WO2024258913A1 - Traitement de tumeurs solides avec un régime de thérapie par radionucléides ciblée et de thérapies à base de cellules immunitaires génétiquement modifiées - Google Patents

Traitement de tumeurs solides avec un régime de thérapie par radionucléides ciblée et de thérapies à base de cellules immunitaires génétiquement modifiées Download PDF

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WO2024258913A1
WO2024258913A1 PCT/US2024/033521 US2024033521W WO2024258913A1 WO 2024258913 A1 WO2024258913 A1 WO 2024258913A1 US 2024033521 W US2024033521 W US 2024033521W WO 2024258913 A1 WO2024258913 A1 WO 2024258913A1
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cell
cells
car
cancer
tumor
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Zachary MORRIS
Christian Capitini
Quaovi SODJI
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Wisconsin Alumni Research Foundation
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Wisconsin Alumni Research Foundation
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Priority to EP24824040.0A priority Critical patent/EP4727561A1/fr
Priority to KR1020257041993A priority patent/KR20260026491A/ko
Priority to IL325273A priority patent/IL325273A/en
Priority to CN202480054121.6A priority patent/CN121712515A/zh
Priority to AU2024303304A priority patent/AU2024303304A1/en
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    • 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
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/31—Chimeric antigen receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
    • A61K51/0408—Phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1092—Details
    • A61N2005/1096—Elements inserted into the radiation path placed on the patient, e.g. bags, bolus, compensators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1092—Details
    • A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device

Definitions

  • the present disclosure is related to methods of treating solid tumors with a combination of targeted radionuclide therapy and CAR T Cell therapy.
  • Chimeric antigen receptor (CAR) T cell therapy represents a form of genetically engineered T cell therapy that has revolutionized cancer immunotherapy.
  • a CAR is composed of an extracellular domain which includes an antigenbinding domain taken from the single-chain variable fragment (scFv) of an antibody, a transmembrane domain, an intracellular domain comprised of a T cell signaling domain (CD3-zeta) and costimulatory domains such as 0X40, 4- IBB or CD28.
  • scFv single-chain variable fragment
  • CD3-zeta T cell signaling domain
  • costimulatory domains such as 0X40, 4- IBB or CD28.
  • CAR T cells targeting CD 19, or B cell maturation antigen are FDA-approved for the treatment of relapsed/refractory B cell lymphoma/leukemia and multiple myeloma respectively, following high rates of complete responses during clinical trials.
  • CAR T cell therapy has not been effective against non-hematological solid tumors for numerous reasons including exhaustion, lack of infiltration into the immunosuppressive tumor microenvironment (TME), and decreased antigen expression by tumor cells.
  • TAE immunosuppressive tumor microenvironment
  • a method of treating a solid tumor in a subject comprises administering to the subject a low dose of a targeted radiotherapy (TRT) agent, waiting a period of 1 to 60 days, and after waiting, administering to the subject a modified immune cell such as CAR T cells, CAR NK cells, CAR macrophages, and the like.
  • TRT targeted radiotherapy
  • FIGs. 1 A-C show third generation virus-free CRISPR GD2 CAR T cells.
  • (1A) Schematic of the domains of the 3 rd generation CAR.
  • the extracellular domain includes the scFV (VH and VL chains connected by a linker) and a hinge.
  • the intracellular domain is comprised of 2 co-stimulatory domains (CD28 and 0X40) and a signaling domain (CD3- Zeta). These two domains are connected by a transmembrane domain (CD28 transmembrane domain).
  • IB Schematic of the GD2 CAR construct inserted into the human T cell receptor alpha constant gene (TRAC).
  • (1C) Schematic of the GD2 CAR T cell used experimentally. It expresses the GD2 CAR but is devoid of T cell receptor due to the CRISPR knockout of the human TRAC gene.
  • scFv single-chain variable fragment
  • VH heavy chain
  • VL Light chain.
  • FIGs. 2A-C show 7 dose-dependent effect of actinium-225 and lutetium- 177 on the viability of GD2 CAR T cells.
  • 2A Experimental scheme: GD2 CAR T cells yvere incubated in cell culture medium containing free 225 Ac or 177 Lu with activities calculated to deliver radiation dose between 1-6 Gy by day 3. CAR T cells were harvested, and their viability was analyzed by flow' cytometry using a live/ dead staining.
  • 2C Both 225 Ac and 177 Lu led to a dose-dependent CAR T cells death.
  • FIGs. 3A-B show dose-independent effect of actinium-225 and lutetium-177 on GD2 CAR T cell cytotoxicity.
  • 3 A Experimental scheme: After irradiation of CAR T cells by 225 Ac or 177 Lu, the CAR T cells were harvested and co-cultured with the GD2- expressing human neuroblastoma cell line CHLA-20 for 24 hrs. The viability of the CHLA- 20 cells was analyzed by flow cytometry’.
  • FIGs 4A- C show 225 Ac and 177 Lu enhance the cytotoxicity of GD2 CAR T cells against the GD-2 expressing melanoma cell line M21.
  • 4A The human melanoma cell line M21 expresses GD2.
  • 4B Experimental scheme: After irradiation of CAR T cells by 225 Ac or 177 LU, the CAR T cells were harvested and co-cultured with the GD2-expressing human melanoma cell line M21 for 24 hrs. The viability' of the M21 cells was analyzed by flow cytometry.
  • FIGs. 5A-D show actinium-225 and lutetium-177 does not impact the expression of exhaustion and activation markers on GD2 CAR T cells.
  • 5 A Experimental scheme: GD2 CAR T cells were incubated in cell culture medium containing free 225 Ac or 177 LU with activities calculated to deliver radiation dose between 1-6 Gy by day 3. CAR T cells were harvested, and the expression of exhaustion and activation markers was analyzed by flow cytometry.
