for the Phase II study described in Example 1 (bottom right).
  • the top panel shows the treatments, sample collection and analysis, and upstream and downstream manufacturing of the individualized cancer vaccines that occur during Screening Part A.
  • MIUC either MIBC or UTUC
  • TURBT transurethral resection of the bladder tumor
  • Upstream manufacturing includes WES and RNA sequencing of the blood and tissue samples as part of individualized cancer vaccine design to identify cancer-specific NEs for each patient.
  • WES results obtained for vaccine design may also be used for subsequent circulating tumor DNA (ctDNA) testing for patients enrolled in Part B.
  • the superscript b indicates that PD-L1 (programmed death ligand 1) testing will be performed on tissue samples from surgical resection, and that PD-L1 testing may be performed on TURBT samples if there is tissue remaining after sequencing and vaccine design (i.e., TURBT tissue is prioritized for autogene cevumeran upstream manufacturing).
  • the superscript c indicates that at least 5 cancer-specific NEs are required per patient for eligibility. Following identification of NEs, downstream manufacturing takes place, and patients proceed to Screening Part B after pathological confirmation of disease status from radical cystectomy or radical nephroureterectomy.
  • the bottom panel shows a schematic of Screening Part B and an overview of the treatment scheme.
  • Screening Part B takes place after Screening Part A and before treatment, and includes eligibility criteria screening and stratification and randomization in parallel with individualized cancer vaccine downstream manufacturing in preparation for treatment administration.
  • Part B begins within 120 days post-cystectomy (in the case of patients with MIBC) or within 120 days post- nephroureterectomy (in the case of patients with UTUC) and includes patients with 5 or more NEs and sufficient tumor material and absence of residual disease or metastases within about 28 days before randomization (R).
  • Patients who, at cystectomy, exhibited MIUC of bladder (MIBC) can be included in Screening Part B and beyond if they were found to have pathological staging of (y)pT3-T4a or (y)pN+ and MO at cystectomy.
  • Patients who, at nephroureterectomy, exhibited MIUC of upper tract (UTUC) can be included in Part B if they were found to have pathological staging of (y)pT3-T4 or (y)pN+ and MO at nephroureterectomy, though the number of patients with UTUC will be capped at no more than approximately 10% of the study population.
  • UTUC upper tract
  • up to 12 patients are enrolled in a safety run-in phase (bottom middle) in which they receive an individualized cancer vaccine (such as, for instance, autogene cevumeran) and a PD-1 axis binding antagonist (such as, for example, nivolumab).
  • an individualized cancer vaccine such as, for instance, autogene cevumeran
  • a PD-1 axis binding antagonist such as, for example, nivolumab
  • FIGS. 2A-2B provide non-limiting diagrams of the design of the study priming phase and at least a portion of the booster phase for arms 1 and 2 of the study described in Example 1 and shown in the bottom right portion of FIG. 1.
  • FIG. 2A shows that, over the course of, for example, 21 28-day Cycles (e.g., over the course of about 21 months postrandomization), patients in the experimental arm receive, for example, 25 pg of individualized cancer vaccine (such as, for example, autogene cevumeran; annotated as “cevu”) in each of, for example, 8 priming doses during the priming phase, and in each of, for example, four booster doses during the booster phase.
  • individualized cancer vaccine such as, for example, autogene cevumeran; annotated as “cevu”
  • Patients in the control arm also receive 480 mg of PD-1 axis binding antagonist (such as, for example, nivolumab) Q4W beginning after administration of the first two “priming” doses of the placebo (i.e., on D9 of Cycle 1 and then on D8 of every cycle thereafter) for up to 1 year of treatment.
  • the priming doses of individualized cancer vaccine or placebo occur, for example, at a rate of about one dose per week, except that no priming dose is given the week before the last priming dose.
  • neither individualized cancer vaccine/placebo nor the PD-1 axis binding antagonist are administered during week 8 (e.g., D22 of Cycle 2) in either arm.
  • the vertical dashed line in week 2 indicates that that the individualized cancer vaccine (in the experimental arm) or the placebo (in the control arm) in cycle (C) 1 week (W) 2 is administered on a different day (D8) than the PD-1 axis binding antagonist in C1W2, which is administered on D9.
  • the priming phase includes, for example, 8 doses of individualized cancer vaccine or placebo and at least the first two of 13 planned doses of PD-1 axis binding antagonist over the first 9 weeks of drug administration following randomization.
  • the booster phase and the priming phase are named based on the administration schedule of the individualized cancer vaccine.
  • the PD-1 axis binding antagonist administered between the priming phase and the booster phase, such as, for example, a third dose of the PD-1 axis binding antagonist administered one week after the last priming dose of the individualized cancer vaccine, shown on W10D8 and W9D1, respectively.
  • the booster phase includes, for example, four booster doses of individualized cancer vaccine or placebo, of which the first two are administered on Day 8 of Cycles 4 and 10, respectively.
  • Superscript a indicates that, in the pictured scheme, the booster dose of individualized cancer vaccine or placebo in Cycle 10 / Week 38 is administered on the same day as a dose of the PD-1 axis binding antagonist.
  • Imaging b indicates that imaging is performed at screening/baseline and every 12 weeks starting from randomization for the first 2 years and then according to the schedule as outlined herein, including at least at about week 60 and about week 84 (asterisks), prior to administration of the third and fourth booster doses, respectively, of individualized cancer vaccine/placebo.
  • FIG. 2B shows an extended timeline of the same events shown in FIG. 2A but without Day or Week labels, and in which the timing of a discontinuation visit (DV) and follow-up are marked.
  • Four booster doses of individualized cancer vaccine or placebo are labeled Bl, B2, B3, and B4, respectively.
  • adverse event refers to any untoward medical occurrence in a patient or clinical study participant temporally associated with the use of a study treatment, whether or not considered related to the study treatment.
  • PD-1 axis binding antagonist refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partner, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis - with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, target cell killing).
  • a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.
  • PD-1 binding antagonist refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD- 1 with one or more of its binding partners, such as PD-L1, PD-L2.
  • the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners.
  • the PD-1 binding antagonist inhibits the binding of PD- 1 to PD-L1 and/or PD-L2.
  • PD-1 binding antagonists include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2.
  • a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • the PD-1 binding antagonist is an anti-PD-1 antibody. Specific examples of PD-1 binding antagonists are provided infra.
  • PD-L1 binding antagonist refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD- L1 with either one or more of its binding partners, such as PD-1, B7-1.
  • a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners.
  • the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1.
  • the PD-L1 binding antagonists include anti-PD-Ll antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1, B7-1.
  • a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • a PD-L1 binding antagonist is an anti-PD-Ll antibody. Specific examples of PD-L1 binding antagonists are provided infra.
  • PD-L2 binding antagonist refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD- L2 with either one or more of its binding partners, such as PD-1.
  • a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners.
  • the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1.
  • the PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1.
  • a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • a PD-L2 binding antagonist is an immunoadhesin.
  • sustained response refers to the sustained effect on reducing tumor growth after cessation of a treatment.
  • the tumor size may remain to be the same or smaller as compared to the size at the beginning of the administration phase.
  • the sustained response has a duration at least the same as the treatment duration, at least 1.5X, 2. OX, 2.5X, or 3. OX length of the treatment duration.
  • composition refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations are sterile. “Pharmaceutically acceptable” excipients (vehicles, additives) are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed.
  • treatment refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis.
  • an individual is successfully “treated” if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and/or prolonging survival of individuals.
  • “delaying progression of a disease” means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late-stage cancer, such as development of metastasis, may be delayed.
  • an “effective amount” is at least the minimum amount required to effect a measurable improvement or prevention of a particular disorder.
  • An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual.
  • An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects.
  • beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
  • an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (z.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (z.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder.
  • an effective amount can be administered in one or more administrations.
  • an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
  • an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • conjunction with refers to administration of one treatment modality in addition to another treatment modality.
  • in conjunction with refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the individual.
  • a “disorder” is any condition that would benefit from treatment including, but not limited to, chronic and acute disorders or diseases including those pathological conditions which predispose the mammal to the disorder in question.
  • cell proliferative disorder and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation.
  • the cell proliferative disorder is cancer.
  • the cell proliferative disorder is a tumor.
  • Tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • a “subject”, “patient” or an “individual” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc.
  • the mammal is human.
  • antibody herein is used in the broadest sense and specifically covers monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity.
  • An “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with research, diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes.
  • an antibody is purified (1) to greater than 95% by weight of antibody as determined by, for example, the Lowry method, and in some embodiments, to greater than 99% by weight; (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of, for example, a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using, for example, Coomassie blue or silver stain.
  • Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.
  • “Native antibodies” are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains.
  • VH variable domain
  • Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains.
  • variable region refers to the aminoterminal domains of the heavy or light chain of the antibody.
  • variable domain of the heavy chain may be referred to as “VH.”
  • variable domain of the light chain may be referred to as “VL.” These domains are generally the most variable parts of an antibody and contain the antigen-binding sites.
  • variable refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called hypervariable regions (HVRs) both in the light-chain and the heavy-chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FR).
  • HVRs hypervariable regions
  • FR framework regions
  • the variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three HVRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure.
  • antibodies can be assigned to different classes.
  • immunoglobulins There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, y, e, y, and p, respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and described generally in, for example, Abbas et al. Cellular and Mol. Immunology, 4th ed. (W.B. Saunders, Co., 2000).
  • An antibody may be part of a larger fusion molecule, formed by covalent or non-covalent association of the antibody with one or more other proteins or peptides.
  • the terms “full length antibody,” “intact antibody” and “whole antibody” are used herein interchangeably to refer to an antibody in its substantially intact form, not antibody fragments as defined below. The terms particularly refer to an antibody with heavy chains that contain an Fc region.
  • Single-chain Fv or “scFv” antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain.
  • the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding.
  • the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible mutations, e.g., naturally occurring mutations, that may be present in minor amounts. Thus, the modifier “monoclonal” indicates the character of the antibody as not being a mixture of discrete antibodies.
  • such a monoclonal antibody typically includes an antibody comprising a polypeptide sequence that binds a target, wherein the target-binding polypeptide sequence was obtained by a process that includes the selection of a single target binding polypeptide sequence from a plurality of polypeptide sequences.
  • the monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81 :6851-6855 (1984)).
  • Chimeric antibodies include PRIMATTZED® antibodies wherein the antigen-binding region of the antibody is derived from an antibody produced by, e.g., immunizing macaque monkeys with the antigen of interest.
  • “Humanized” forms of non-human (e.g, murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
  • a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from a HVR of the recipient are replaced by residues from a HVR of a non- human species (donor antibody) such as mouse, rat, rabbit, or nonhuman primate having the desired specificity, affinity, and/or capacity.
  • donor antibody such as mouse, rat, rabbit, or nonhuman primate having the desired specificity, affinity, and/or capacity.
  • FR residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications may be made to further refine antibody performance.
  • a “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
  • Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSETM technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology.
  • hypervariable region when used herein refers to the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops.
  • antibodies comprise six HVRs; three in the VH (Hl, H2, H3), and three in the VL (LI, L2, L3).
  • H3 and L3 display the most diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies.
  • Samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebro-spinal fluid, saliva, sputum, tears, perspiration, mucus, tumor lysates, and tissue culture medium, tissue extracts such as homogenized tissue, tumor tissue, cellular extracts, and combinations thereof.
  • the sample is a sample obtained from the cancer of an individual (e.g., a tumor sample) that comprises tumor cells and, optionally, tumor-infiltrating immune cells.
  • the sample can be a tumor specimen that is embedded in a paraffin block, or that includes freshly cut, serial unstained sections.
  • the sample is from a biopsy and includes 50 or more viable tumor cells (e.g., from a core-needle biopsy and optionally embedded in a paraffin block; excisional, incisional, punch, or forceps biopsy; or a tumor tissue resection).
  • tissue sample tissue specimen
  • tissue sample a collection of similar cells obtained from a tissue, for example a tumor, of a subject or individual.
  • the source of the tissue or cell sample may be solid tissue (e.g., a tumor) as from a fresh, frozen and/or preserved organ, tissue sample, biopsy, and/or aspirate; blood or any blood constituents such as plasma; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject.
  • the tissue sample may also be primary or cultured cells or cell lines.
  • the tissue or cell sample is obtained from a disease tissue/organ.
  • the tissue sample may contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like.
  • a “reference sample”, “reference cell”, “reference tissue”, “control sample”, “control cell”, or “control tissue”, as used herein, refers to a sample, cell, tissue, standard, or level that is used for comparison purposes.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissue or cells) of the same subject or individual.
  • healthy and/or non-diseased cells or tissue adjacent to the diseased cells or tissue e.g., cells or tissue adjacent to a tumor.
  • a reference sample is obtained from an untreated tissue and/or cell of the body of the same subject or individual.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissues or cells) of an individual who is not the subject or individual.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and/or cell of the body of an individual who is not the subject or individual.
  • the reference sample is from essentially the same type of cells, tissue, organ, or body fluid source as the sample from the individual or patient subjected to the method of the invention, e.g., if according to the invention, blood is used as a sample to determine the level of de novo SE TCR clones in the individual, the reference level, reference number, or reference frequency is also determined in blood or a part thereof.
  • At least a portion of the data is collected within about 30, about 25, about 20, about 18-20, about 16-18, about 14-16, about 12-14, about 10-12, about 8-10, about 6-8, about 4-6, about 2-4, about 1-2, or about 0-1 weeks prior to administration of the first priming dose of the RNA vaccine. In some embodiments, at least a portion of the data is collected within about 4 weeks prior to administration of the first priming dose of the RNA vaccine. In some embodiments, at least a portion of the data is collected within 1 week prior to administration of the first priming dose of the RNA vaccine.
  • At least a portion of the data is collected every 6-8 weeks, every 8-10 weeks, every 10-12 weeks, every 12-14 weeks, every 14-16 weeks, every 16-18 weeks, every 18-20 weeks, every 20-22 weeks, or every 22-24 weeks in the second year after day 1 of the priming phase. In some embodiments, at least a portion of the data is collected every 12 weeks ⁇ 2 weeks in the second year after day 1 of the priming phase. In some embodiments, at least a portion of the data is collected every 12 weeks ⁇ 1 week in the second year after day 1 of the priming phase.
  • At least a portion of the data is collected every 6-8 weeks, every 8-10 weeks, every 10-12 weeks, every 12-14 weeks, every 14-16 weeks, every 16-18 weeks, every 18-20 weeks, every 20-22 weeks, or every 22-24 weeks in the third year after day 1 of the priming phase. In some embodiments, at least a portion of the data is collected every 16 weeks ⁇ 2 weeks in the third year after day 1 of the priming phase. In some embodiments, at least a portion of the data is collected every 16 weeks ⁇ 1 week in the third year after day 1 of the priming phase.