  • 5B Almost all irradiated GD2 CAR T cells do not upregulate the expression of the T cell exhaustion marker PD-1.
  • 5C Irradiation does not result in a major impact on the activation marker NKG2D.
  • 5D Similarly, no major impact is seen on the expression of the T cell activation marker CD69.
  • FIG. 6 shows the combination TRT and GD2 CAR-T cell therapy controls tumor growth in a xenograft model of neuroblastoma.
  • FIGs 7A-E show B7-H3 tumor antigen targeting and LMD killing via CAR-T cell and potential synergy with radiation (radiopharmaceutical therapy (RPT) and external beam radiation therapy (EBRT)).
  • RPT radiopharmaceutical therapy
  • EBRT external beam radiation therapy
  • 7 A The targetable tumor CAR-T antigen B7-H3 is expressed in >95% of cells for multiple cancer lines (SK-N-AS: neuroblastoma, LMD-BR3: breast cancer LMD).
  • 7C B7-H3 intensity of expression on LMD-BR3 tumor cells is
  • FIG. 8A shows imaging of luciferase-expressing IV injected SK-N-AS human neuroblastoma in NRG mice at 27 days after treatment with anti-B7-H3 CAR-T cells (5xl0 6 , IV) and/or 177 Lu-NM600 (50 pCi, IV). Only combination treatment eradicates tumor.
  • 8B In NRG mice with BR3 LMD, B7-H3 CAR-T cells injected intrathecally (5 x 10 6 cells) and low dose 2 Gy craniospinal irradiation (CSI) EBRT reduce tumor growth vs untransduced T cells (UTD) or CAR-T cells alone. (*:p ⁇ 0.05; **:p ⁇ 0.01. In prior studies (not shown), EBRT alone up to 5 Gy does not significantly slow BR3 tumor growth. [0014]
  • modified immune cell therapy e.g., CAR T cell therapy (FIG. 1 A)
  • CAR T cell therapy has not been effective against non-hematological solid tumors.
  • TRT targeted radionuclide therapy
  • radioactive compounds are selectively delivered to malignant cells using tumor homing ligands.
  • TRT enables the systemic delivery of radiation to all sites of disease in patients with metastatic disease and has demonstrated a survival benefit in patients with castration-resistant prostate cancer.
  • emerging data suggests that low-dose radiation delivered by TRT elicits a favorable immune response by activating and enhancing the infiltration of endogenous T cells into the TM.
  • TRT may help overcome some of the shortcomings of modified immune cell therapy against non- hematological solid tumors.
  • T cell receptor alpha constant gene (TRAC) knocked into the T cell receptor alpha constant gene (TRAC) locus resulting in GD2 CAR T cells devoid of T cell receptors (FIG. 1C).
  • RT Radiation therapy
  • RT increases the expression of MHC-I on tumor cells, potentially facilitating tumor recognition by a patient’s own tumor-specific T cells.
  • poorly immunogenic tumors such as pediatric neuroblastoma
  • low tumor mutation burden translates to few tumor-associated neoantigens and limited potential for endogenous T cell recognition.
  • Targeted radionuclide therapy is a growing class of cancer therapeutics that selectively deliver RT to malignant cells in vivo using a tumor-selective ligand (small molecule or antibody) labeled with a radionuclide.
  • a tumor-selective ligand small molecule or antibody
  • RT is delivered to TMEs throughout the body with markedly less toxicity than whole-body RT.
  • STING/cGAS pathway By activating the STING/cGAS pathway, low-dose TRT stimulates a pro-inflammatory response that enhances endogenous T cell infiltration and activation in the TME of solid tumors.
  • Exemplary TRT agents include metaiodobenzylguanidine (MIBG), where the iodine atom in the MIBG is a radioactive iodine isotope; radiolabeled tumor-targeting antibodies; a radioactive isotope of radium, such as Ra-223; and radioactive phospholipid ether metal chelates having the formula:
  • Ri includes (a) a chelating agent that is chelated to a metal atom, wherein the metal atom is an alpha, beta or Auger emitting metal isotope with a half-life of greater than 6 hours and less than 30 days or (b) a radioactive halogen isotope; a is 0 or 1; n is an integer from 12 to 30; m is 0 or 1; Y is — H, — OH, — COOH, — COOX, — OCOX, or — OX, wherein X is an alkyl or an arylalkyl; R 2 is — N + H 3 — N + H 2 Z, — N + HZ 2 , or — N + Z 3 , wherein each Z is independently an alkyl or an aryl; and b is 1 or 2.
  • R 1 when R 1 is (a) a chelating agent that is chelated to a metal atom, wherein the metal atom is an alpha, beta or Auger emitting metal isotope with a half-life of greater than 6 hours and less than 30 days
  • metal isotopes that could be used include Sc-47, Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, Pb-212, and Th-227.
  • R 1 when R 1 is a (b) a radioactive halogen isotope, the radioactive halogen isotope is 123 I, 124 I, 125 I, 131 I, 211 At, 76 Br, or 77 Br.
  • a is 1 and m is 0.
  • n is 18.
  • R2 is — N + (CH3) 3 .
  • a is 1, m is 0, and n is 18.
  • the radioactive halogen isotope is 123 1, 124 1, 125 I, or 131 I
  • the radiohalogenated phospholipid ether is [ 123 I]-NM404, [ 124 I]-NM404, [ 125 I]-NM404, [ 131 I]-NM404, [ 211 At]-NM404, [ 76 Br]-NM404, or [ 77 Br]-NM404).
  • n is an integer from 12 to 30, and R 2 is — N + Z 3 , wherein each Z is independently an alkyl or an aryl: or (ii) m is 1, b is 1, n is an integer from 12 to 30, and R 2 is — N + Z 3 .
  • each Z is independently an alkyl or an aryl; or (iii) m is 0, b is 1, n is 18, and R 2 is — N + Z 3 , wherein each Z is independently an alkyl or an aryl; or (iv) m is 1, b is 1, n is 18, and R 2 is — N + Z 3 , wherein each Z is independently an alkyl or an aryl.
  • Exemplary chelating agents include 1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid (DO3A) or one of its derivatives; 1,4,7-triazacyclononane-l,4-diacetic acid (NODA) or one of its derivatives; 1,4,7-triazacyclononane-l,4,7-triacetic acid (NOTA) or one of its derivatives; 1,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid1 (D1OTA) or one of its derivatives; 1,4,7-triazacyclononane, 1 -glutaric acid-4, 7-diacetic acid (NODAGA) or one of its derivatives; 1,4,7,10-tetraazacyclodecane, 1-glutaric acid-4,7, 10-triacetic acid (DOTAGA) or one of its derivatives; 1,4,8,11-tetraazacyclotetradecane
  • a is 1 (aliphatic aryl-alkyl chain). In other embodiments, a is 0 (aliphatic alkyl chain). In some embodiments, m is 1 (acylphospholipid series). In some such embodiments, n is an integer between 12 and 20. In some embodiments, Y is — OCOX, — COOX or — OX. In some embodiments, X is — CH 2 CH 3 or — CH 3 . In some embodiments, m is 0 (alkylphospholipid series). In some embodiments, b is 1. In some embodiments, n is 18.
  • R 2 is — N + Z 3 .
  • each Z is independently — CH 2 CH 3 or — CH 3 .
  • each Z is — CH 3 .
  • the chelating agent chelated to the metal atom is:
  • the chelating agent chelated to the metal atom is:
  • the phospholipid ether metal chelate in the phospholipid ether metal chelate structure, a is 1, b is 1, m is 0, n is 18, and R 2 is — N-(CH 3 ) 3
  • the phospholipid ether metal chelate is NM600 chelated to the metal atom, such as (but not limited to) 90 Y- NM600.
  • NM600 with 64 Cu as the metal atom is shown below:
  • the TRT agent is metaiodobenzylguanidine (MIBG), where the iodine atom in the MIBG is a radioactive iodine isotope.
  • MIBG metaiodobenzylguanidine
  • the TRT agent is a radiolabeled tumor-targeting antibody.
  • exemplary radiolabeled tumor-targeting antibodies include 177 Lu-girentuximab, rosopatamab radiolabeled with yttrium-90 and lutetium-177, 131 I-labetuzumab, panitumumab conjugated to ⁇ -emitter, 212 Pb, 90 Y labeled anti-MUCl antibody, nti-TAG-72 intact antibodies radiolabeled with iodine-131, yttrium-90, and lutehum-177, 90 Y-clivatuzumab tetraxetan, 31 I-labeled mAb 81C6, and the like.
  • the TRT agent is a radioactive isotope of radium such as radium-223 dichloride.
  • Radionuclides are radioactive atoms and historically for TRT patients have been prescribed a given activity (unit curie, Ci), which is the rate of disintegration or radioactive decay. For research and mechanism-driven therapeutic approaches, however, it the absorbed dose (unit gray: Gy) of RT that will be administered from a given activity is determined. This is because absorbed dose, which is defined as the energy absorbed per unit mass of tissue, mediates the biological effects of radionuclides.
  • a low dose of TRT agent can be used.
  • the radiation doses (Gy) described herein for tumors implanted in mice should translate to humans because the tumors implanted were derived from human cancer cell lines.
  • the optimal radiation dose can vary from one tumor to the other, however, in general, a low dose of a TRT agent is a dose that is less than the typical dose used for TRT monotherapy, that is, the dose of TRT expected to kill tumor cells.
  • low dose TRT is administered at a dose that is less than 10 %, specifically less than 6% and more specifically less than 5% of the dose used to kill tumor cells, which can be as high as 36 Gy.
  • a low dose of a TRT agent provides a 1 to 6 Gy, specifically 1 to 3 Gy radiation dose for a human patient, including a child or an adult.
  • T cells typically interact with the target of their endogenous T cell receptor (TCR), enabling highly specific responses against peptides presented in the context of human leukocyte antigen (HLA).
  • TCR T cell receptor
  • HLA human leukocyte antigen
  • Immune cells like T cells can be engineered to bind novel antigens and targets by inserting a new receptor with the desired specificity.
  • Genetically modified immune cells include an extracellular domain comprising an antigen recognition domain linked to a first intracellular domain through a first transmembrane domain.
  • the antigen recognition domain is a monoclonal antibody-derived single-chain variable fragment (scFv) capable of targeting an antigen such as a specific tumor-associated antigen.
  • the immune cell is a T-cell, a Natural Killer (NK) cell, an innate lymphoid cell, a Cytokine Induced Killer (CIK) cell, a hematopoietic progenitor cell, a peripheral blood (PB) derived immune cell, a bone marrow derived immune cell, a macrophage, or an umbilical cord blood (UCB) derived immune cell.
  • the immune cell is an embryonic or induced pluripotent stem cell (iPSC)-derived immune cell.
  • the immune cells are modified autologous cells isolated from a patient in need of cancer treatment, or modified cells from an allogeneic healthy donor with intent to treat a patient with cancer.
  • the foregoing immune cells can be genetically engineered to express a CAR.
  • the immune cells may be isolated from subjects, particularly mammalian subjects such as human subjects and companion animals.
  • the immune cells can be obtained from a subject of interest, such as a subject suspected of having a particular disease or condition, a subject suspected of having a predisposition to a particular disease or condition, or a subject who is undergoing therapy for a particular disease or condition.
  • the immune cells may be enriched/purified from any tissue where they reside including, but not limited to, blood (including blood collected by blood banks or cord blood banks), spleen, bone marrow, tissues removed and/or exposed during surgical procedures, and tissues obtained via biopsy procedures.