  • At least a portion of the data is collected every 10-12 weeks, every 12-14 weeks, every 14-16 weeks, every 16-18 weeks, every 18-20 weeks, every 20-22 weeks, every 22-24, every 24-26 weeks, every 26-28 weeks, every 28-30 weeks, every 30-32 weeks, or every 32-34 weeks in the third year after day 1 of the priming phase. In some embodiments, at least a portion of the data is collected every 24 weeks ⁇ 2 weeks in the fourth and fifth years after day 1 of the priming phase. In some embodiments, at least a portion of the data is collected every 24 weeks ⁇ 1 week in the fourth and fifth years after day 1 of the priming phase.
  • the methods for treating MIUC provided herein comprise administering to a patient, such as a human patient in need thereof, an individualized RNA vaccine and a PD-1 axis binding antagonist during a priming phase of treatment.
  • the priming phase is named in reference to “priming” doses of the RNA vaccine, though as detailed below, at least one dose of a PD-1 axis binding antagonist may also be administered during the priming phase.
  • the priming phase begins at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, or at least about 17 weeks after resection of a MIUC tumor from the patient, such as an MIUC tumor.
  • the priming phase begins at least about 28 days after resection of a MIUC tumor from the patient, such as an MIUC tumor.
  • the priming phase begins less than about 124 days after resection of a MIUC tumor from the patient, such as an MIUC tumor. In some embodiments, the priming phase begins about 28- 90 days after resection of a MIUC tumor from the patient, such as an MIUC tumor. In some embodiments, the priming phase begins about 90 days after resection of a MIUC tumor from the patient, such as an MIUC tumor. In some embodiments, the priming phase begins about 90-120 days after resection of a MIUC tumor from the patient, such as an MIUC tumor.
  • the RNA vaccine is not administered during the third week. In some embodiments, the RNA vaccine is not administered during the fourth week. In some embodiments, the RNA vaccine is not administered during the fifth week. In some embodiments, the RNA vaccine is not administered during the sixth week. In some embodiments, the RNA vaccine is not administered during the seventh week. In some embodiments, the RNA vaccine is not administered during the eighth week.
  • the priming phase comprises administering the RNA vaccine once per week (QW), e.g., once every 7 days, except for during one week in which no RNA vaccine is administered. In some embodiments, administration of the RNA vaccine during priming phase begins on day 1 of week 1 of the priming phase.
  • the priming phase comprises administering the RNA vaccine on day 1 of week 1 of the priming phase and once per week (QW), e.g., once every 7 days, thereafter, except for, in some embodiments, during one week in which no RNA vaccine is administered.
  • the one week in which no RNA vaccine is administered is the second, third, fourth, fifth, sixth, seventh, or eighth week.
  • the priming phase comprises administering the RNA vaccine on day 1 of week 1 of the priming phase and once per week (QW), e.g., once every 7 days, thereafter, except for, in some embodiments, during one or more weeks selected from the group consisting of: the second, third, fourth, fifth, sixth, seventh, and eighth weeks.
  • 2 doses of the RNA vaccine are administered to the patient during the priming phase before administration of the PD-1 axis binding antagonist.
  • any dose of the PD-1 axis binding antagonist administered to the patient during the priming phase is administered on the same day as the administration of a dose of the RNA vaccine.
  • a dose of the PD-1 axis binding antagonist is administered to the patient after completion of administration of that day’s dose of the RNA vaccine.
  • the dose of the PD-1 axis binding antagonist is administered to the patient at least about 1-15, at least about 15-30, at least about 30-45, at least about 45-60, at least about 60-120, or at least about 120-180 minutes after completion of administration of that day’s dose of the RNA vaccine.
  • the priming phase comprises administering to the patient two doses of the PD-1 axis binding antagonist.
  • the first dose of the PD-1 axis binding antagonist is administered to the patient no sooner than after administration of 2 doses of the RNA vaccine.
  • the first dose of the PD-1 axis binding antagonist is administered to the patient 1-4 days after administration of the second priming dose of the RNA vaccine.
  • the first dose of the PD-1 axis binding antagonist is administered to the patient about 1 day after administration of the second priming dose of the RNA vaccine.
  • the first dose of the PD-1 axis binding antagonist is administered to the patient no sooner than after administration of more than 2 doses of the RNA vaccine, e.g., after administration of at least 3, at least 4, at least 5, at least 6, or at least 7 doses of the RNA vaccine.
  • the priming phase comprises administering to the patient one dose of the PD-1 axis binding antagonist.
  • the first dose of the PD-1 axis binding antagonist is administered to the patient 1-7 weeks after administration of the second priming dose of the RNA vaccine.
  • the first dose of the PD-1 axis binding antagonist is administered to the patient about 1 month after administration of the second priming dose of the RNA vaccine.
  • the PD-1 axis binding antagonist is administered once per week (QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W).
  • the PD-1 axis binding antagonist is administered once every four weeks (Q4W), e.g., once every 28 days, ⁇ 3 days.
  • administration of the PD-1 axis binding antagonist during priming phase begins the day after the day of administration of the second priming dose of the RNA vaccine.
  • administration of the PD-1 axis binding antagonist during priming phase begins on day 2 of week 2 of the priming phase.
  • the priming phase comprises administering the PD-1 axis binding antagonist on day 2 of week 2 of the priming phase and once every four weeks (Q4W), e.g., once every 28 days, thereafter, ⁇ 3 days.
  • the priming phase comprises administering the PD-1 axis binding antagonist on the day after the day of administration of the second priming dose of the RNA vaccine and once every four weeks (Q4W), e.g., once every 28 days, thereafter.
  • Q4W administration of the PD-1 axis binding antagonist continues through the end of the priming phase.
  • Q4W administration of the PD-1 axis binding antagonist continues between the end of the priming phase and the beginning of the booster phase. In some embodiments, Q4W administration of the PD-1 axis binding antagonist continues through the beginning of the booster phase.
  • the priming phase comprises administering the PD-1 axis binding antagonist on the day after the day of administration of the second priming dose of the RNA vaccine and once every four weeks (Q4W), e.g., once every 28 days, thereafter, for up to one year after the first administration of the PD-1 axis binding antagonist.
  • Q4W once every four weeks
  • the one or more polynucleotides of the RNA vaccine are formulated with one or more lipids.
  • the RNA vaccine is formulated as a lipid nanoparticle, wherein the one or more polynucleotides of the RNA vaccine and one or more lipids form the lipid nanoparticle.
  • the RNA vaccine is formulated as a lipoplex, wherein the one or more polynucleotides of the RNA vaccine and one or more lipids form the lipoplex.
  • the lipoplex comprises one or more lipids that form a multilamellar structure that encapsulates the one or more polynucleotides of the RNA vaccine.
  • the PD-1 axis binding antagonist is an anti-PD-Ll antibody, e.g., as described below.
  • the anti-PD-Ll antibody is nivolumab, avelumab, durvalumab, or atezolizumab.
  • the anti-PD-Ll antibody is nivolumab.
  • the anti-PD-Ll antibody is administered to the patient at a dose of about 240 mg, about 480 mg, about 1200 mg, or about 1680 mg.
  • the anti-PD-Ll antibody is administered to the patient at a dose of about 480 mg.
  • the PD-1 axis binding antagonist is administered intravenously to the patient.
  • the boost phase begins 5 weeks after the end of the after the end of the priming phase, e.g., after the last priming administration of the RNA vaccine. In some embodiments, the boost phase begins 4 weeks after the end of the after the end of the priming phase, e.g., after the last priming administration of the RNA vaccine. In some embodiments, the boost phase begins no later than about 6 weeks after the end of the after the end of the priming phase, e.g., after the last priming administration of the RNA vaccine. In some embodiments, the booster phase begins on week 14 (e.g., day 1 of week 14), timing starting with week 1 of the priming phase.
  • week 14 e.g., day 1 of week 14
  • the booster phase comprises administering to the patient at least two doses of the PD-1 axis binding antagonist. In some embodiments, the booster phase comprises administering to the patient any of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or more than 15 doses of the PD-1 axis binding antagonist. In some embodiments, between 1 and 13, between 6 and 14, between 8 and 12, or either 9 or 10 doses of the PD-1 axis binding antagonist are administered to the patient during the booster phase. In some embodiments, 10 doses of the PD-1 axis binding antagonist are administered to the patient during the booster phase.
  • any dose of the PD-1 axis binding antagonist administered to the patient during the booster phase is administered on the same day as the administration of a dose of the RNA vaccine.
  • a dose of the PD-1 axis binding antagonist is administered to the patient after completion of administration of that day’s dose of the RNA vaccine.
  • the dose of the PD-1 axis binding antagonist is administered to the patient at least about 1-15, at least about 15-30, at least about 30-45, at least about 45-60, at least about 60-120, or at least about 120-180 minutes after completion of administration of that day’s dose of the RNA vaccine.
  • the booster phase comprises administering the PD-1 axis binding antagonist on day 1 of week 1 of the booster phase and once every four weeks (Q4W), e.g., once every 28 days, thereafter, ⁇ 5 days, until a total of at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 doses of the PD-1 axis binding antagonist have been administered since week 1, day 1 of the priming phase.
  • Q4W once every four weeks
  • the booster phase comprises administering the PD-1 axis binding antagonist on day 1 of week 1 of the booster phase and once every four weeks (Q4W), e.g., once every 28 days, thereafter, ⁇ 5 days, until a total of at least 12 doses of the PD-1 axis binding antagonist have been administered since week 1, day 1 of the priming phase.
  • the booster phase comprises administering the PD-1 axis binding antagonist on day 1 of week 1 of the booster phase and once every four weeks (Q4W), e.g., once every 28 days, thereafter, ⁇ 5 days, until a total of 13 doses of the PD-1 axis binding antagonist have been administered since week 1, day 1 of the priming phase.
  • the booster phase comprises administering the PD-1 axis binding antagonist on day 1 of week 1 of the booster phase and once every four weeks (Q4W), e.g., once every 28 days, thereafter, ⁇ 5 days, until a total of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 doses of the PD-1 axis binding antagonist have been administered during the booster phase.
  • Q4W once every four weeks
  • the booster phase comprises administering the PD-1 axis binding antagonist on day 1 of week 1 of the booster phase and once every four weeks (Q4W), e.g., once every 28 days, thereafter, ⁇ 5 days, until a total of 10 doses of the PD-1 axis binding antagonist have been administered during the booster phase.
  • the booster phase comprises administering the PD-1 axis binding antagonist 1-3 days after the day of administration of a booster dose of the RNA vaccine.
  • the booster phase comprises administering the PD-1 axis binding antagonist 1-3 days before the day of administration of a booster dose of the RNA vaccine.
  • the booster phase comprises administering the RNA vaccine to the patient approximately 2-4, approximately 8-10, approximately 13-15, and/or approximately 19-21 months after administration of the second priming dose of the RNA vaccine. In some embodiments, the booster phase comprises administering the RNA vaccine to the patient approximately 3, approximately 9, approximately 14, and/or approximately 20 months after administration of the second priming dose of the RNA vaccine. In some embodiments, the booster phase comprises administering the RNA vaccine to the patient approximately 3, approximately 9, approximately 14, and approximately 20 months after administration of the second priming dose of the RNA vaccine.
  • the booster phase comprises administering the RNA vaccine to the patient on day 1 of week 14, ⁇ 5 days, and/or on day 1 of week 10, ⁇ 5 days, timing starting from week 1, day 1 of the priming phase. In some embodiments, the booster phase comprises administering the RNA vaccine to the patient on day 1 of week 14, ⁇ 5 days, and/or on day 1 of week 10, ⁇ 5 days, timing starting from week 1, day 1 of the priming phase. In some embodiments, the booster phase comprises administering the RNA vaccine to the patient approximately 15 months post-initiation of the PD-1 axis binding antagonist. In some embodiments, the booster phase comprises administering the RNA vaccine to the patient after review of an imaging assessment conducted approximately 60 weeks after week 1, day 1 of the priming phase.
  • the booster phase comprises administering the RNA vaccine to the patient approximately 21 months post-initiation of the PD-1 axis binding antagonist. In some embodiments, the booster phase comprises administering the RNA vaccine to the patient after review of an imaging assessment conducted approximately 84 weeks after week 1, day 1 of the priming phase.
  • administration of the RNA vaccine and/or the PD-1 axis binding antagonist during the booster phase begins on day 1 of week 1 of the booster phase.
  • the booster phase comprises administering the RNA vaccine and/or the PD-1 axis binding antagonist to the patient on day 1 of the boost phase, and administration of the PD-1 axis binding antagonist once every four weeks (Q4W), e.g., once every 28 days, thereafter, until 10 doses of the PD-1 axis binding antagonist have been administered during the booster phase.
  • the booster phase comprises administering the RNA vaccine and/or the PD-1 axis binding antagonist to the patient on day 1 of the boost phase, and administration of the RNA vaccine three more times thereafter, wherein administration of the second, third, and fourth booster doses are spaced approximately 6 months apart between week 1, day 1 of the booster phase and approximately 21 months thereafter.
  • the RNA vaccine is administered in 24-week cycles (e.g., 168-day cycles) for at least 4 cycles during the booster phase. In other embodiments, the RNA vaccine is administered in 24-week cycles (e.g., 168-day cycles) for no more than 4 cycles during the booster phase.
  • the PD-1 axis binding antagonist is administered in 4-week cycles (e.g., 28-day cycles) for at least 10 cycles during the booster phase. In other embodiments, the PD-1 axis binding antagonist is administered in 4-week cycles (e.g., 28-day cycles) for no more than 10 cycles during the booster phase.
  • the boost phase begins in week 14 (e.g., day 1 of week 14), timing starting with week 1 of the priming phase, e.g., as described above.
  • the boost phase comprises administering to the patient the RNA vaccine starting on day 1 of week 33, timing starting with week 1 of the priming phase, e.g., as described above, and approximately every 6 sets of 28-day cycles thereafter, for example, for a total of 4 administration of the RNA vaccine.
  • the booster phase comprises administering to the patient the RNA vaccine on day 1 of week 14, day 1 of week 38, one day during week 60 or 61, and one day during week 84 or 85, timing starting with week 1 of the priming phase.
  • the boost phase comprises administering to the patient the PD-1 axis binding antagonist on day 1 of week 14, day 1 of week 18, day 1 of week 22, day 1 of week 26, day 1 of week 30, day 1 of week 34, day 1 of week 38, day 1 of week 42, day 1 of week 46, and day 1 of week 50 of the booster phase, timing starting with week 1 of the priming phase.
  • the booster phase comprises administering to the patient the RNA vaccine on day 1 of week 14, day 1 of week 38, one day during week 60 or 61, and one day during week 84 or 85, timing starting with week 1 of the priming phase, and administering to the patient the PD-1 axis binding antagonist on day 1 of week 14, day 1 of week 18, day 1 of week 22, day 1 of week 26, day 1 of week 30, day 1 of week 34, day 1 of week 38, day 1 of week 42, day 1 of week 46, and day 1 of week 50 of the booster phase, timing starting with week 1 of the priming phase.
  • An exemplary booster phase is provided in Table 2, below.
  • the RNA vaccine is administered to the patient during the booster phase at a dose of between about 15 pg to about 50 pg (e.g., any of about 15 pg, about 20 pg, about 25 pg, about 30 pg, about 35 pg, about 38 pg, about 40 pg, about 45 pg, or about 50 pg).
  • the RNA vaccine is administered to the patient at a dose of about 15 pg, about 21 pg, about 21.3 pg, about 25 pg, about 38 pg, or about 50 pg.
  • the RNA vaccine is administered to the patient at a dose of 25 pg.
  • the two equal half-doses are administered sequentially, optionally with an observation period between the administered equal half-doses.
  • the dose of about 25 pg is split into two equal half-doses of about 12.5 pg, each administered over 1 minute, optionally with a 5- minute observation period between the administered equal half-doses.
  • the RNA vaccine comprises one or more polynucleotides encoding 5-20 or 10-20 neoepitopes resulting from cancer-specific somatic mutations present in a tumor specimen from the patient.
  • the one or more polynucleotides of the RNA vaccine are formulated with one or more lipids.
  • the radical cystectomy has a negative surgical margin (i.e., RO resection).
  • the human patient has received a histologically confirmed diagnosis of MIBC and carcinoma in situ (CIS) at the distal ureteral or urethral margin.
  • the radical cystectomy does not have a positive R2 margin (i.e., a tumor identified at the inked perivesical fat margin surrounding the cystectomy specimen).
  • the radical cystectomy does not have an R1 margin (i.e., evidence of microscopic disease identified at the tumor margin).
  • the radical cystectomy has an R1 margin and the patient has carcinoma in situ (CIS) at the distal ureteral or urethral margin.
  • the human patient has MIBC prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the human patient has UTUC prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the human patient has MIBC and UTUC prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the human patient has received platinum-based neoadjuvant chemotherapy (NAC) prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the human patient has received at least three cycles of a platinum-containing neoadjuvant chemotherapy (NAC) prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • NAC platinum-based neoadjuvant chemotherapy