  • Tissues/organs from which the immune cells are enriched, isolated, and/or purified may be isolated from both living and non-living subjects, wherein the non-living subjects are organ donors.
  • the isolated immune cells may be used directly, or they can be stored for a period of time, such as by freezing.
  • the population of immune cells can be obtained from a subject in need of therapy or suffering from a disease associated with reduced immune cell activity. Thus, the cells will be autologous to the subject in need of therapy.
  • the population of immune cells can be obtained from a donor such as an allogenic healthy donor.
  • the immune cell population can be harvested from PB, cord blood, bone marrow, spleen, or any other organ/tissue in which immune cells reside in said subject or donor.
  • the immune cells can be isolated from a pool of subjects and/or donors, such as from pooled cord blood.
  • the population of immune cells can be derived from iPSCs and/or any other stem cell known in the art.
  • the iPSCs and/or stem cells used to derive the population of immune cells can be obtained from a subject in need of therapy or suffering from a disease associate with reduced immune cell activity, thus these iPSCs and/or stem cells will be autologous to the subject in need of therapy.
  • the iPSCs and/or stem cells can be obtained from a healthy donor and therefore be allogeneic to the subject in need of therapy.
  • the donor is preferably allogeneic, provided the cells obtained are subject- compatible in that they can be introduced into the subject.
  • Allogeneic donor cells may or may not be human leukocyte antigen (HLA)-compatible.
  • HLA human leukocyte antigen
  • allogeneic cells can be treated to reduce immunogenicity.
  • Immune cells and human T cells can be edited such that a CAR is inserted into the genome randomly using a viral vector (retrovirus, lenti virus, AAV, etc.) or inserted into a targeted region in the genome of a T cell using non-viral approaches (electroporation, mRNA, lipid nanoparticle, etc.) coupled with CRISPR/Cas9, TALEN or Zinc finger nucleases.
  • the CAR can be inserted into an endogenous T cell receptor alpha subunit constant gene (TRAC), or an endogenous T cell receptor beta subunit constant gene (TRBC).
  • a CAR comprises an antigen-specific extracellular domain (e.g., a single chain variable fragment [scFV] that can bind a surface-expressed antigen of a malignancy) coupled to an intracellular domain (e.g., CD28, 1COS, CD27, 4-1BB, 0X40, CD40L, CD3- ⁇ , or a combination thereof) by a transmembrane domain (e.g., derived from a CD4, CD8, CD28, CH2CH3, NKG2D, IgG or CD3- ⁇ transmembrane domain).
  • an antigen-specific extracellular domain e.g., a single chain variable fragment [scFV] that can bind a surface-expressed antigen of a malignancy
  • an intracellular domain e.g., CD28, 1COS, CD27, 4-1BB, 0X40, CD40L, CD3- ⁇ , or a combination thereof
  • a transmembrane domain e.g
  • the antigen-specific extracellular domain can also include a spacer linking the Vh and VL chains of the scFV, which can be the hinge region of IgGl and is sufficient for most scFv-based constructs.
  • the antigen-specific extracellular domain of a CAR recognizes and specifically binds an antigen, typically a surface-expressed antigen of a malignancy.
  • An antigen-specific extracellular domain specifically binds an antigen when, for example, it binds the antigen with an affinity constant or affinity of interaction (KD) between about 0. 1 pM to about 10 pM, specifically about 0.1 pM to about 1 ⁇ M, more specifically about 0. 1 pM to about 100 nM.
  • KD affinity constant or affinity of interaction
  • An antigen-specific extracellular domain suitable for use in a CAR may be any antigen- binding polypeptide, one or more scFv, or another antibody based recognition domain (cAb VHH (camelid antibody variable domains) or humanized versions thereof, IgNAR VH (shark antibody variable domains) and humanized versions thereof, sdAb VH (single domain antibody variable domains) and "‘camelized” antibody variable domains are suitable for use.
  • T cell receptor (TCR) based recognition domains such as single chain TCR may be used as well as ligands for cytokine receptors.
  • the present disclosure provides chimeric antigen receptors (CARs) that bind to an antigen of interest.
  • the CAR binds to a tumor antigen.
  • Any tumor antigen (antigenic peptide) can be used in the tumor-related embodiments described herein.
  • Sources of antigen include, but are not limited to, cancer proteins.
  • the antigen can be expressed as a peptide or as an intact protein or portion thereof. The intact protein or a portion thereof can be native or mutagenized.
  • Non-limiting examples of tumor antigens that are CAR targets include carbonic anhydrase IX (CAIX), carcinoembryonic antigen (CEA), CD8, CD7, CD10, CD19, CD20, CD22, CD30, CD33, CLL1, CD34, CD38, CD41, CD44, CD49f, CD56, CD74, CD133, CD138, CD123, CD44V6, an antigen of a cytomegalovirus (CMV) infected cell (e.g., a cell surface antigen), epithelial glycoprotein-2 (EGP-2), epithelial glycoprotein-40 (EGP-40), epithelial cell adhesion molecule (EpCAM), receptor tyrosine-protein kinases erb-B2,3,4 (erb-B2,3,4), folate-binding protein (FBP), fetal acetylcholine receptor (AChR), adult AChR subunits, folate receptor-a, Ganglioside G2 (GD2), Gan
  • the intracellular domain transmits the T cell activation signal.
  • the intracellular domain can increase CAR T cell cytokine production and facilitate T cell replication.
  • the intracellular domain reduces CAR T cell exhaustion, increases T cell antitumor activity, and enhances survival of CAR T cells in patients.
  • Exemplary intracellular domains comprise co-stimulatory domains, including those from CD27, CD28, CD137 or 4- IBB, CD154 or CD40L, CD244 or 2B4, CD278 or ICOS, CD134 or 0X40, CD3- ⁇ and combinations thereof, and signaling domains (also called cytotoxicity domains), including those from CD16, DAP10, DAP12, CD28, ICOS, CD27, 0X40, CD40L, CD3- ⁇ , and combinations thereof.
  • a costimulatory domain is derived from the intracellular signaling domains of costimulatory proteins that enhance cytokine production, proliferation, cytotoxicity, and/or persistence in vivo.
  • the antigen-specific extracellular domain is linked to the intracellular domain of the CAR by a transmembrane domain, e.g., derived from a CD4, CD8, CD28, CH2CH3 or NKG2D, IgG or CD3- ⁇ transmembrane domain.
  • the transmembrane domain traverses the cell membrane, anchors the CAR to the T cell surface, and connects the extracellular domain to the intracellular signaling domain, thus impacting expression of the CAR on the T cell surface.
  • CARs may also further comprise one or more spacers.
  • a spacer or hinge connects (i) the antigen-specific extracellular domain to the transmembrane domain, (ii) the transmembrane domain to a costimulatory domain, (Hi) a costimulatory domain to the intracellular domain, and/or (iv) the transmembrane domain to the intracellular domain.
  • a spacer domain e.g., IgGl, IgG2, IgG4, CD28, CD8
  • Suitable transmembrane domains, costimulatory domains, and spacers are known in the art.
  • the CAR comprises a tumor antigen binding domain that targets Ganglioside G2 (GD2), coupled to a transmembrane domain from CD8, CD28, CH2CH3 or NKG2D, coupled to an intracellular domain comprising a costimulatory domain from CD27, CD28, CD137, CD154, CD244, CD278, or a combination thereof, and a cytotoxicity domain from CD3 ⁇ , DAP 10, DAP 12, CD 16, or a combination thereof.
  • GD2 Ganglioside G2
  • the CAR can be inserted into the genome of the unmodified T cells using viral or non-viral methods.
  • the viral vectors include retroviruses (including lenti virus), adenovirus and adeno-associated virus. Production of CAR T cells using viral methods to insert the CAR are well-known in the art. Methods of making non-viral CAR T cell products are described in US2020/0000851; WO2021/173925 and WO2023/023635, incorporated herein by reference for their disclosure of making non-viral CAR T cell products.
  • Unmodified T cells include autologous T cells that are collected from a patient, such as a cancer patient, by peripheral blood draw or leukapheresis. Unmodified T cells can also include T cells from allogeneic healthy donors or induced pluripotent stem cells which can be used to produce universal T cells for administration to a patient. T cells are generally modified ex vivo, that is outside of the patient, and then the modified T cells such as CAR T cells are returned to the patient, such as by intravenous infusion, subcutaneous, intratumoral, intraperitoneal or intracerebral ventricular injection.
  • a Cas9 RNP and a non-viral double-stranded HDR template including the CAR are introduced into the unmodified T cells by electroporation to provide genome-edited T cells comprising the CAR.
  • Genome editing of the T cells can employ a CRISPR system, or Cas9 ribonucleoprotein.
  • CRISPR refers to the Clustered Regularly Interspaced Short Palindromic Repeats type II system used by bacteria and archaea for adaptive defense. This system enables bacteria and archaea to detect and silence foreign nucleic acids, e.g., from viruses or plasmids, in a sequence-specific manner.
  • guide RNA interacts with Cas9 and directs the nuclease activity of Cas9 to target DNA sequences complementary to those present in the guide RNA.
  • Guide RNA base pairs with complementary sequences in target DNA. Cas9 nuclease activity then generates a double-stranded break in the target DNA.
  • a method of treating a solid tumor in a subject comprises administering to the subject a low dose of a targeted radiotherapy ⁇ (TRT) agent, waiting a period of 1 to 60 days, and after waiting, administering to the subject a modified immune cell (e.g., chimeric antigen receptor (CAR) T cell) therapy.
  • TRT targeted radiotherapy ⁇
  • CAR chimeric antigen receptor
  • a modified immune cell for use in a method of treating a solid tumor in a subject, wherein the method comprises administering to the subject a low dose of a TRT agent, waiting a period of 1 to 60 days, and after waiting, administering to the subject the modified immune cell therapy.
  • a modified immune cell for use in a method of treating a solid tumor in a subject, the method comprising administering to the subject the modified immune cell, wherein the subject has been administered a low dose of a TRT agent 1 to 60 days prior to the administration of the modified immune cell.
  • a modified immune cell e.g., a CAR T cell
  • the method comprises administering to the subject a low dose of a TRT agent, waiting a period of 1 to 60 days, and after waiting, administering to the subject the modified immune cell.
  • the time period for waiting between therapies is based on the half-life of the TRT agent and the starting radiation dose. Because the TRT is expected to decrease the viability of the CAR T cells, the waiting period is an important part of the method. Exemplary waiting periods include 1 to 60 days, 1 to 30 days, 2 to 30 days, 2 to 20 days, 2 to 12 days, 3 to 10 days, 3 to 9 days or 3 to 6 days.
  • the subject is a mammalian subject, specifically a human or canine subject.
  • Non-limiting examples of the cancers presenting as malignant solid tumors include melanoma, neuroblastoma, lung cancer, adrenal cancer, colon cancer, colorectal cancer, ovarian cancer, prostate cancer, renal cell carcinoma, non-small cell lung cancer, head or neck cancer, bladder cancer, hepatocellular carcinoma, spinal chordoma, cholangiocarcinoma, liver cancer, subcutaneous cancer, squamous cell cancer of the skin or head and neck, intestinal cancer, retinoblastoma, cervical cancer, glioma, breast cancer, pancreatic cancer, soft tissue sarcomas, Ewings sarcoma, rhabdomyosarcoma, osteosarcoma, retinoblastoma, Wilms' tumor, medulloblastoma, ependymoma, pineoblastoma, peripheral neuroectodermal tumor, or germ cell tumor.