  • the human patient has not received platinum -based neoadjuvant chemotherapy (NAC) prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • NAC platinum -based neoadjuvant chemotherapy
  • the human patient has been ineligible to receive adjuvant cisplatin-based therapy either due to cisplatin ineligibility, patient refusal, or investigator decision prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has been ineligible to receive adjuvant cisplatin-based therapy due to cisplatin ineligibility prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has refused adjuvant cisplatin-based therapy prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the UC tumor has tumor, lymph node, metastasis (TNM) pathological staging values (y)pT3-4a or (y)pN+ for MIBC patients, or (y)pT3-4 or (y)pN+ for UTUC patients, and MO prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the staging values are assessed as per the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 7th edition (Edge, S. et al., eds., American Joint Committee on Cancer (AJCC) Cancer Staging Manual; 8th ed. New York: Springer 2011).
  • a surgical tumor specimen is provided from the patient.
  • the surgical tumor specimen is from TURBT.
  • the surgical tumor specimen is from cystectomy.
  • the surgical tumor specimen is from nephroureterectomy.
  • surgical tumor specimen is used for determining PD-L1 expression.
  • surgical tumor specimen is used for exploratory biomarker research.
  • nucleic acids from the surgical tumor specimen are sequenced.
  • the sequencing comprises whole exome sequencing.
  • the sequencing comprises RNA sequencing.
  • data (e.g., sequencing data) from the surgical tumor specimen are used in designing the RNA vaccine.
  • the surgical tumor specimen is provided with an associated pathology report.
  • the surgical tumor specimen comprises an FFPE tumor block.
  • the surgical tumor specimen comprises an intact FFPE tumor block.
  • the surgical tumor specimen comprises 1-10, 10-15, 15-20, 20-25, 25-30, 30-35, or 35-40 slides comprising sections derived from an FFPE tumor block.
  • the surgical tumor specimen comprises 10-30 slides comprising sections derived from an FFPE tumor block.
  • the surgical tumor specimen comprises about 20 slides comprising sections derived from an FFPE tumor block.
  • the sections comprise unstained, freshly cut serial sections derived from an FFPE tumor block.
  • the patient has fully recovered from cystectomy within about 20-30, about 30-50, about 50-70, about 70-90, about 90-100, about 100-110, about 110-115, about 115-120, about 120-125, about 125-130, about 130-150, about 150-170, about 170-190, about 190-210, or more than about 210 days following surgery prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the patient has fully recovered from cystectomy within about 115-125 days following surgery prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the patient has fully recovered from cystectomy within 120 days following surgery prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the patient has fully recovered from cystectomy within 120 days following surgery prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the patient has fully recovered from nephroureterectomy within 120 days following surgery prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the patient has fully recovered from nephroureterectomy within 120 days following surgery prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 7, 18, 19, 20, or more than 20 neoepitopes resulting from cancer-specific somatic mutations are present in the tumor specimen obtained from the human patient prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, at least five neoepitopes resulting from cancer-specific somatic mutations are present in the tumor specimen obtained from the human patient prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • ECOG Performance Status evaluates a patient’s ability to care for themself, their daily activity, and their physical ability (for example, walking, working, etc.).
  • the human patient has adequate hematologic and endorgan function prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • Adequate hematologic and end-organ function may comprise any of the following laboratory results obtained within 14 days prior to the administration of the RNA vaccine: ANC ⁇ 1000 cells/pL; WBC >2000/pL; Platelet count ⁇ 100,000/pL; Hemoglobin ⁇ 9.0 g/dL; AST, ALT ⁇ 3.0 times the upper limit of normal (ULN); Serum bilirubin ⁇ 1.5 times ULN; PTT/PT ⁇ 1.5 x ULN or INR ⁇ 1.7 times ULN; Serum creatinine ⁇ 1.5 times ULN; creatinine clearance ⁇ 30 mL/min (using the Cockcroft-Gault formula).
  • a patient is transfused to meet the hemoglobin ⁇ 9.0 g/dL criteria. In some embodiments, a patient receives erythropoietic treatment to meet the hemoglobin ⁇ 9.0 g/dL criteria. In some embodiments, a patient has known Gilbert disease and a serum bilirubin level ⁇ 3 times ULN. In some embodiments, a patient has PTT/PT ⁇ 1.5 x ULN or INR ⁇ 1.7 times ULN and is not receiving therapeutic anti coagulation. In some embodiments, a patient does not have PTT/PT ⁇ 1.5 x ULN or INR ⁇ 1.7 times ULN and is receiving a stable dose of therapeutic anti coagulation.
  • a patient has had a past or resolved hepatitis B infection prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • a past or resolved hepatitis B infection may comprise a negative HbsAg test, a positive total hepatitis B core antibody (HbcAb) test, and a hepatitis B virus (HBV) DNA test demonstrating absence of active infection prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • a patient has negative hepatitis C virus (HCV) antibody test prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • a patient has positive hepatitis C virus (HCV) antibody test followed by a negative HCV RNA test prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has not received an approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has not received adjuvant chemotherapy for MIUC following surgical resection prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has not received radiation therapy for MIUC following surgical resection prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has not received antegrade or retrograde instillation of chemotherapy or BCG for UTUC following surgical resection prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has received a single dose of intravesical chemotherapy for UTUC following nephroureterectomy prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has not received a diagnosis of a malignancy other than a MIUC within 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, or 14-15 years prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the human patient has not received a diagnosis of a malignancy other than a MIUC within 5 years prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has received a diagnosis of localized low risk prostate cancer (e.g, Stage ⁇ T2b, Gleason score ⁇ 7, and/or prostate-specific antigen (PSA) at prostate cancer diagnosis ⁇ 20 ng/mL), which was subsequently treated with curative intent and without PSA recurrence within 5 years prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • a diagnosis of localized low risk prostate cancer e.g, Stage ⁇ T2b, Gleason score ⁇ 7, and/or prostate-specific antigen (PSA) at prostate cancer diagnosis ⁇ 20 ng/mL
  • PSA prostate-specific antigen
  • the human patient has received a diagnosis of low-risk prostate cancer (e.g., Stage Tl/T2a, Gleason score ⁇ 7, and/or PSA ⁇ 10 ng/mL) within 5 years prior to administration of the RNA vaccine and the PD-1 axis binding antagonist and is treatment- naive and undergoing active surveillance at the time of administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has received, within 5 years prior to administration of the RNA vaccine and the PD-1 axis binding antagonist, a diagnosis of a malignancy with a negligible risk of metastasis or death.
  • the patient having received the diagnosis of a malignancy with a negligible risk of metastasis or death has no evidence of recurrence or metastasis by follow-up imaging and any disease-specific tumor markers by a time within 5 years prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the MIUC tumor exhibits a nodal stage of N+ prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the MIUC tumor exhibits a nodal stage of N+ within about a week, within about 5 days, within about 3 days, or less than 3 days before administration of the RNA vaccine. In some embodiments, the MIUC tumor exhibits a nodal stage of NO prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the MIUC tumor exhibits a nodal stage of NO within about a week, within about 5 days, within about 3 days, or less than 3 days before administration of the RNA vaccine.
  • the MIUC tumor exhibits a PD-L1 IHC score of ⁇ 1% prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the MIUC tumor exhibits a PD-L1 IHC score of ⁇ 1% within about a week, within about 5 days, within about 3 days, or less than 3 days before administration of the RNA vaccine. In some embodiments, the MIUC tumor exhibits a PD-L1 IHC score of ⁇ 1% prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the MIUC tumor exhibits a PD-L1 IHC score of >1% within about a week, within about 5 days, within about 3 days, or less than 3 days before administration of the RNA vaccine. In some embodiments, the MIUC tumor exhibits an indeterminate PD-L1 IHC score prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the MIUC tumor exhibits an indeterminate PD-L1 IHC score within about a week, within about 5 days, within about 3 days, or less than 3 days before administration of the RNA vaccine. In some embodiments, the patient has received neoadjuvant therapy for treatment of the MIUC prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the patient has not received neoadjuvant therapy for treatment of the MIUC prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient has not received a diagnosis of a significant cardiovascular disease (such as, for example, New York Heart Association Class II or greater cardiac disease, myocardial infarction, cerebrovascular accident, unstable arrhythmia, and/or unstable angina), within 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, or 12-13 months prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • a cardiovascular disease such as, for example, New York Heart Association Class II or greater cardiac disease, myocardial infarction, cerebrovascular accident, unstable arrhythmia, and/or unstable angina
  • the human patient has not received a diagnosis of a significant cardiovascular disease (such as, for example, New York Heart Association Class II or greater cardiac disease, myocardial infarction, cerebrovascular accident, unstable arrhythmia, and/or unstable angina), within 3 months prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • a significant cardiovascular disease such as, for example, New York Heart Association Class II or greater cardiac disease, myocardial infarction, cerebrovascular accident, unstable arrhythmia, and/or unstable angina
  • the patient does not have clinically significant liver disease at the time of administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • Clinically significant liver disease may comprise active viral, alcoholic, or other hepatitis, cirrhosis, inherited liver disease, and/or current alcohol abuse.
  • the patient does not have active autoimmune disease or immune deficiency at the time of administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the patient does not have a history of autoimmune disease or immune deficiency at the time of administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • autoimmune diseases include but are not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, granulomatosis with polyangiitis, Sjogren syndrome, Guillain Barre syndrome, and multiple sclerosis.
  • the patient has eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., not psoriatic arthritis) at the time of administration of the RNA vaccine and the PD-1 axis binding antagonist, and meet at least one of the following criteria at the time of administration of the RNA vaccine and the PD-1 axis binding antagonist: the rash covers less than 10% of patient’s body surface area; the disease is well controlled at baseline and requires only low-potency topical corticosteroids; and there has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.
  • the rash covers less than 10% of patient’s body surface area
  • the disease is well controlled at baseline and requires only low-potency topical corticosteroids
  • the human patient has a spleen prior to administration of the RNA vaccine and the PD-1 axis binding antagonist. In some embodiments, the human patient has not had loss of spleen due to splenectomy, splenic injury/infarction, or functional asplenia prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the human patient does not have a known primary cellular immunodeficiency (e.g., DiGeorge syndrome, T negative severe combined immunodeficiency (SCID)) prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • SCID T negative severe combined immunodeficiency
  • the human patient does not have a known primary combined T- and B-cell immunodeficiency (e.g., T- and B-negative SCID, Wiskott-Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency) prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the patient has not been treated with systemic immunosuppressive medication (including, but not limited to: corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents) within 2 weeks prior to administration of the RNA vaccine and the PD-1 axis binding antagonist, or anticipation of need for systemic immunosuppressive medication during administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • a patient has received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy).
  • a patient has received mineralocorticoids (e.g., fludrocortisone), inhaled or low dose corticosteroids (defined as less than or equal to 10 mg oral prednisone per day or daily equivalent) for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency.
  • mineralocorticoids e.g., fludrocortisone
  • corticosteroids defined as less than or equal to 10 mg oral prednisone per day or daily equivalent
  • corticosteroids for orthostatic hypotension or adrenal insufficiency.
  • a patient does not have a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • a patient does not have known active or latent tuberculosis prior to administration of the RNA vaccine and the PD-1 axis binding antagonist.
  • the clinical assessments are administered in the following order: EORTC QLQ-C30, PRO-CTCAE, EORTC IL46, and EQ-5D-5L.
  • the QLQ-C30 consists of 30 questions that assess five aspects of patient functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), global health and quality of life, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. Scale scores can be obtained for the multi-item scales.
  • PRO CTCAE is used to characterize the presence, frequency of occurrence, severity, and/or degree of interference with daily function of 78 patient-reportable symptomatic treatment toxi cities (see, e.g., Basch et al., J Natl Cancer Inst;106:dju244 (2014); and Dueck et al., JAMA Oncol; 1 : 1051-1059 (2015)).
  • the PRO- CTCAE contains 124 questions that are rated either dichotomously (for determination of presence vs. absence) or on a 5-point Likert scale (for determination of frequency of occurrence, severity, and interference with daily function).
  • Treatment toxi cities can occur with observable signs (e.g., vomiting) or non-observable symptoms (e.g., nausea).
  • the standard PRO-CTCAE recall period is the previous 7 days.
  • IL46 is a validated single-item question used to assess the overall impact of side effects and is used along with the PRO CTCAE to assess treatment tolerability.
  • Symptomatic adverse events from the PRO-CTCAE item bank include, but may not be limited to, mouth/throat sores, nausea, vomiting, diarrhea, shortness of breath, cough, rash, hair loss, hand-foot syndrome, neuropathy, dizziness, headache, arthralgia, fatigue, bruising, chills, nosebleeds, injection- or IV-site pain.
  • the EQ- 5D-5L is a validated self-reported health status questionnaire that is used to calculate a health status utility score for use in health economic analyses (EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).
  • VAS Visual Analog Scale
  • the EQ-5D-5L is designed to capture a patient’s current health status. Published weighting systems allow for creation of a single composite score of the patient’s health status.
  • RNA vaccine and the PD-1 axis binding antagonist results in an improvement in the one or more clinical assessments as compared to the one or more clinical assessments in the human patient prior to administration of the RNA vaccine and the PD-1 axis binding antagonist, and/or as compared to the one or more clinical assessments in a corresponding human patient who is not administered the RNA vaccine and the PD-1 axis binding antagonist.
  • the RNA vaccine comprises a poly(A) tail at its 3 ’end.
  • the poly(A) tail comprises more than 50 or more than 100 adenine nucleotides.
  • the poly(A) tail comprises 120 adenine nucleotides. This poly(A) tail has been demonstrated to enhance RNA stability and translation efficiency (Holtkamp, S. et al. (2006) Blood 108:4009-4017).
  • the RNA comprising a poly(A) tail is generated by transcribing a DNA molecule comprising in the 5’ -> 3’ direction of transcription, a polynucleotide sequence that encodes at least 50, 100, or 120 adenine consecutive nucleotides and a recognition sequence for a type IIS restriction endonuclease.
  • exemplary poly(A) tail and 3’ UTR sequences that improve translation are found, e.g., in U.S. Pat. No. 9,476,055.
  • an RNA vaccine or molecule of the present disclosure comprises the general structure (in the 5’->3’ direction): (1) a 5’ cap; (2) a 5’ untranslated region (UTR); (3) a polynucleotide sequence encoding a secretory signal peptide; (4) a polynucleotide sequence encoding at least a portion of a transmembrane and cytoplasmic domain of a major histocompatibility complex (MHC) molecule; (5) a 3’ UTR comprising: (a) a 3’ untranslated region of an Amino-Terminal Enhancer of Split (AES) mRNA or a fragment thereof; and (b) non-coding RNA of a mitochondrially encoded 12S RNA or a fragment thereof; and (6) a poly(A) sequence.
  • AES Amino-Terminal Enhancer of Split
  • an RNA vaccine or molecule of the present disclosure comprises, in the 5’->3’ direction: the polynucleotide sequence GGCGAACUAGUAUUCUUCUGGUCCCCACAGACUCAGAGAGAACCCGCCACCAU GAGAGUGAUGGCCCCCAGAACCCUGAUCCUGCUGCUGUCUGGCGCCCUGGCCC UGACAGAGACAUGGGCCGGAAGC (SEQ ID NO: 19); and the polynucleotide sequence AUCGUGGGAAUUGUGGCAGGACUGGCAGUGCUGGCCGUGGUGGUGAUCGGAG CCGUGGUGGCUACCGUGAUGUGCAGACGGAAGUCCAGCGGAGGCAAGGGCGGC AGCUACAGCCAGGCCGCCAGCUCUGAUAGCGCCCAGGGCAGCGACGUGUCACU GACAGCCUAGUAACUCGAGCUGGUACUGCAUGCACGCAAUGCUAGCUGCCCCU UUCCCGUCCUGGGUACCCCGAGUCUCCCCCGACCUCGGGUCCCAGGUAUGCUC CC CCCGACC
  • RNA vaccines comprising this combination and orientation of structures or sequences are characterized by one or more of: improved RNA stability, enhanced translational efficiency, improved antigen presentation and/or processing (e.g., by DCs), and increased protein expression.
  • an RNA vaccine or molecule of the present disclosure comprises the sequence (in the 5’->3’ direction) of SEQ ID NO:42.