  • the disclosure is inclusive of the compounds described herein (including intermediates) in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), tautomers, salts, solvates, polymorphs, prodrugs, and the like. It should be understood that the term “compound’’ includes any or all of such forms, whether explicitly stated or not (although at times, “salts’” may be explicitly stated).
  • “Pharmaceutically acceptable” as used herein means that the compound or composition or carrier is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the necessity of the treatment.
  • the term “effective amount,” as used herein, refers to the amount of the compounds or dosages that will elicit the biological or medical response of a subject, tissue or cell that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • pharmaceutically-acceptable carrier includes any and all dry powder, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like.
  • Pharmaceutically-acceptable carriers are materials, useful for the purpose of administering the compounds in the method of the present invention, which are preferably non-toxic, and may be solid, liquid, or gaseous materials, which are otherwise inert and pharmaceutically acceptable, and are compatible with the compounds described herein.
  • Such carriers include, without limitation, various lactose, mannitol, oils such as com oil, buffers such as PBS, saline, polyethylene glycol, glycerin, polypropylene glycol, dimethylsulfoxide, an amide such as dimethylacetamide, a protein such as albumin, and a detergent such as Tween 80, mono- and oligopolysaccharides such as glucose, lactose, cyclodextrins and starch.
  • oils such as com oil
  • buffers such as PBS, saline
  • polyethylene glycol such as glycerin
  • polypropylene glycol dimethylsulfoxide
  • dimethylsulfoxide dimethylsulfoxide
  • an amide such as dimethylacetamide
  • a protein such as albumin
  • a detergent such as Tween 80
  • mono- and oligopolysaccharides such as glucose, lactose, cyclodextrins and starch
  • '‘administering” or '‘administration,” as used herein, refers to providing the compound or pharmaceutical composition of the invention to a subject suffering from or at risk of the diseases or conditions to be treated or prevented.
  • a route of administration in pharmacology is the path by which a drug is taken into the body.
  • Routes of administration may be generally classified by the location at which the substance is applied. Common examples may include oral and intravenous administration. Routes can also be classified based on where the target of action is. Action may be topical (local), enteral (system-wide effect, but delivered through the gastrointestinal tract), or parenteral (systemic action, but delivered by routes other than the GI tract), via lung by inhalation.
  • One form of local administration is intratumoral (IT), whereby an agent is injected directly into, or adjacent to, a known tumor site.
  • a topical administration emphasizes local effect, and substance is applied directly where its action is desired. Sometimes, however, the term topical may be defined as applied to a localized area of the body or to the surface of a body part, without necessarily involving target effect of the substance, making the classification rather a variant of the classification based on application location.
  • the desired effect is systemic (non-local), substance is given via the digestive tract.
  • the desired effect is systemic, and substance is given by routes other than the digestive tract.
  • parenteral administrations may include intravenous (into a vein), e.g. many drugs, total parenteral nutrition intra-arterial (into an artery), e.g., vasodilator drugs in the treatment of vasospasm and thrombolytic drugs for treatment of embolism, intraosseous infusion (into the bone marrow), intra-muscular, intracerebral (into the brain parenchyma), intracerebroventricular (into cerebral ventricular system), intrathecal (an injection into the spinal canal), and subcutaneous (under the skin).
  • intraosseous infusion is, in effect, an indirect intravenous access because the bone marrow drains directly into the venous system.
  • Intraosseous infusion may be occasionally used for drugs and fluids in emergency medicine and pediatrics when intravenous access is difficult.
  • GD2 CAR T cells The virus-free CRISPR GD2 CAR T cells were manufactured as previously described in Mueller et al. 2022 J Immunother Cancer, 2022;10:e004446. doi: 10. 1136/jitc-2021 -004446 and cultured in ImmunoCult TM -XF T cell Expansion Medium supplemented with 500 U/rnL of IL-2 (Peprotech) and maintained 37 °C in 5% CO 2 .
  • TLDs Thermoluminescent dosimeters
  • the mean absorbed dose to cells was calculated using the Geant4 Monte Carlo toolkit and using an extension of RAPID.
  • a model of a flat bottom 6-well plate has been developed in Geant4 using manufacturing specifications where the diameter of each well is 36 mm, and the height of each well is 10.7 mm.
  • the cell volume can be defined as a thin water-equivalent layer at the bottom of the well.
  • In vitro GD2 CAR T cell irradiation The GD2 CAR T cells were irradiated with various doses of radiation delivered over 3 days by 177 Lu or 225 Ac diluted in 3 mL of ImmunoCultTM-XF T cell Expansion Medium. Doses of radiation delivered by 177 Lu were 1, 2 and 6 Gy whereas with 225 Ac, 1 and 2 Gy were delivered.
  • Flow cytometry Cells were harvested, washed with PBS, and resuspended into single cell solution in PBS as previously reported in the art. Fc blocking (Biolegend, 422302) and Live/Dead staining with Ghost DyeTM Red 780 (Tonbo Biosciences, 13-0865- T100) were performed for 10 minutes at 4°C.
  • the fluorophore-conjugated antibodies including anti-CD45-APC (Biolegend, 304012), anti-GD2-PE-Dazzle584 (Biolegend, 357320), anti-PD-l-PE (Biolegend, 329906), anti-CD69-BV510 (Biolegend, 310936), anti- NKG2D-BV605 (Biolegend, 320832) were incubated for 20 minutes at 4°C and washed with 2% FBS in PBS. The analysis of the sample was performed using the AttuneTM NxT Flow Cytometer (ThermoFisher) and the collected data was analyzed using FlowJo software.