  • N refers to a polynucleotide sequence encoding at least 2, at least 3, at least 4, at least 5, at least
  • N refers to a polynucleotide sequence encoding one or more linker-epitope modules (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least
  • N refers to a polynucleotide sequence encoding one or more linker-epitope modules (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or 30 different linkerepitope modules) and an additional amino acid linker at the 3’ end.
  • linker-epitope modules e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or 30 different linkerepitope modules
  • the RNA vaccine or molecule further comprises a polynucleotide sequence encoding at least one neoepitope; wherein the polynucleotide sequence encoding the at least one neoepitope is between the polynucleotide sequence encoding the secretory signal peptide and the polynucleotide sequence encoding the at least portion of the transmembrane and cytoplasmic domain of the MHC molecule in the 5’->3’ direction.
  • the RNA molecule comprises a polynucleotide sequence encoding at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 different neoepitopes.
  • the RNA vaccine or molecule further comprises, in the 5’->3’ direction: a polynucleotide sequence encoding an amino acid linker; and a polynucleotide sequence encoding a neoepitope.
  • the polynucleotide sequences encoding the amino acid linker and the neoepitope form a linker-neoepitope module (e.g., a continuous sequence in the 5’->3’ direction in the same open-reading frame).
  • the polynucleotide sequences forming the linker-neoepitope module are between the polynucleotide sequence encoding the secretory signal peptide and the polynucleotide sequence encoding the at least portion of the transmembrane and cytoplasmic domain of the MHC molecule, or between the sequences of SEQ ID NO: 19 and SEQ ID NO:20, in the 5’->3’ direction.
  • the RNA vaccine or molecule comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 28, 29, or 30 linker-epitope modules.
  • each of the linkerepitope modules encodes a different neoepitope.
  • the RNA vaccine or molecule comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 linkerepitope modules, and the RNA vaccine or molecule comprises polynucleotides encoding at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 different neoepitopes.
  • the RNA vaccine or molecule comprises 5, 10, or 20 linker-epitope modules.
  • each of the linkerepitope modules encodes a different neoepitope.
  • the linker-epitope modules form a continuous sequence in the 5 ’->3’ direction in the same open-reading frame.
  • the polynucleotide sequence encoding the linker of the first linkerepitope module is 3’ of the polynucleotide sequence encoding the secretory signal peptide.
  • the RNA vaccine is at least 800 nucleotides, at least 1000 nucleotides, or at least 1200 nucleotides in length. In some embodiments, the RNA vaccine is less than 2000 nucleotides in length.
  • the RNA vaccine is at least 800 nucleotides but less than 2000 nucleotides in length, at least 1000 nucleotides but less than 2000 nucleotides in length, at least 1200 nucleotides but less than 2000 nucleotides in length, at least 1400 nucleotides but less than 2000 nucleotides in length, at least 800 nucleotides but less than 1400 nucleotides in length, or at least 800 nucleotides but less than 2000 nucleotides in length.
  • the constant regions of an RNA vaccine comprising the elements described above are approximately 800 nucleotides in length.
  • an RNA vaccine comprising 5 tumor-specific neoepitopes is greater than 1300 nucleotides in length. In some embodiments, an RNA vaccine comprising 10 tumor-specific neoepitopes (e.g., each encoding 27 amino acids) is greater than 1800 nucleotides in length.
  • the one or more polynucleotides of the RNA vaccine are formulated with one or more lipids.
  • the RNA vaccine is formulated as a lipid nanoparticle, wherein the one or more polynucleotides of the RNA vaccine and one or more lipids form the lipid nanoparticle.
  • the RNA vaccine is formulated as a lipoplex, wherein the one or more polynucleotides of the RNA vaccine and one or more lipids form the lipoplex.
  • the lipoplex comprises one or more lipids that form a multilamellar structure that encapsulates the one or more polynucleotides of the RNA vaccine.
  • the lipid nanoparticles or the lipoplexes comprise at least one cationic lipid.
  • the cationic lipid can be monocationic or polycationic. Any cationic amphiphilic molecule, e.g., a molecule which comprises at least one hydrophilic and lipophilic moiety is a cationic lipid within the meaning of the present invention.
  • the positive charges are contributed by the at least one cationic lipid and the negative charges are contributed by the RNA.
  • the lipid nanoparticle or lipoplex comprise at least one helper lipid.
  • the helper lipid may be a neutral or an anionic lipid.
  • the helper lipid may be a natural lipid, such as a phospholipid or an analogue of a natural lipid, or a fully synthetic lipid, or lipid-like molecule, with no similarities with natural lipids.
  • the cationic lipid and/or the helper lipid is a bilayer forming lipid.
  • the at least one cationic lipid comprises 1,2-di-O-octadecenyl- 3 -trimethylammonium propane (DOTMA) or analogs or derivatives thereof and/or 1,2- dioleoyl-3-trimethylammonium-propane (DOTAP) or analogs or derivatives thereof.
  • DOTMA 1,2-di-O-octadecenyl- 3 -trimethylammonium propane
  • DOTAP 1,2- dioleoyl-3-trimethylammonium-propane
  • the at least one helper lipid comprises l,2-di-(9Z- octadecenoyl)-sn-glycero-3 -phosphoethanolamine (DOPE) or analogs or derivatives thereof, cholesterol (Choi) or analogs or derivatives thereof and/or l,2-dioleoyl-sn-glycero-3- phosphocholine (DOPC) or analogs or derivatives thereof.
  • DOPE di-(9Z- octadecenoyl)-sn-glycero-3 -phosphoethanolamine
  • DOPC l,2-dioleoyl-sn-glycero-3- phosphocholine
  • the molar ratio of the at least one cationic lipid to the at least one helper lipid is from 10:0 to 3:7, preferably 9: 1 to 3:7, 4: 1 to 1 :2, 4: 1 to 2:3, 7:3 to 1 : 1, or 2: 1 to 1 : 1, preferably about 1 : 1.
  • the molar amount of the cationic lipid results from the molar amount of the cationic lipid multiplied by the number of positive charges in the cationic lipid.
  • the lipid is comprised in a vesicle encapsulating said RNA.
  • the vesicle may be a multilamellar vesicle, an unilamellar vesicle, or a mixture thereof.
  • the vesicle may be a lipoplex or lipid nanoparticle.
  • RNA vaccine formulations with one or more lipids described herein can be formed by adjusting a positive to negative charge, depending on the (+/-) charge ratio of a cationic lipid to RNA and mixing the RNA and the cationic lipid.
  • the lipoplexes or lipid nanoparticles comprise DOTAP and DOPE in a molar ratio of 10:0 to 1 :9, preferably 8:2 to 3:7, and more preferably of 7:3 to 5:5, wherein the charge ratio of positive charges in DOTMA to negative charges in the RNA is 1.8:2 to 0.8:2, more preferably 1.6:2 to 1 :2, even more preferably 1.4:2 to 1.1 :2 and even more preferably about 1.2:2.
  • the lipoplexes or lipid nanoparticles comprise DOTMA and DOPE in a molar ratio of 2: 1 to 1 :2, preferably 2: 1 to 1 : 1, wherein the charge ratio of positive charges in DOTMA to negative charges in the RNA is 1.4: 1 or less.
  • the lipoplexes or lipid nanoparticles comprise DOTMA and cholesterol in a molar ratio of 2: 1 to 1 :2, preferably 2: 1 to 1 : 1, wherein the charge ratio of positive charges in DOTMA to negative charges in the RNA is 1.4: 1 or less.
  • the lipoplexes or lipid nanoparticles comprise DOTAP and DOPE in a molar ratio of 2: 1 to 1 :2, preferably 2: 1 to 1 : 1, wherein the charge ratio of positive charges in DOTAP to negative charges in the RNA is 1.4: 1 or less.
  • the zeta potential of the lipoplexes or lipid nanoparticles is -5 or less, -10 or less, -15 or less, -20 or less or -25 or less. In various embodiments, the zeta potential of the lipoplexes or lipid nanoparticles is -35 or higher, -30 or higher or -25 or higher. In one embodiment, the lipoplexes or lipid nanoparticles have a zeta potential from 0 mV to -50 mV, preferably 0 mV to -40 mV or -10 mV to -30 mV.
  • the poly dispersity index of the lipoplexes or lipid nanoparticles is 0.5 or less, 0.4 or less, or 0.3 or less, as measured by dynamic light scattering.
  • the lipoplexes or lipid nanoparticles have an average diameter in the range of about 50 nm to about 1000 nm, from about 100 nm to about 800 nm, from about 200 nm to about 600 nm, from about 250 nm to about 700 nm, or from about 250 nm to about 550 nm, as measured by dynamic light scattering.
  • the RNA vaccine is administered to the human patient at a dose of about 21.3 pg. More than one individualized cancer vaccine may be administered to a subject, e.g., subject is administered one individualized cancer vaccine with a combination of neoepitopes and also administered a separate individualized cancer vaccine with a different combination of neoepitopes.
  • a first individualized cancer vaccine with five neoepitopes is administered in combination with a second individualized cancer vaccine with five alternative epitopes.
  • a first individualized cancer vaccine with ten neoepitopes is administered in combination with a second individualized cancer vaccine with ten alternative epitopes.
  • a DNA molecule of the present disclosure comprises the general structure (in the 5’->3’ direction): (1) a polynucleotide sequence encoding a 5’ untranslated region (UTR); (2) a polynucleotide sequence encoding a secretory signal peptide; (3) a polynucleotide sequence encoding at least a portion of a transmembrane and cytoplasmic domain of a major histocompatibility complex (MHC) molecule; (4) a polynucleotide sequence encoding a 3’ UTR comprising: (a) a 3’ untranslated region of an Amino-Terminal Enhancer of Split (AES) mRNA or a fragment thereof; and (b) non-coding RNA of a mitochondrially encoded 12S RNA or a fragment thereof; and (5) a polynucleot
  • AES Amino-Terminal Enhancer of Split
  • a DNA molecule of the present disclosure comprises, in the 5’->3’ direction: the polynucleotide sequence GGCGAACTAGTATTCTTCTGGTCCCCACAGACTCAGAGAGAACCCGCCACCATG AGAGTGATGGCCCCCAGAACCCTGATCCTGCTGCTGTCTGGCGCCCTGGCCCTGA CAGAGACATGGGCCGGAAGC (SEQ ID NO:40); and the polynucleotide sequence ATCGTGGGAATTGTGGCAGGACTGGCAGTGCTGGCCGTGGTGGTGATCGGAGCC GTGGTGGCTACCGTGATGTGCAGACGGAAGTCCAGCGGAGGCAAGGGCGGCAGC TACAGCCAGGCCGCCAGCTCTGATAGCGCCCAGGGCAGCGACGTGTCACTGACA GCCTAGTAACTCGAGCTGGTACTGCATGCACGCAATGCTAGCTGCCCCTTTCCCG TCCTGGGTACCCCGAGTCTCCCCCGACCTCGGGTCCCAGGTATGCTCCCACCTCC ACCTGCC
  • the DNA molecule further comprises, in the 5’->3’ direction: a polynucleotide sequence encoding an amino acid linker; and a polynucleotide sequence encoding a neoepitope.
  • the polynucleotide sequences encoding the amino acid linker and the neoepitope form a linker-neoepitope module (e.g., a continuous sequence in the 5’->3’ direction in the same open-reading frame).
  • the polynucleotide sequences forming the linker-neoepitope module are between the polynucleotide sequence encoding the secretory signal peptide and the polynucleotide sequence encoding the at least portion of the transmembrane and cytoplasmic domain of the MHC molecule, or between the sequences of SEQ ID NO:40 and SEQ ID NO:41, in the 5’->3’ direction.
  • the DNA molecule comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 28, 29, or 30 linker-epitope modules, and each of the linker-epitope modules encodes a different neoepitope.
  • the linker-epitope modules form a continuous sequence in the 5’->3’ direction in the same open-reading frame.
  • the polynucleotide sequence encoding the linker of the first linker-epitope module is 3’ of the polynucleotide sequence encoding the secretory signal peptide.
  • the polynucleotide sequence encoding the neoepitope of the last linker-epitope module is 5’ of the polynucleotide sequence encoding the at least portion of the transmembrane and cytoplasmic domain of the MHC molecule.
  • RNA vaccine of the present disclosure comprising transcribing (e.g., by transcription of linear, double-stranded DNA or plasmid DNA, such as by in vitro transcription) a DNA molecule of the present disclosure.
  • the methods further comprise isolating and/or purifying the transcribed RNA molecule from the DNA molecule.
  • an RNA or DNA molecule of the present disclosure comprises a type IIS restriction cleavage site, which allows RNA to be transcribed under the control of a 5' RNA polymerase promoter and which contains a polyadenyl cassette (poly(A) sequence), wherein the recognition sequence is located 3' of the poly(A) sequence, while the cleavage site is located upstream and thus within the poly(A) sequence. Restriction cleavage at the type IIS restriction cleavage site enables a plasmid to be linearized within the poly(A) sequence, as described in U.S. Pat. Nos. 9,476,055 and 10,106,800.
  • the linearized plasmid can then be used as template for in vitro transcription, the resulting transcript ending in an unmasked poly(A) sequence.
  • Any of the type IIS restriction cleavage sites described in U.S. Pat. Nos. 9,476,055 and 10,106,800 may be used.
  • the one or more lipids include at least one cationic lipid and at least one helper lipid.
  • the one or more lipids include (R)-N,N,N-trimethyl-2,3-dioleyloxy-l-propanaminium chloride (DOTMA) and l,2-dioleoyl-sn-glycero-3 -phosphoethanolamine (DOPE).
  • DOTMA DOTMA-N,N,N-trimethyl-2,3-dioleyloxy-l-propanaminium chloride
  • DOPE l,2-dioleoyl-sn-glycero-3 -phosphoethanolamine
  • at physiological pH the overall charge ratio of positive charges to negative charges of the liposome is 1.3:2 (0.65).
  • the RNA vaccine includes an RNA molecule including, in the 5’->3’ direction: (1) a 5’ cap; (2) a 5’ untranslated region (UTR); (3) a polynucleotide sequence encoding a secretory signal peptide; (4) a polynucleotide sequence encoding the one or more neoepitopes resulting from cancer-specific somatic mutations present in the tumor specimen; (5) a polynucleotide sequence encoding at least a portion of a transmembrane and cytoplasmic domain of a major histocompatibility complex (MHC) molecule; (6) a 3’ UTR including: (a) a 3’ untranslated region of an Amino-Terminal Enhancer of Split (AES) mRNA or a fragment thereof; and (b) non-coding RNA of a mitochondrially encoded 12S RNA or a fragment thereof; and (7) a poly(A) sequence.
  • AES Amino-Terminal Enhanc
  • the RNA molecule further includes, in the 5’->3’ direction: at least a second linker-epitope module, wherein the at least second linker-epitope module includes a polynucleotide sequence encoding an amino acid linker and a polynucleotide sequence encoding a neoepitope; wherein the polynucleotide sequences forming the second linker-neoepitope module are between the polynucleotide sequence encoding the neoepitope of the first linker-neoepitope module and the polynucleotide sequence encoding the at least portion of the transmembrane and cytoplasmic domain of the MHC molecule in the 5’->3’ direction; and wherein the neoepitope of the first linker-epitope module is different from the neoepitope of the second linker-epitope module.
  • the secretory signal peptide includes the amino acid sequence MRVMAPRTLILLLS GAL ALTET WAGS (SEQ ID NO:27).
  • the polynucleotide sequence encoding the secretory signal peptide includes the sequence
  • the RNA vaccine includes an RNA molecule including, in the 5’->3’ direction: the polynucleotide sequence GGCGAACUAGUAUUCUUCUGGUCCCCACAGACUCAGAGAGAACCCGCCACCAU GAGAGUGAUGGCCCCCAGAACCCUGAUCCUGCUGCUGUCUGGCGCCCUGGCCC UGACAGAGACAUGGGCCGGAAGC (SEQ ID NO: 19); a polynucleotide sequence encoding the one or more neoepitopes resulting from cancer-specific somatic mutations present in the tumor specimen; and the polynucleotide sequence AUCGUGGGAAUUGUGGCAGGACUGGCAGUGCUGGCCGUGGUGGUGAUCGGAG CCGUGGUGGCUACCGUGAUGUGCAGACGGAAGUCCAGCGGAGGCAAGGGCGGC AGCUACAGCCAGGCCGCCAGCUCUGAUAGCGCCCAGGGCAGCGACGUGUCACU GACAGCCUAGUAACUCGAGCU
  • an individualized cancer vaccine (e.g., an RNA vaccine) of the present disclosure is administered in combination with a PD-1 axis binding antagonist.
  • a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PDL1 binding antagonist and a PDL2 binding antagonist.
  • Alternative names for “PD-1” include CD279 and SLEB2.
  • Alternative names for “PDL1” include B7-H1, B7-4, CD274, and B7-H.
  • Alternative names for “PDL2” include B7-DC, Btdc, and CD273.
  • PD-1, PDL1, and PDL2 are human PD-1, PDL1 and PDL2.
  • the heavy chain comprises the amino acid sequence:
  • the light chain comprises the amino acid sequence:
  • the anti-PD-1 antibody comprises the six HVR sequences from SEQ ID NO: 11 and SEQ ID NO: 12 (e.g., the three heavy chain HVRs from SEQ ID NO: 11 and the three light chain HVRs from SEQ ID NO: 12). In some embodiments, the anti- PD-1 antibody comprises the heavy chain variable domain from SEQ ID NO: 11 and the light chain variable domain from SEQ ID NO: 12.
  • the heavy chain comprises the amino acid sequence: QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGG INPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMG FDYW GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GV
  • REGN2810 is a human anti-PDl antibody also known as LIBTAYO® and cemiplimab-rwlc.
  • the anti-PD-1 antibody is BGB-108 (BeiGene). In some embodiments, the anti-PD-1 antibody is BGB-A317 (BeiGene).
  • the PD-1 binding antagonist is a peptide or small molecule compound.
  • the PD-1 binding antagonist is AUNP-12 (PierreFabre/Aurigene). See, e.g., WO2012/168944, WO2015/036927, WO2015/044900, W02015/033303, WO2013/144704, WO2013/132317, and WO2011/161699.
  • the PDL1 binding antagonist is a small molecule that inhibits PD-1. In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL1. In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL1 and VISTA. In some embodiments, the PDL1 binding antagonist is CA-170 (also known as AUPM-170). In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL1 and TIM3. In some embodiments, the small molecule is a compound described in W02015/033301 and WO2015/033299.
  • the PD-1 axis binding antagonist is an anti-PDLl antibody.
  • anti-PDLl antibodies are contemplated and described herein.
  • the isolated anti-PDLl antibody can bind to a human PDL1, for example a human PDL1 as shown in UniProtKB/Swiss-Prot Accession No. Q9NZQ7.1, or a variant thereof.
  • the anti-PDLl antibody is capable of inhibiting binding between PDL1 and PD-1 and/or between PDL1 and B7-1.
  • the anti-PDLl antibody is a monoclonal antibody.
  • the anti-PDLl antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.
  • the anti-PDLl antibody is a humanized antibody.
  • the anti-PDLl antibody is a human antibody. Examples of anti-PDLl antibodies useful for the methods of this invention, and methods for making thereof are described in PCT patent application WO 2010/077634 Al and US Patent No. 8,217,149, which are incorporated herein by reference.
  • the anti-PDLl antibody comprises a heavy chain variable region and a light chain variable region, wherein:
  • the light chain variable region comprises an HVR-L1, HVR-L2, and HVR-L3 sequence of RASQDVSTAVA (SEQ ID NO:4), SASFLYS (SEQ ID NO:5) and QQYLYHPAT (SEQ ID NO:6), respectively.
  • the anti-PDLl antibody is MPDL3280A, also known as atezolizumab and TECENTRIQ® (CAS Registry Number: 1422185-06-5), with a WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4, published January 16, 2015 (see page 485) described therein.
  • the anti-PDLl antibody comprises a heavy chain and a light chain sequence, wherein:
  • the light chain comprises the amino acid sequence:
  • the light chain comprises the amino acid sequence: QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRP SGVSNRFSGSKSGNTASLTISGLQAEDEAD YYC S S YTS S STRVFGTGTKVTVLGQPKA NPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQS NNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 16).
  • the anti-PDLl antibody comprises the six HVR sequences from SEQ ID NO: 15 and SEQ ID NO: 16 (e.g., the three heavy chain HVRs from SEQ ID NO: 15 and the three light chain HVRs from SEQ ID NO: 16). In some embodiments, the anti- PDLl antibody comprises the heavy chain variable domain from SEQ ID NO: 15 and the light chain variable domain from SEQ ID NO: 16.
  • the light chain comprises the amino acid sequence:
  • the anti-PDLl antibody comprises the six HVR sequences from SEQ ID NO: 17 and SEQ ID NO: 18 (e.g., the three heavy chain HVRs from SEQ ID NO: 17 and the three light chain HVRs from SEQ ID NO: 18). In some embodiments, the anti- PDLl antibody comprises the heavy chain variable domain from SEQ ID NO: 17 and the light chain variable domain from SEQ ID NO: 18.
  • the anti-PDLl antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PDLl antibody described in W02007/005874.
  • the anti-PDLl antibody is LY3300054 (Eli Lilly).
  • the anti-PDLl antibody is KN035 (Suzhou Alphamab).
  • KN035 is single-domain antibody (dAB) generated from a camel phage display library.
  • the PDL1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from a PDL1 antibody described in US20160108123 (Assigned to Novartis), W02016/000619 (Applicant: Beigene), WO2012/145493 (Applicant: Amplimmune), US9205148 (Assigned to Medlmmune), WO2013/181634 (Applicant: Sorrento), and W02016/061142 (Applicant: Novartis).
  • HVR sequences e.g., the three heavy chain HVRs and the three light chain HVRs
  • the pharmaceutical formulation comprising said antibody is prepared.
  • the antibody to be formulated has not been subjected to prior lyophilization, and the formulation of interest herein is an aqueous formulation.
  • the antibody is a full-length antibody.
  • the antibody in the formulation is an antibody fragment, such as an F(ab')2.
  • the therapeutically effective amount of antibody present in the formulation is determined by taking into account the desired dose volumes and mode(s) of administration, for example.
  • a pharmaceutical composition and/or formulation described herein is a liquid, is formulated for direct administration to a human subject without dilution, and comprises RNA lipoplex particles comprising: RNA; at least one cationic lipid, and at least one additional lipid; sodium chloride at a concentration of about 10 mM or less; a stabilizer at a concentration of more than about 10% weight by volume percent (% w/v) and less than about 15% weight by volume percent (% w/v); and a buffer.
  • the sodium chloride is at a concentration from about 5 mM to about 10 mM. In some embodiments, the sodium chloride is at a concentration of about 8.2 mM.
  • the buffer is selected from the group consisting of 2-[4-(2-hydroxyethyl)piperazin-l- yl]ethanesulfonic acid (HEPES), histidine, acetic acid/sodium acetate, and MES (2-(N- morpholino)ethanesulfonic acid).
  • the buffer is HEPES.
  • the composition has a pH from 6.0 to 7.5, from 6.5 to 7.5, from 6.5 to 7.3, from 6.5 to 7.2, from 6.7 to 7.2, or from 6.5 to 7.0. In some embodiments, the composition has a pH of about 6.7.
  • the composition further comprises a chelating agent.
  • the chelating agent is ethylenediaminetetraacetic acid (EDTA).
  • EDTA is at a concentration of about 3.5 mM or less, or from about 0.25 mM to about 3.5 mM, or about 0.25 mM to about 2.5 mM.
  • the RNA encodes a peptide or protein comprising at least one epitope, wherein the ratio of positive charges to negative charges in the composition is from about 1 :2 to about 1.9:2, or about 1.3:2.0.
  • the RNA lipoplex particles have an average diameter that ranges from about 200 to about 800 nm, from about 250 to about 700 nm, from about 400 to about 600 nm, from about 300 nm to about 500 nm, or from about 350 nm to about 400 nm.
  • the amount of RNA in the composition is from about 0.01 mg/mL to about 1 mg/mL, about 0.05 mg/mL to about 0.5 mg/mL, or about 0.025 mg/mL.
  • the composition is in a liquid, frozen or dehydrated state. In some embodiments, the frozen composition is stable at a temperature of about -15°C for at least six months.
  • kits comprising an individualized RNA vaccine, for use in a method for treating a UC in a human in need thereof, wherein the RNA vaccine is to be administered in combination with a PD-1 axis binding antagonist according to the method described herein, wherein the RNA vaccine comprises one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a UC tumor specimen obtained from the human.
  • the kit comprises a PD-1 axis binding antagonist for use in a method for treating a UC in a human in need thereof, wherein the PD-1 axis binding antagonist is to be administered in combination with an individualized RNA vaccine according to the method described herein, wherein the RNA vaccine comprises one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a UC tumor specimen obtained from the human.
  • Part A The study consists of two screening phases (Part A and Part B), a treatment period consisting of priming, boost, and post-nivolumab boost phases, and a follow-up period. Since the individualized cancer vaccine is designed and manufactured for each individual patient, screening Part A preferably begin as soon as possible (ideally, prior to TURBT resection).
  • Part A patients provide a tumor specimen sample (TURBT specimens strongly preferred, though some samples from radical cystectomy or radical nephroureterectomy may be acceptable as outlined below) and matching blood sample to begin upstream manufacturing of autogene cevumeran.
  • Part B screening begins after pathological confirmation of disease status from radical cystectomy or radical nephroureterectomy and includes eligibility criteria screening in parallel with downstream manufacturing of the individualized cancer vaccine.
  • Neoadjuvant cisplatin based therapy is the standard of care in patients with MIUC that have a high risk of recurrence prior to cystectomy based on randomized trials demonstrating small survival benefit. In patients who do not receive neoadjuvant chemotherapy, adjuvant cisplatin therapy is an option. However, many patients are not eligible to receive cisplatin-based chemotherapy due to co-morbidities such as hearing loss, peripheral neuropathy, or impaired renal function.
  • Autogene cevumeran is an individualized neoantigen-specific immunotherapy (i.e., an individualized cancer vaccine), which is a therapeutic mRNA platform that has been shown to induce antigen-specific T-cell responses to the neoantigens encoded (Braiteh et al. A phase la study to evaluate RO7198457, an individualized neoantigen specific immunotherapy (iNeST), in patients with locally advanced or metastatic solid tumors [abstract]. Cancer Res 2020;80 (Suppl 16):CT169, Lopez et al.
  • RNA vaccines described herein such as autogene cevumeran
  • Blocking the PD-1 pathway with a PD-1 axis binding antagonist such as nivolumab may augment the activity of the RNA vaccine by enhancing the initial priming or reactivation of T cells upon antigen encounter and/or improving the activity of dysfunctional T cells after persistent antigen exposure in the tumor.
  • a PD-1 axis binding antagonist such as nivolumab
  • the combination of, for example, autogene cevumeran with nivolumab may result in more robust anti-tumor immune responses, leading to improved clinical efficacy.
  • PD-1 expression in cancer cells correlates with responsiveness to immune checkpoint inhibitors.
  • a PD-1 -adaptive upregulation can be induced by cancer vaccine- induced T cells and the release of interferon-y.
  • priming the immune system with the individualized cancer vaccine, and the resulting priming of T cells as well as PD-1 upregulation may increase the response to checkpoint blockade.
  • the priming and first round of substantial expansion of vaccine-induced T cells typically takes about 2-3 weeks.
  • Checkpoint inhibitors such as an anti -PD-1 agent, may synergistically enhance the activity of cancer vaccine-induced T cells within the tumor microenvironment after their development.
  • TURBT specimens from patients will be prospectively tested for PD- L1 expression by a central laboratory during the screening period.
  • the study will enroll individuals regardless of PD-L1 status; however, PD-L1 status (H4C score of ⁇ 1% vs. ⁇ 1%) will be used as one of the stratification factors, as discussed above.
  • This study enrolls approximately 362 patients (including up to 12 participants enrolled in the safety run in) across approximately 110 sites in a global enrollment phase.
  • the Phase II study includes i) a two-part screening period (Part A and Part B; shown in FIG. 1); ii) a treatment period consisting of two treatment arms (experimental and control), each with three phases (priming, boost, and post-nivolumab boost phases); and iii) a follow-up period.
  • the total duration of study participation for each patient is expected to be approximately 6 years.
  • Patients who have histologically confirmed muscle-invasive MIBC or UTUC are eligible. Patients with UTUC will be limited to no more than approximately 10% of the study population. Patients with MIBC as the site of primary involvement must have undergone radical cystectomy with lymph node dissection. Patients with UTUC as the site of primary involvement must have undergone radical nephroureterectomy (RNU) with excision of the bladder cuff regardless of the location of the tumor in the upper urinary tract, and the RNU must include lymph node dissection.
  • RNU radical nephroureterectomy
  • Patients who have received prior neoadjuvant chemotherapy are eligible and must have tumor staging of ypT3-4a or ypN+ (for patients with MIBC; ypT3-4 or ypN+ for patients with UTUC) at pathological examination of resected specimen and M0 radiographically.
  • Patients who have not received neoadjuvant chemotherapy must be ineligible for or declined treatment with cisplatin-based adjuvant chemotherapy and have tumor staging of pT3-4a or pN+ (for patients with MIBC; pT3-4 or pN+ for patients with UTUC) and M0.
  • Part A Screening occurs in two parts, termed Part A and Part B (FIG. 1, Table 4).
  • Part A participants will undergo limited screening for eligibility.
  • transurethral resection of the bladder tumor (TURBT) and paired whole blood samples from patients diagnosed with MIBC (cT3-T4 or N+) are preferably submitted for upstream manufacturing of individualized cancer vaccine (including, e.g., for Whole Exome Sequencing (WES), RNA sequencing, and neoepitope identification).
  • WES Whole Exome Sequencing
  • RNA sequencing RNA sequencing
  • neoepitope identification e.g., for Whole Exome Sequencing (WES), RNA sequencing, and neoepitope identification.
  • WES Whole Exome Sequencing
  • RNA sequencing RNA sequencing
  • neoepitope identification neoepitope identification
  • TURBT samples are submitted for upstream manufacturing prior to radical cystectomy (in the case of patients with MIBC) or prior to radical nephroureterectomy (RNU; in the case of patients with UTUC) in order to ensure that vaccine manufacturing can be completed within an acceptable timeframe and does not lead to a delay in the administration of adjuvant therapy.
  • Collection and submission of blood for manufacturing of autogene cevumeran is recommended to be performed at least 6 weeks prior to the planned randomization date and prior to cystectomy /nephroureterectomy to avoid delays in administration of adjuvant therapy.
  • a surgical resection specimen (e.g., from a cystectomy or from a nephroureterectomy) may be submitted.
  • a surgical resection specimen obtained from RNU may be submitted for individualized cancer vaccine manufacturing, or for patients diagnosed with MIBC, a surgical resection specimen obtained from radical cystectomy may be submitted for individualized cancer vaccine manufacturing.
  • TURBT samples are strongly preferred to be submitted to reduce the risk of individualized cancer vaccine manufacturing delays.
  • WES obtained from upstream manufacturing may also be used for subsequent ctDNA testing. Leftover tissue from upstream manufacturing may be used for exploratory biomarker testing.
  • Each mRNA strand encodes up to 10 MHCI and MHCII neoepitopes, formulated in approximately 400 nm diameter lipoplex nanoparticles (e.g., as described in Kranz et al., Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy.
  • Downstream manufacturing of individualized cancer vaccine begins once pathology from surgical resection specimen is confirmed and at least 5 cancer-specific neoepitopes (NEs) have been identified. At least 5 cancer-specific NEs are required for eligibility.
  • Concomitant medications include medication (e.g., prescription drugs, over-the- counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a participant in addition to protocol-mandated treatment (including prophylactic treatment for autogene cevumeran/placebo administration and medications resulting from an adverse event) from 7 days prior to screening Part B to the treatment discontinuation visit.
  • protocol-mandated treatment including prophylactic treatment for autogene cevumeran/placebo administration and medications resulting from an adverse event
  • Randomization is stratified by pathological nodal staging (N ⁇ vs. NO), PD-L1 IHC status (tumor cell score ⁇ 1% vs. ⁇ 1% or indeterminate), and whether prior neoadjuvant chemotherapy was administered (yes vs. no). Randomization occurs within 120 days after surgical resection of the primary tumor. Study drug administration begins within 3 calendar days after randomization; if possible, patients should receive their first dose of the individualized cancer vaccine on the day of randomization. Participants must have no evidence of disease (NED) by imaging within 28 days prior to randomization in order to be eligible.
  • NED evidence of disease
  • Cycle 1 28 Days: Individualized cancer vaccine 25 pg IV or placebo on Days 1, 8, 15, and 22 (individualized cancer vaccine (or placebo) priming doses 1, 2, 3, and 4, respectively), for a total of 4 individualized cancer vaccine (or placebo) priming doses within the 28 days of Cycle 1; and nivolumab 480 mg IV on Day 9 (nivolumab dose 1), for a total of 1 dose of nivolumab within the 28 days of Cycle 1, such that two doses of the individualized cancer vaccine (or placebo) are administered before starting nivolumab.
  • the first dose of nivolumab is administered 24 or more hours after administration of the second priming dose of the individualized cancer vaccine (or placebo).
  • Cancer-related assessments include imaging (e.g., radiographic assessments), clinical evaluation for signs and symptoms of disease, and/or tumor assessments. Serum samples will be collected to monitor biomarker subsets, ctDNA clearance, and T-cell response. Blood samples for exploratory biomarker analyses, pharmacokinetic analyses, and immunogenicity analyses are collected at various timepoints. Plasma samples are collected at every scheduled imaging assessment for tumor recurrence to evaluate ctDNA clearance.
  • imaging e.g., radiographic assessments
  • Serum samples will be collected to monitor biomarker subsets, ctDNA clearance, and T-cell response.
  • Blood samples for exploratory biomarker analyses, pharmacokinetic analyses, and immunogenicity analyses are collected at various timepoints. Plasma samples are collected at every scheduled imaging assessment for tumor recurrence to evaluate ctDNA clearance.
  • a standard dose of nivolumab is 480 mg. Modification of the nivolumab dose is not permitted.
  • Standard radiographic assessments conducted as part of this study may include any of the following: Contrast-enhanced CT (computed tomography) chest, contrast-enhanced CT abdomen, contrast-enhanced CT pelvis, and PET (positron emission tomography)-CT (if needed to clarify indeterminate or suspicious lesions seen on CT of the chest/abdomen/pelvis or MRI). Imaging of the upper urinary tracts is not required if covered by abdomen and pelvis scans.
  • any of the following radiographic assessments may be used: Non-contrast CT chest, MRI with gadolinium abdomen, MRI with gadolinium pelvis, CT urography (recommended with reduced contrast), MRI urogram (recommended), ureteroscopy, IVP X-ray, or renal ultrasound with retrograde pyelogram (X-ray).
  • CT urography recommended with reduced contrast
  • MRI urogram recommended
  • ureteroscopy IVP X-ray
  • renal ultrasound with retrograde pyelogram X-ray
  • any of the following radiographic assessments may be used: Non-contrast MRI urogram with static fluid T2-weighted sequences, or ureteroscopy.
  • Imaging of the upper urinary tracts may include one or more of the following: IVP, CT urography, renal ultrasound with retrograde pyelogram, ureteroscopy, or MRI urogram.
  • IVP intracranial pressure
  • CT urography computed tomography
  • renal ultrasound with retrograde pyelogram renal ultrasound with retrograde pyelogram
  • ureteroscopy or MRI urogram.
  • imaging for tumor assessments for UC recurrence during the study period should use the same imaging modality that was used at screening and be performed at the timepoints specified in Table 6, regardless of drug delays or interruptions.
  • Lymph nodes must be non-pathologic, which is defined as less than 1.0 cm in short axis;
  • biopsy is recommended, if feasible. If biopsy is not feasible, lesions that are radiographically consistent with urothelial malignancy, or demonstrating growth over at least two post operative imaging tests (either CT or MRI) at least 4 weeks apart should be considered recurrence.
  • determination of disease recurrence may include the following scenarios:
  • Tumor tissue from bone metastases that have been decalcified is not acceptable. o In situations where multiple specimens were received from different sites or at different times, the score from the surgical resection of the primary tumor or lymph node dissection specimen will be used for both primary and secondary analyses. o In situations in which multiple specimens are received from different sites or at different times, the score from the surgical resection of the primary tumor or lymph node dissection specimen is used for both primary and secondary analyses.
  • liver disease including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse as determined by the investigator
  • autoimmune disease or immune deficiency including: Acute disseminated encephalomyelitis, Addison disease, Ankylosing spondylitis, Anti-phospholipid antibody syndrome, Aplastic anemia, Autoimmune hemolytic anemia, Autoimmune hepatitis, Autoimmune hypoparathyroidism, Autoimmune hypophysitis, Autoimmune myelitis, Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune thrombocytopenic purpura, Behget disease, Bullous pemphigoid, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy, Churg- Strauss syndrome, Crohn disease, Dermatomyositis, Diabetes mellitus type 1, Dysautonomia, Epidermolysis bullosa acquisita, Gestational pemphigoid, Giant cell arteritis, Goodpasture syndrome, Graves
  • ⁇ Rash must cover ⁇ 10% of body surface area
  • Recent acute infection defined as severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety;
  • VAS visual analogue scale
  • AD As anti-drug antibodies
  • Nivolumab heavy chain sequence (SEQ ID NO: 11) QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWY DGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTL

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne des méthodes de traitement d'un individu atteint d'un carcinome urothélial avec un vaccin anticancéreux individualisé et un antagoniste de l'axe PD-1.
PCT/US2025/011687 2024-01-16 2025-01-15 Méthodes de traitement du carcinome urothélial avec un antagoniste de liaison à l'axe pd-1 et un vaccin à arn Pending WO2025155607A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463621511P 2024-01-16 2024-01-16
US63/621,511 2024-01-16

Publications (1)

Publication Number Publication Date
WO2025155607A1 true WO2025155607A1 (fr) 2025-07-24

Family

ID=94633567

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/011687 Pending WO2025155607A1 (fr) 2024-01-16 2025-01-15 Méthodes de traitement du carcinome urothélial avec un antagoniste de liaison à l'axe pd-1 et un vaccin à arn

Country Status (2)

Country Link
TW (1) TW202539700A (fr)
WO (1) WO2025155607A1 (fr)

Citations (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
EP0404097A2 (fr) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application
WO1991010741A1 (fr) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation d'anticorps xenogeniques
WO1993001161A1 (fr) 1991-07-11 1993-01-21 Pfizer Limited Procede de preparation d'intermediaires de sertraline
US5545807A (en) 1988-10-12 1996-08-13 The Babraham Institute Production of antibodies from transgenic animals
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
WO1996034096A1 (fr) 1995-04-28 1996-10-31 Abgenix, Inc. Anticorps humains derives de xeno-souris immunisees
WO1996033735A1 (fr) 1995-04-27 1996-10-31 Abgenix, Inc. Anticorps humains derives d'une xenosouris immunisee
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
WO1998024893A3 (fr) 1996-12-03 1998-08-20 Abgenix Inc MAMMIFERES TRANSGENIQUES POSSEDANT DES LOCI DE GENES D'IMMUNOGLOBULINE D'ORIGINE HUMAINE, DOTES DE REGIONS VH ET Vλ, ET ANTICORPS PRODUITS A PARTIR DE TELS MAMMIFERES
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6171586B1 (en) 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
US6267958B1 (en) 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
US20050260186A1 (en) 2003-03-05 2005-11-24 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases
US6982321B2 (en) 1986-03-27 2006-01-03 Medical Research Council Altered antibodies
WO2006044908A2 (fr) 2004-10-20 2006-04-27 Genentech, Inc. Formulations d'anticorps
US20060104968A1 (en) 2003-03-05 2006-05-18 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases
US7087409B2 (en) 1997-12-05 2006-08-08 The Scripps Research Institute Humanization of murine antibody
WO2006121168A1 (fr) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Anticorps monoclonaux humains pour mort programmee 1 (mp-1) et procedes pour traiter le cancer en utilisant des anticorps anti-mp-1 seuls ou associes a d’autres immunotherapies
WO2007005874A2 (fr) 2005-07-01 2007-01-11 Medarex, Inc. Anticorps monoclonaux humains diriges contre un ligand de mort programmee de type 1(pd-l1)
WO2009114335A2 (fr) 2008-03-12 2009-09-17 Merck & Co., Inc. Protéines de liaison avec pd-1
WO2010027827A2 (fr) 2008-08-25 2010-03-11 Amplimmune, Inc. Polypeptides co-stimulateurs ciblés et leurs procédés d'utilisation dans le traitement du cancer
WO2010077634A1 (fr) 2008-12-09 2010-07-08 Genentech, Inc. Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t
WO2011066342A2 (fr) 2009-11-24 2011-06-03 Amplimmune, Inc. Inhibition simultanée de pd-l1/pd-l2
WO2011066389A1 (fr) 2009-11-24 2011-06-03 Medimmmune, Limited Agents de liaison ciblés dirigés contre b7-h1
WO2011161699A2 (fr) 2010-06-25 2011-12-29 Aurigene Discovery Technologies Limited Composés modulateurs de l'immunosuppression
US8153773B2 (en) 2007-06-19 2012-04-10 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Synthesis and use of anti-reverse phosphorothioate analogs of the messenger RNA cap
US8178653B2 (en) 2003-10-14 2012-05-15 Biontech Ag Recombinant vaccines and use thereof
WO2012145493A1 (fr) 2011-04-20 2012-10-26 Amplimmune, Inc. Anticorps et autres molécules qui se lient à b7-h1 et à pd-1
WO2012168944A1 (fr) 2011-06-08 2012-12-13 Aurigene Discovery Technologies Limited Composés thérapeutiques pour une immunomodulation
WO2013132317A1 (fr) 2012-03-07 2013-09-12 Aurigene Discovery Technologies Limited Composés peptidomimétiques utilisés comme immunomodulateurs
WO2013144704A1 (fr) 2012-03-29 2013-10-03 Aurigene Discovery Technologies Limited Composés cycliques d'immunomodulation provenant de la boucle bc de pd1 humain
WO2013181634A2 (fr) 2012-05-31 2013-12-05 Sorrento Therapeutics Inc. Protéines liant un antigène qui lient pd-l1
WO2014179664A2 (fr) 2013-05-02 2014-11-06 Anaptysbio, Inc. Anticorps dirigés contre la protéine de mort programmée 1 (pd-1)
WO2014194302A2 (fr) 2013-05-31 2014-12-04 Sorrento Therapeutics, Inc. Protéines de liaison à l'antigène qui se lient à pd-1
WO2014206107A1 (fr) 2013-06-26 2014-12-31 上海君实生物医药科技有限公司 Anticorps anti-pd-1 et son utilisation
WO2015033299A1 (fr) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited Dérivés 1,2,4-oxadiazole utilisés comme immunomodulateurs
WO2015033303A1 (fr) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited Composés peptidomimétiques cycliques utilisés comme immunomodulateurs
WO2015033301A1 (fr) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited Dérivés 1,3,4-oxadiazole et 1,3,4-thiadiazole servant d'immunomodulateurs
WO2015035606A1 (fr) 2013-09-13 2015-03-19 Beigene, Ltd. Anticorps anti-pd1 et leur utilisation comme produits thérapeutiques et produits de diagnostic
WO2015036927A1 (fr) 2013-09-10 2015-03-19 Aurigene Discovery Technologies Limited Dérivés peptidomimétiques d'immunomodulation
US20150086612A1 (en) 2012-03-26 2015-03-26 Biontech Ag RNA Formulation for Immunotherapy
WO2015044900A1 (fr) 2013-09-27 2015-04-02 Aurigene Discovery Technologies Limited Composés immunomodulateurs thérapeutiques
WO2015085847A1 (fr) 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Anticorps anti-pd-1, son fragment de liaison à l'antigène, et son application médicale
WO2015112900A1 (fr) 2014-01-24 2015-07-30 Dana-Farber Cancer Institue, Inc. Molécules d'anticorps anti-pd-1 et leurs utilisations
WO2015112805A1 (fr) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Anticorps humains dirigés contre pd-l1
WO2015112800A1 (fr) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Anticorps humains se liant à pd-1
WO2015119930A1 (fr) 2014-02-04 2015-08-13 Pfizer Inc. Association d'un antagoniste du pd-1 et d'un inhibiteur du vegfr pour traiter le cancer
WO2015119923A1 (fr) 2014-02-04 2015-08-13 Pfizer Inc. Combinaison d'un antagoniste de pd -1 et d'un agoniste de 4-1bb pour le traitement du cancer
WO2016000619A1 (fr) 2014-07-03 2016-01-07 Beigene, Ltd. Anticorps anti-pd-l1 et leur utilisation comme agents thérapeutiques et diagnostiques
WO2016032927A1 (fr) 2014-08-25 2016-03-03 Pfizer Inc. Combinaison d'un antagoniste de pd-1 et d'un inhibiteur d'alk dans le traitement du cancer
US9295717B2 (en) 2009-08-05 2016-03-29 Biontech Ag Vaccine composition comprising 5′-cap modified RNA
US20160108123A1 (en) 2014-10-14 2016-04-21 Novartis Ag Antibody molecules to pd-l1 and uses thereof
WO2016089873A1 (fr) 2014-12-02 2016-06-09 Celgene Corporation Traitements combinés
WO2016106160A1 (fr) 2014-12-22 2016-06-30 Enumeral Biomedical Holdings, Inc. Procédés de criblage de composés thérapeutiques
US9476055B2 (en) 2005-09-28 2016-10-25 Biontech Ag Modification of RNA, producing an increased transcript stability and translation efficiency
WO2016187508A2 (fr) * 2015-05-20 2016-11-24 The Broad Institute Inc. Néo-antigènes partagés
US20190071682A1 (en) 2015-10-07 2019-03-07 Biontech Rna Pharmaceuticals Gmbh 3'-UTR Sequences for Stabilization of RNA
WO2022069632A1 (fr) 2020-10-01 2022-04-07 BioNTech SE Préparation et stockage de formulations d'arn liposomal appropriées pour une thérapie