  • EXAMPLE 1 RADIATION DELIVERED BY 177 Lu AND 225 Ac RESULTS IN A DOSE DEPENDENT GD2 CAR T CELL DEATH
  • EXAMPLE 2 RADIATION DELIVERED BY 177 Lu AND 225 Ac ENHANCES THE CYTOTOXIC ACTIVITY OF GD2 CAR T CELLS AGAINST THE GD2-EXPRESSING NEUROBLASTOMA CELL LINE CHLA-20
  • the impact of such radiation on the effector function of the GD2 CAR T cells was also determined.
  • the GD2 CAR T cells were co-cultured with the GD2-expressing neuroblastoma cell line CHLA-20 for 24 hrs.
  • the killing potential of the irradiated GD2 CAR T cells was determined by measuring the viability of CHLA-20 cells by flow cytometry (FIG. 3A).
  • the viable CHLA-20 cells were identified as CD45 negative and live/dead stain (Ghost DyeTM Red) negative (CD45-/ ghost DyeTM Red -).
  • non-irradiated GD2 CAR T cells displayed a potent cytotoxicity activity against CHLA-20 cells.
  • the viability of the CHLA-20 cells decreased to 6.9% after a 24 hrs. co-culture with GD2 CAR T cells compared to 52.2% in the absence of GD2 CAR T cells (FIG. 3B).
  • the irradiation of GD2 CAR T cells prior to co-culture with CHLA-20 cells enhanced their cytotoxic activity of the CAR T cells, resulting in a near complete eradication of CHLA-20 cells (FIG. 3B).
  • the enhanced cytotoxicity of the GD2 CAR T cell was independent of the type of particle emitted (a vs p particle) and radiation dose delivered (FIG. 3B).
  • the radiation-induced enhancement of GD2 CAR T cell cytotoxic activity was also observed against the human melanoma cell line M21 which also expresses GD2 (FIG. 4A-C).
  • EXAMPLE 3 RADIATION DELIVERED BY 177 Lu AND 225 Ac DOES NOT IMPACT THE EXPRESSION OF EXHAUSTION AND ACTIVATION MARKERS ON GD2 CAR T CELLS
  • TRT Due to the increasing therapeutic role of TRT in the clinical management of cancer and its immunostimulatory effects at low dose, the combination of TRT with CAR T cell therapy represents a therapeutic approach for selected patients with metastatic solid tumor.
  • ⁇ -emitters due to their higher LET (50-230 keV/ ⁇ m), induce 10-20 double strand DNA breaks (DSB) per 10 ⁇ m resulting in potent cytotoxicity, whereas ⁇ -emitters induce more single strand DNA breaks which are easily repaired.
  • a-particle emiters induce multiple DSBs that are in close vicinity resulting in the depletion of p53-binding protein 1 (53BP1), a DNA damage response protein, required for double strand DNA breaks.
  • p53-binding protein 1 p53-binding protein 1
  • Such depletion leads to insufficient amount of 53BP1 to adequately repair all DSBs, further accentuating the biological effectiveness of high LET a-particle emitters.
  • the low dose of radiation tested herein (1 or 2 Gy) delivered by a-emitter might not be ideal for a potential therapeutic combination with CAR T cells, making ⁇ -emitters the preferred candidates. Instead, 1 Gy delivered by a ⁇ - particle emitter may be ideal because all other radiation doses evaluated (2 or 6 Gy) enhanced CAR T cell cytotoxic function to the same extent while inducing higher rates of GD2 CAR T cell death.
  • This study provides the answers to key questions such as the optimal dose of radiation, type of radionuclide, timing and sequence of combination and enable the rational design of in vivo studies evaluating the combination of CART cell therapy and TRT.
  • the tumor volume was monitored until euthanasia is performed when tumor reaches 1500 mm 3 or ulceration is noted.
  • CART cells have had limited success against solid tumors. In patients with metastatic disease, it is not possible to irradiate all sites of disease with EBRT. TRT can irradiate all of sites of disease but at low doses is likely to be ineffective as a single agent. Giving TRT followed by CART cells can significantly enhance killing of metastatic solid tumors without impacting CART viability or proli feration.
  • LMD cerebrospinal fluid
  • CSF cerebrospinal fluid
  • LMD leptomeningeal disease
  • CSF cerebrospinal fluid
  • medulloblastoma the risk of CSF spread is sufficiently high that preemptive treatment is necessitated.
  • CSI cerebral irradiation
  • CSI EBRT In children, CSI EBRT additionally leads to stunting of grow th and cognitive impairment that can be severe. These toxicities arise because CSI EBRT treats not only the CSF space where LMD is located but also the entire brain, spinal cord, and vertebral bodies. This radiation of normal tissues leads to long-term permanent toxicities that compromise quality of life for survivors. Thus, there is enormous need for a new therapeutic approach that can effectively treat LMD with greater specificity and potency to eliminate cancer cells while minimizing effects on normal tissues around the CSF.
  • the methods described herein can provide effective and less toxic treatments for patients with LMD or high risk of CSF dissemination of cancer.
  • intrathecal delivery of a novel radiopharmaceutical therapy (RPT) will enable more effective delivery' of radiation to LMD while reducing toxicity by minimizing radiation of normal tissues compared to CSI EBRT.
  • RPT radiopharmaceutical therapy
  • CAR-T cell therapy will overcome the limitations of intrathecal administration of RPT alone.
  • CAR-T cells are standardly used for treatment of hematologic cancers, but have not yet proven effective against bulky solid tumors because of limited infiltration, activation, and persistence in established tumor microenvironments (TME).
  • EBRT can enhance the infiltration and expansion of CART cells in the TME of brain tumors in murine models, resulting in a potent and durable antitumor response mediated in part by the CAR T cells.
  • Increased CAR-T cell killing activity can be achieved without inducing exhaustion markers in vitro when tumor cells are treated with RPT.
  • RPT By immunomodulating the TME of tumor sites, generating inflammation in the TME, and increasing tumor cell susceptibility to CAR-T cell killing, it is hypothesized that RPT will exhibit cooperative therapeutic efficacy in conjunction with CAR-T cells.
  • the small absolute volume of disease in settings of LMD could be particularly well targeted by such a combination.
  • intrathecal CAR-T cells may encounter fewer inhibitory components of the host immune system in the CSF relative to blood as treatment via this route has yielded among the most promising clinical results to date against solid tumors.
  • these clinical studies demonstrate safety of intrathecal administration of CAR-T cells with limited and manageable toxicities.
  • B7-H3 tumor-specific antigen expression in cancer and CAR-T cell targeting is an immune checkpoint that is overexpressed on the cell surface of tumor cells in pediatric brain cancers, neuroblastoma, melanoma, sarcomas, and a variety of other cancers, yet B7-H3 has little to no expression on normal tissues.
  • B7-H3 is a is a pan-cancer antigen for targeting multiple forms of cancer with one CAR-T cell product. Nearly uniform cell surface expression of B7-H3 on the human BR3 LMD breast cancer cell line and the human SK-N-AS neuroblastoma cell line was observed by flow cytometry (FIG. 7A).
  • CAR-T cell targeting of B7-H3 + cancers CAR-T cells targeting human B7- H3 demonstrate preclinical efficacy against microscopic disease in neuroblastoma, medulloblastoma, and other xenograft tumor models in immunodeficient mice.
  • the B7-H3 CAR-T cells were designed as second-generation CD8H/Tm-CD28-CD3 ⁇ (28 ⁇ ) CAR format comprising the CD8a H/Tm sequences and CD28 and CD3£ signaling domains.
  • These B7- H3 CAR-T cells induced rapid and robust killing of LMD BR3 cells in vitro, compared to minimal or no killing from untransduced (UTD) control T cells (FIG. 7B).
  • Radiation promotes anti -tumor activity of anti-B7-H3 CAR-T cells.
  • the inflammatory effects of radiation including EBRT and RPT, promote tumor cell upregulation of cell surface expression of various immune checkpoint receptors.
  • EBRT and RPT promote tumor cell upregulation of cell surface expression of various immune checkpoint receptors.
  • B7-H3 CAR-T cell efficacy can be dependent upon high target antigen density on the surface of tumor cells. Induction of tumor cell surface expression of B7-H3 could be a mechanism for synergy between RPT and anti-B7-H3 CAR-T cells.
  • mice receiving a combination of anti-B7-H3 CAR-T cells and low dose CSI EBRT exhibit reduced LMD burden compared to UTC or CAR-T cell alone controls (FIG. 8B).

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Abstract

L'invention concerne une méthode de traitement d'une tumeur solide chez un sujet comprenant l'administration au sujet d'une faible dose d'un agent de radiothérapie ciblée (TRT), l'attente d'une période de 1 à 60 jours, et après l'attente, l'administration au sujet d'une thérapie par lymphocytes T à récepteur antigénique chimérique (CAR).
PCT/US2024/033521 2023-06-16 2024-06-12 Traitement de tumeurs solides avec un régime de thérapie par radionucléides ciblée et de thérapies à base de cellules immunitaires génétiquement modifiées Ceased WO2024258913A1 (fr)

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KR1020257041993A KR20260026491A (ko) 2023-06-16 2024-06-12 표적 방사성 핵종 치료 및 유전자 조작 면역 세포 치료의 용법에 의한 고형 종양의 치료
IL325273A IL325273A (en) 2023-06-16 2024-06-12 Treatment of solid tumors with a regimen of targeted radionuclide therapy and genetically engineered immune cell therapies
CN202480054121.6A CN121712515A (zh) 2023-06-16 2024-06-12 用靶向放射性核素疗法和基因工程化免疫细胞疗法的方案治疗实体瘤
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Citations (5)

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US20180153974A1 (en) * 2014-12-19 2018-06-07 The Trustees Of The University Of Pennsylvania Combination Therapies With Recombinant Listeria Strains
WO2019094657A1 (fr) * 2017-11-10 2019-05-16 Wisconsin Alumni Research Foundation Utilisation d'une radiothérapie ciblée (trt) en vue de déclencher une réponse immunitaire antitumorale à des immunothérapies
US20210309757A1 (en) * 2018-07-24 2021-10-07 Beijing Meikang Geno-Immune Biotechnology Co. Ltd. Gd2-based chimeric antigen receptor and application thereof
WO2022076743A1 (fr) * 2020-10-07 2022-04-14 Board Of Regents, The University Of Texas System Induction par rayonnement à faible dose de cibles de cellules cancéreuses pour une thérapie cellulaire ou à base de petites molécules
US20220202967A1 (en) * 2019-04-25 2022-06-30 Actinium Pharmaceuticals, Inc. Compositions and methods of immunodepletion for the treatment of malignant and non-malignant hematological diseases

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US20180153974A1 (en) * 2014-12-19 2018-06-07 The Trustees Of The University Of Pennsylvania Combination Therapies With Recombinant Listeria Strains
WO2019094657A1 (fr) * 2017-11-10 2019-05-16 Wisconsin Alumni Research Foundation Utilisation d'une radiothérapie ciblée (trt) en vue de déclencher une réponse immunitaire antitumorale à des immunothérapies
US20210309757A1 (en) * 2018-07-24 2021-10-07 Beijing Meikang Geno-Immune Biotechnology Co. Ltd. Gd2-based chimeric antigen receptor and application thereof
US20220202967A1 (en) * 2019-04-25 2022-06-30 Actinium Pharmaceuticals, Inc. Compositions and methods of immunodepletion for the treatment of malignant and non-malignant hematological diseases
WO2022076743A1 (fr) * 2020-10-07 2022-04-14 Board Of Regents, The University Of Texas System Induction par rayonnement à faible dose de cibles de cellules cancéreuses pour une thérapie cellulaire ou à base de petites molécules

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