Patent Citations (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US6982321B2 (en) 1986-03-27 2006-01-03 Medical Research Council Altered antibodies
US5545807A (en) 1988-10-12 1996-08-13 The Babraham Institute Production of antibodies from transgenic animals
EP0404097A2 (fr) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1991010741A1 (fr) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation d'anticorps xenogeniques
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
WO1993001161A1 (fr) 1991-07-11 1993-01-21 Pfizer Limited Procede de preparation d'intermediaires de sertraline
WO1996033735A1 (fr) 1995-04-27 1996-10-31 Abgenix, Inc. Anticorps humains derives d'une xenosouris immunisee
WO1996034096A1 (fr) 1995-04-28 1996-10-31 Abgenix, Inc. Anticorps humains derives de xeno-souris immunisees
US6267958B1 (en) 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
WO1998024893A3 (fr) 1996-12-03 1998-08-20 Abgenix Inc MAMMIFERES TRANSGENIQUES POSSEDANT DES LOCI DE GENES D'IMMUNOGLOBULINE D'ORIGINE HUMAINE, DOTES DE REGIONS VH ET Vλ, ET ANTICORPS PRODUITS A PARTIR DE TELS MAMMIFERES
US6171586B1 (en) 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
US7087409B2 (en) 1997-12-05 2006-08-08 The Scripps Research Institute Humanization of murine antibody
US20050260186A1 (en) 2003-03-05 2005-11-24 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases
US20060104968A1 (en) 2003-03-05 2006-05-18 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases
US8178653B2 (en) 2003-10-14 2012-05-15 Biontech Ag Recombinant vaccines and use thereof
US8637006B2 (en) 2003-10-14 2014-01-28 Biontech Ag Recombinant vaccines and use thereof
WO2006044908A2 (fr) 2004-10-20 2006-04-27 Genentech, Inc. Formulations d'anticorps
WO2006121168A1 (fr) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Anticorps monoclonaux humains pour mort programmee 1 (mp-1) et procedes pour traiter le cancer en utilisant des anticorps anti-mp-1 seuls ou associes a d’autres immunotherapies
WO2007005874A2 (fr) 2005-07-01 2007-01-11 Medarex, Inc. Anticorps monoclonaux humains diriges contre un ligand de mort programmee de type 1(pd-l1)
US9476055B2 (en) 2005-09-28 2016-10-25 Biontech Ag Modification of RNA, producing an increased transcript stability and translation efficiency
US10106800B2 (en) 2005-09-28 2018-10-23 Biontech Ag Modification of RNA, producing an increased transcript stability and translation efficiency
US8153773B2 (en) 2007-06-19 2012-04-10 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Synthesis and use of anti-reverse phosphorothioate analogs of the messenger RNA cap
WO2009114335A2 (fr) 2008-03-12 2009-09-17 Merck & Co., Inc. Protéines de liaison avec pd-1
WO2010027827A2 (fr) 2008-08-25 2010-03-11 Amplimmune, Inc. Polypeptides co-stimulateurs ciblés et leurs procédés d'utilisation dans le traitement du cancer
US8217149B2 (en) 2008-12-09 2012-07-10 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
WO2010077634A1 (fr) 2008-12-09 2010-07-08 Genentech, Inc. Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t
US9295717B2 (en) 2009-08-05 2016-03-29 Biontech Ag Vaccine composition comprising 5′-cap modified RNA
WO2011066389A1 (fr) 2009-11-24 2011-06-03 Medimmmune, Limited Agents de liaison ciblés dirigés contre b7-h1
WO2011066342A2 (fr) 2009-11-24 2011-06-03 Amplimmune, Inc. Inhibition simultanée de pd-l1/pd-l2
US20130034559A1 (en) 2009-11-24 2013-02-07 Medlmmune Limited Targeted Binding Agents Against B7-H1
WO2011161699A2 (fr) 2010-06-25 2011-12-29 Aurigene Discovery Technologies Limited Composés modulateurs de l'immunosuppression
WO2012145493A1 (fr) 2011-04-20 2012-10-26 Amplimmune, Inc. Anticorps et autres molécules qui se lient à b7-h1 et à pd-1
US9205148B2 (en) 2011-04-20 2015-12-08 Medimmune, Llc Antibodies and other molecules that bind B7-H1 and PD-1
WO2012168944A1 (fr) 2011-06-08 2012-12-13 Aurigene Discovery Technologies Limited Composés thérapeutiques pour une immunomodulation
WO2013132317A1 (fr) 2012-03-07 2013-09-12 Aurigene Discovery Technologies Limited Composés peptidomimétiques utilisés comme immunomodulateurs
US20150086612A1 (en) 2012-03-26 2015-03-26 Biontech Ag RNA Formulation for Immunotherapy
WO2013144704A1 (fr) 2012-03-29 2013-10-03 Aurigene Discovery Technologies Limited Composés cycliques d'immunomodulation provenant de la boucle bc de pd1 humain
WO2013181634A2 (fr) 2012-05-31 2013-12-05 Sorrento Therapeutics Inc. Protéines liant un antigène qui lient pd-l1
WO2014179664A2 (fr) 2013-05-02 2014-11-06 Anaptysbio, Inc. Anticorps dirigés contre la protéine de mort programmée 1 (pd-1)
WO2014194302A2 (fr) 2013-05-31 2014-12-04 Sorrento Therapeutics, Inc. Protéines de liaison à l'antigène qui se lient à pd-1
WO2014206107A1 (fr) 2013-06-26 2014-12-31 上海君实生物医药科技有限公司 Anticorps anti-pd-1 et son utilisation
WO2015033301A1 (fr) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited Dérivés 1,3,4-oxadiazole et 1,3,4-thiadiazole servant d'immunomodulateurs
WO2015033303A1 (fr) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited Composés peptidomimétiques cycliques utilisés comme immunomodulateurs
WO2015033299A1 (fr) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited Dérivés 1,2,4-oxadiazole utilisés comme immunomodulateurs
WO2015036927A1 (fr) 2013-09-10 2015-03-19 Aurigene Discovery Technologies Limited Dérivés peptidomimétiques d'immunomodulation
WO2015035606A1 (fr) 2013-09-13 2015-03-19 Beigene, Ltd. Anticorps anti-pd1 et leur utilisation comme produits thérapeutiques et produits de diagnostic
WO2015044900A1 (fr) 2013-09-27 2015-04-02 Aurigene Discovery Technologies Limited Composés immunomodulateurs thérapeutiques
WO2015085847A1 (fr) 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Anticorps anti-pd-1, son fragment de liaison à l'antigène, et son application médicale
WO2015112805A1 (fr) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Anticorps humains dirigés contre pd-l1
WO2015112800A1 (fr) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Anticorps humains se liant à pd-1
US20150210769A1 (en) 2014-01-24 2015-07-30 Novartis Ag Antibody molecules to pd-1 and uses thereof
WO2015112900A1 (fr) 2014-01-24 2015-07-30 Dana-Farber Cancer Institue, Inc. Molécules d'anticorps anti-pd-1 et leurs utilisations
WO2015119923A1 (fr) 2014-02-04 2015-08-13 Pfizer Inc. Combinaison d'un antagoniste de pd -1 et d'un agoniste de 4-1bb pour le traitement du cancer
WO2015119930A1 (fr) 2014-02-04 2015-08-13 Pfizer Inc. Association d'un antagoniste du pd-1 et d'un inhibiteur du vegfr pour traiter le cancer
WO2016000619A1 (fr) 2014-07-03 2016-01-07 Beigene, Ltd. Anticorps anti-pd-l1 et leur utilisation comme agents thérapeutiques et diagnostiques
WO2016032927A1 (fr) 2014-08-25 2016-03-03 Pfizer Inc. Combinaison d'un antagoniste de pd-1 et d'un inhibiteur d'alk dans le traitement du cancer
US20160108123A1 (en) 2014-10-14 2016-04-21 Novartis Ag Antibody molecules to pd-l1 and uses thereof
WO2016061142A1 (fr) 2014-10-14 2016-04-21 Novartis Ag Molécules d'anticorps de pd-l1 et leurs utilisations
WO2016089873A1 (fr) 2014-12-02 2016-06-09 Celgene Corporation Traitements combinés
WO2016106160A1 (fr) 2014-12-22 2016-06-30 Enumeral Biomedical Holdings, Inc. Procédés de criblage de composés thérapeutiques
WO2016187508A2 (fr) * 2015-05-20 2016-11-24 The Broad Institute Inc. Néo-antigènes partagés
US20190071682A1 (en) 2015-10-07 2019-03-07 Biontech Rna Pharmaceuticals Gmbh 3'-UTR Sequences for Stabilization of RNA
WO2022069632A1 (fr) 2020-10-01 2022-04-07 BioNTech SE Préparation et stockage de formulations d'arn liposomal appropriées pour une thérapie

Non-Patent Citations (98)

* Cited by examiner, † Cited by third party
Title
"American Joint Committee on Cancer (AJCC) Cancer Staging Manual", 2011, SPRINGER
"International Nonproprietary Names for Pharmaceutical Substances", WHO DRUG INFORMATION, vol. 28, no. 1422185-06-5, 16 January 2015 (2015-01-16), pages 485
"NCBI", Database accession no. NC_012920
"Remington's Pharmaceutical Sciences", 1980
"Swiss-Prot", Database accession no. Q9NZQ7.1
ABOL-ENEIN ET AL.: "Neo-adjuvant chemotherapy in the treatment of invasive transitional bladder cancer: a controlled prospective randomised study.", BR J UROL, vol. 79, 1997, pages 174
ALEXANDROV ET AL.: "Signatures of mutational processes in human cancer", NATURE, vol. 500, 2013, pages 415 - 421, XP055251628, DOI: 10.1038/nature12477
APOLO, ABMILOWSKY MIKIM L ET AL.: "Eligibility and Radiologic Assessment in Adjuvant Clinical Trials in Bladder Cancer.", JAMA ONCOL, vol. 5, no. 12, 2019, pages 1790 - 8
BAJORIN ET AL.: "Adjuvant nivolumab versus placebo in muscle-invasive urothelial carninoma.", NEW ENGL J MED, vol. 384, 2021, pages 2102 - 14
BOERNER ET AL., J. IMMUNOL., vol. 147, no. 1, 1991, pages 86 - 95
BRAITEH ET AL.: "A phase Ia study to evaluate RO7198457, an individualized neoantigen specific immunotherapy (iNeST), in patients with locally advanced or metastatic solid tumors [abstract].", CANCER RES, vol. 80, 2020, pages CT169
BRAITEH F. ET AL: "Abstract CT169: A phase Ia study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in patients with locally advanced or metastatic solid tumors | Cancer Research | American Association for Cancer Research", CANCER RESEARCH, vol. 80, no. 16_Supplement, 15 August 2020 (2020-08-15), pages CT169 - CT169, XP093267457, ISSN: 0008-5472, Retrieved from the Internet <URL:https://aacrjournals.org/cancerres/article/80/16_Supplement/CT169/645309/Abstract-CT169-A-phase-Ia-study-to-evaluate> DOI: 10.1158/1538-7445.AM2020-CT169 *
BROWN ET AL.: "Neoantigens predicted by tumor genome meta analysis correlate with increased patient survival.", GENOME RES, vol. 106, 2014, pages dju244 - 50
BRUGGEMANN ET AL., YEAR IN IMMUNOL., vol. 7, 1993, pages 33
CHALASANI ET AL.: "Histologic variants of urothelial bladder cancer and nonurothelial histology in bladder cancer.", CAN UROL ASSOC J, vol. 3, 2009, pages 193 - 8
CLACKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628
COGNETTI ET AL.: "Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial.", ANN ONCOL, vol. 23, 2012, pages 695 - 700
COLE ET AL.: "Monoclonal Antibodies and Cancer Therapy", 1985, ALAN R. LISS, pages: 77
DE SANTIS ET AL.: "Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer ''unfit'' for cisplatin-based chemotherapy: phase II results of EORTC study 30986.", J CLIN ONCOL, vol. 27, 2009, pages 5634 - 9
DUECK ET AL., JAMA ONCOL, vol. 1, 2015, pages 1051 - 1059
DURAISWAMY ET AL.: "Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors.", CANCER RES, vol. 73, 2013, pages 3591 - 603, XP055218335, DOI: 10.1158/0008-5472.CAN-12-4100
FELLOUSE, PROC. NATL. ACAD. SCI. USA, vol. 101, no. 34, 2004, pages 12467 - 12472
FISHWILD ET AL., NATURE BIOTECHNOL., vol. 14, 1996, pages 826 - 851
FU ET AL.: "Preclinical evidence that PD 1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors.", CANCER RES, vol. 74, 2014, pages 4042 - 52, XP055166598, DOI: 10.1158/0008-5472.CAN-13-2685
GARON ET AL.: "Pembrolizumab for the treatment of non-small-cell lung cancer.", N ENGL J MED, vol. 372, 2015, pages 2018 - 28, XP055306209, DOI: 10.1056/NEJMoa1501824
GOLAY JOS�E ET AL: "Combined Anti-Cancer Strategies Based on Anti-Checkpoint Inhibitor Antibodies", ANTIBODIES, vol. 9, no. 2, 20 May 2020 (2020-05-20), CH, pages 17, XP093268162, ISSN: 2073-4468, DOI: 10.3390/antib9020017 *
GROSSMAN ET AL.: "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer.", N ENGL J MED, vol. 349, 2003, pages 859 - 66
GSCHWEND ET AL.: "Disease specific survival as endpoint of outcome for bladder cancer patients following radical cystectomy.", EUR UROL, vol. 41, 2002, pages 440 - 8
HAMERS-CASTERMAN ET AL., NATURE, vol. 363, 1993, pages 446 - 448
HAMMERLING ET AL.: "Monoclonal Antibodies and T-Cell Hybridomas", 1981, ELSEVIER, pages: 563 - 681
HARRIS, BIOCHEM. SOC. TRANSACTIONS, vol. 23, 1995, pages 1035 - 1038
HAUTMANN ET AL.: "Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients.", EUR UROL, vol. 61, 2012, pages 1039 - 47
HERBST ET AL.: "Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.", NATURE, vol. 515, 2014, pages 563 - 7, XP037922694, DOI: 10.1038/nature14011
HOLTKAMP ET AL.: "Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells.", BLOOD, vol. 108, 2006, pages 4009 - 4017, XP055044965, DOI: 10.1182/blood-2006-04-015024
HOLTKAMP, S. ET AL., BLOOD, vol. 108, 2006, pages 4009 - 4017
HONGO ET AL., HYBRIDOMA, vol. 14, no. 3, 1995, pages 253 - 260
HOOGENBOOMWINTER, J. MOL. BIOL., vol. 222, 1991, pages 581
HUDSON ET AL., NAT. MED., vol. 9, 2003, pages 129 - 134
HURLEGROSS, CURR. OP. BIOTECH., vol. 5, 1994, pages 428 - 433
JAKOBOVITS ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 2551 - 6448
JOHNSONWU: "Methods in Molecular Biology", vol. 248, 2003, HUMAN PRESS, pages: 1 - 25
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, PUBLIC HEALTH SERVICE, NATIONAL INSTITUTES OF HEALTH
KAUFMAN ET AL.: "Bladder cancer.", LANCET, vol. 374, 2009, pages 239 - 49
KOHLERMILSTEIN, NATURE, vol. 256, 1975, pages 495 - 97
KOZAK, M., J. MOL. BIOL., vol. 196, 1987, pages 947 - 950
KRANZ ET AL.: "Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy.", NATURE, vol. 534, 2016, pages 396 - 401, XP055565453, DOI: 10.1038/nature18300
KREITER ET AL.: "Mutant MHC class II epitopes drive therapeutic immune responses to cancer.", NATURE, vol. 520, 2015, pages 692 - 696, XP055231810, DOI: 10.1038/nature14426
KREITER, S. ET AL., J. IMMUNOL., vol. 180, 2008, pages 309 - 318
KUHN, A.N., GENE THER., vol. 17, 2010, pages 961 - 971
LE ET AL.: "PD-1 blockade in tumors with mismatch-repair deficiency.", N ENGL J MED, vol. 372, 2015, pages 2509 - 20, XP055390373, DOI: 10.1056/NEJMoa1500596
LEE ET AL., J. IMMUNOL. METHODS, vol. 284, no. 1-2, 2004, pages 119 - 132
LEOW ET AL.: "Upper tract urothelial carcinoma: a different disease entity in terms of management.", ESMO OPEN, vol. 1, 2017, pages e000126
LI ET AL., PROC. NATL. ACAD. SCI., vol. 103, 2006, pages 3557 - 3562
LONBERG ET AL., NATURE, vol. 368, 1994, pages 812 - 813
LONBERGHUSZAR, INTERN. REV. IMMUNOL., vol. 13, 1995, pages 65 - 93
LOPEZ ET AL.: "A phase Ib study to evaluate RO7198457, an individualized neoantigen-specific immunotherapy (iNeST), in combination with atezolizumab, in patients with locally advanced or metastatic solid tumors [abstract", CANCER RES, vol. 80, 2020, pages CT301
LOPEZ J. S. ET AL: "Abstract CT301: A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumab in patients with locally advanced or metastatic solid tumors | Cancer Research | American Association for Cancer Research", CANCER RESEARCH, vol. 80, no. 16_Supplement, 15 August 2020 (2020-08-15), pages CT301 - CT301, XP093267462, ISSN: 0008-5472, Retrieved from the Internet <URL:https://aacrjournals.org/cancerres/article/80/16_Supplement/CT301/645052/Abstract-CT301-A-phase-Ib-study-to-evaluate> DOI: 10.1158/1538-7445.AM2020-CT301 *
LORENTZEN CATHRINE LUND ET AL: "Clinical advances and ongoing trials of mRNA vaccines for cancer treatment", THE LANCET ONCOLOGY, vol. 23, no. 10, 7 October 2022 (2022-10-07), AMSTERDAM, NL, pages e450 - e458, XP093162232, ISSN: 1470-2045, Retrieved from the Internet <URL:https://pdf.sciencedirectassets.com/272203/1-s2.0-S1470204522X00119/1-s2.0-S1470204522003722/main.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjECMaCXVzLWVhc3QtMSJHMEUCIBjeoDiK297yNu457/IWbF5CMwDmNt1v5n7biYoLN1cmAiEAzqtsk6KPXq68BhSvnPx7uIIOH8HSFNK1sIZ25KErcHUqvAUIjP//////////ARAFGgwwNTkwMDM1NDY4NjUiDMGSs> DOI: 10.1016/S1470-2045(22)00372-2 *
MADERSBACHER ET AL.: "Radical cystectomy for bladder cancer today-a homogeneous series without neoadjuvant therapy.", J CLIN ONCOL, vol. 21, 2003, pages 690 - 6
MARKS ET AL., BIO/TECHNOLOGY, vol. 10, 1992, pages 779 - 783
MARKS ET AL., J. MOL. BIOL., vol. 222, 1992, pages 581 - 597
MEEKS ET AL.: "A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer.", EUR UROL, vol. 62, 2012, pages 523 - 33, XP028424715, DOI: 10.1016/j.eururo.2012.05.048
MORRISON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 81, 1984, pages 6851 - 6855
NADAL ET AL.: "Overview of current and future adjuvant therapy for muscle-invasive urothelial carcinoma.", CURR TREAT OPTIONS ONCOL, vol. 28, no. 19, 2018, pages 36
PATEL DIXITA M. ET AL: "A Comprehensive Review of Immunotherapy Clinical Trials for Metastatic Urothelial Carcinoma: Immune Checkpoint Inhibitors Alone or in Combination, Novel Antibodies, Cellular Therapies, and Vaccines", CANCERS, vol. 16, no. 2, 12 January 2024 (2024-01-12), CH, pages 335, XP093268166, ISSN: 2072-6694, DOI: 10.3390/cancers16020335 *
PAZ ARES ET AL.: "Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01study [abstract LBA4518].", J CLIN ONCOL, vol. 28, 2010, pages LBA4518
PETRELLI ET AL.: "Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis.", EUR UROL, vol. 65, 2014, pages 350 - 7
PRESTA, CURR. OP. STRUCT. BIOL., vol. 2, 1992, pages 593 - 596
RAGHAVAN ET AL.: "Biology and management of bladder cancer.", N ENGL J MED, vol. 322, 1990, pages 1129 - 38
RAMALINGAM ET AL.: "Abstract CT078: Tumor mutational burden (TMB) as a biomarker for clinical benefit from dual immune checkpoint blockade with nivolumab (nivo) + ipilimumab (ipi) in first-line (1L) non-small cell lung cancer (NSCLC): identification of TMB cutoff from CheckMate 568 [abstract", CANCER RES, vol. 78, 2018, pages CT078
RIECHMANN ET AL., NATURE, vol. 332, 1988, pages 323 - 329
RIZVI ET AL.: "Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.", SCIENCE, vol. 348, 2015, pages 124 - 8
ROJAS ET AL., NATURE, vol. 618, 2023, pages 144 - 50
ROJAS ET AL.: "Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.", NATURE, vol. 618, 2023, pages 144 - 150, XP093181724, Retrieved from the Internet <URL:https://doi.org/10.1038/s41586-023-06063-y> DOI: 10.1038/s41586-023-06063-y
ROSENBERG ET AL.: "Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherpay: a single-arm, multi centre, Phase 2 trial.", LANCET, vol. 387, 2016, pages 1909 - 20
ROSENBLATT ET AL.: "Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer.", EUR UROL, vol. 61, 2012, pages 1229 - 38
SHERIFF ET AL., NATURE STRUCT. BIOL., vol. 3, 1996, pages 733 - 736
SIDHU ET AL., J. MOL. BIOL., vol. 340, no. 5, 2004, pages 1073 - 1093
SNYDER ET AL.: "Genetic basis for clinical response to CTLA-4 blockade in melanoma.", N ENGL J MED, vol. 371, 2014, pages 2189 - 99, XP055262135, DOI: 10.1056/NEJMoa1406498
SONPAVDE: "Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium.", LANCET ONCOL, vol. 11, 2010, pages 861 - 70, XP027598727, DOI: 10.1016/S1470-2045(10)70086-3
STADLER ET AL.: "Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status.", J CLIN ONCOL, vol. 29, 2011, pages 3443 - 9
STEIN ET AL.: "Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients.", J CLIN ONCOL, vol. 19, 2001, pages 666 - 75
STENZL ET AL.: "The updated EAU guidelines on muscle-invasive and metastatic bladder cancer.", EUR UROL, vol. 55, 2009, pages 815 - 25, XP026002617, DOI: 10.1016/j.eururo.2009.01.002
STERNBERG ET AL.: "Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial.", LANCET ONCOL, vol. 16, 2015, pages 76 - 86
STERNBERG ET AL.: "Thoughts on a systematic review and meta-analysis of adjuvant chemotherapy in muscle-invasive bladder cancer.", EUR UROL, vol. 66, 2014, pages 55 - 6
SUN ET AL.: "Regulation and Function of the PD-L1 Checkpoint.", IMMUNITY, vol. 48, no. 3, 2018, pages 434 - 52, XP055649217, DOI: 10.1016/j.immuni.2018.03.014
TRAN EROBBINS PFLU YC ET AL., N ENGLJ MED, vol. 375, 2016, pages 2255 - 62
TUMEH ET AL.: "PD-1 blockade induces responses by inhibiting adaptive immune resistance.", NATURE, vol. 515, 2014, pages 568 - 71, XP055247294, DOI: 10.1038/nature13954
VALE: "Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data. Advanced Bladder Cancer (ABC) Meta-Analysis Collaboration.", EUR UROL, vol. 48, 2005, pages 189 - 201
VAN ALLEN ET AL.: "Genomic correlates of response to CTLA 4 blockade in metastatic melanoma.", SCIENCE, vol. 350, 2015, pages 207 - 11, XP055586974, DOI: 10.1126/science.aad0095
VAN DIJKVAN DE WINKEL, CURR. OPIN. PHARMACOL., vol. 5, 2001, pages 368 - 74
VAN ROOIJ ET AL.: "Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma.", J CLIN ONCOL, vol. 31, 2013, pages e439 - 42, XP055322802, DOI: 10.1200/JCO.2012.47.7521
VASWANIHAMILTON, ANN. ALLERGY, ASTHMA & IMMUNOL., vol. 1, 1998, pages 105 - 115
VERDEGAAL EMDE MIRANDA NFVISSER M ET AL., NATURE, vol. 536, 2016, pages 91 - 5
VERMA ET AL., NAT IMMUNOL., vol. 20, 2019, pages 1231 - 1243
VON DER MAASE: "Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.", J CLIN ONCOL, vol. 23, 2005, pages 4602 - 8
XU ET AL., IMMUNITY, vol. 13, 2000, pages 37 - 45
ZAPATA, PROTEIN ENG, vol. 8, no. 10, 1995, pages 1057 - 1062

Also Published As

Publication number Publication date
TW202539700A (zh) 2025-10-16

Similar Documents

Publication Publication Date Title
US11866509B2 (en) Humanized antibodies against CEACAM1
TWI872040B (zh) 用於癌症療法之ｒｎａ分子
TWI643633B (zh) 用於治療腫瘤之抗ｂ７－ｈ１抗體
JP2023511595A (ja) 抗ｔｉｇｉｔアンタゴニスト抗体を用いたがんを処置するための方法
JP2019517498A (ja) 再発性小細胞肺癌の処置方法において使用するための抗ｐｄ−１抗体
EP4559477A2 (fr) Compositions et méthodes de traitement du cancer
US20220378910A1 (en) Methods of inducing neoepitope-specific t cells with a pd-1 axis binding antagonist and an rna vaccine
KR20210034622A (ko) Pd-1 축 결합 길항제, 항 대사제, 및 백금 제제를 이용한 폐암 치료 방법
US20250367275A1 (en) Methods of treating pancreatic cancer with a pd-1 axis binding antagonist and an rna vaccine
US11427647B2 (en) Polynucleotides encoding humanized antibodies against CEACAM1
TW202539700A (zh) 用ｐｄ－１軸結合拮抗劑及ｒｎａ疫苗治療泌尿上皮癌之方法
US20240092934A1 (en) Assessment of ceacam1 expression on tumor infiltrating lymphocytes
RU2854990C2 (ru) Способы лечения рака с помощью связывающего ось pd-1 антагониста и рнк-вакцины
HK40121936A (zh) 用pd-1轴结合拮抗剂和rna疫苗治疗胰腺癌的方法
HK40080471A (en) Methods of treating cancer with pd-1 axis binding antagonists and rna vaccines
TW202320848A (zh) 治療癌症之方法及組成物
HK40119150A (zh) 用於治疗癌症的方法和组合物
CN116209466A (zh) 抗pd-1抗体在治疗鼻咽癌中的用途
HK40062147A (en) Methods of treating cancer with a pd-1 axis binding antagonist and an rna vaccine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25705726

Country of ref document: EP

Kind code of ref document: A1