WO2020161535A1 - Préparation d'un vaccin polyclonal contre le cancer pour une immunothérapie personnalisée - Google Patents

Préparation d'un vaccin polyclonal contre le cancer pour une immunothérapie personnalisée Download PDF

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WO2020161535A1
WO2020161535A1 PCT/IB2019/058411 IB2019058411W WO2020161535A1 WO 2020161535 A1 WO2020161535 A1 WO 2020161535A1 IB 2019058411 W IB2019058411 W IB 2019058411W WO 2020161535 A1 WO2020161535 A1 WO 2020161535A1
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cells
tumor
xct
polyclonal
cancer
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Rajesh Kumar GANDHIRAJAN
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    • 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
    • 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
    • A61K2039/80—Vaccine for a specifically defined cancer
    • A61K2039/876—Skin, melanoma

Definitions

  • the present invention relates to immunotherapy of cancer. Specifically, the present invention relates to polyclonal vaccines and their method of preparation. The present invention further relates to a method of preparation of polyclonal vaccines, applicable against all leukemic and solid tumors.
  • Cancer is a stepwise evolution of malignant cells with acquired failures to halt disease progression.
  • the incidence of cancer continues to rise with 14.1 million new cases every year.
  • somatic driver mutations leading to molecular classification of tumor types.
  • Detection of relevant somatic mutations driving the growth and progression of tumors has led to development of small molecules and antibody therapies that has improved clinical outcome.
  • a subset of patients with aggressive disease develop resistance to all existing therapies (radiotherapy, chemotherapy antibody therapy and small molecule therapy) leading to fatality. This could be due to the clonal evolution of tumors leading to resistance to therapy by accumulation of novel somatic driver mutations.
  • Immunotherapy is a cancer treatment intended to make the body’s immune system able to detect and destroy cancer cells.
  • Immune checkpoint inhibitors have been a successful approach because it pushes the immune system into high gear to fight cancer.
  • Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer and are rapidly transforming the practice of medical oncology. Whereas cytotoxic chemotherapy and small molecule inhibitors largely act on cancer cells directly, immune checkpoint inhibitors reinvigorate anti-cancer immune responses by disrupting co-inhibitory T- cell signaling.
  • Immune checkpoint inhibitor therapy has been particularly successful in melanoma, on-small cell lung cancer, renal cell carcinoma, bladder cancer, head and neck squamous cell carcinoma, MSI-high colorectal carcinoma, Merkel cell carcinoma, and Hodgkin lymphoma, for which approved treatments now include anti-PD-1 (nivolumab and pembrolizumab), anti-CTLA-4 (ipilimumab), and combination anti-PD-l/CTLA-4 regimens (nivolumab-ipilimumab).
  • the major drawback associated with ICI is the routine development resistance. Some patients do not respond to the treatment and succumb at a rate consistent with the natural history of disease.
  • CAR T-cell therapy Another approach is CAR T-cell therapy, wherein a patient’s T cells are removed and taken to a laboratory. The T cells are genetically changed so they will attack cancer cells. These CAR T cells are grown in large numbers and then injected into the patient. One of the remarkable things about this treatment is that it is a“living therapy.” CAR T cells typically have to be injected only once, because they go on to multiply in the body. CAR T cells continue fighting the cancer in the patient’s body, and their effectiveness may even grow over time.
  • CAR T cells target a unique antigen on tumor cells, thereby leading to clonal selection of tumor cells ii)
  • This approach is only available for blood cancers but not for solid tumors iii)
  • the costs involved in generating such cells might be heavy burden on the patient.
  • Dendritic Cell therapy or DC therapy is a immunotherapeutic approach involving dendritic cells aim to capitalize on the ability of the cells to direct cytotoxic T lymphocytes and natural killer cells to become potent antitumor effectors capable of eradicating malignant cell. This is commonly known as Dendritic Cell (DC) therapy.
  • DCs are key mediators of tumor immunity owing to their unique capacity for cross-presenting self-tumor antigens to CD8 + T cells.
  • the immature dendritic cells are isolated from patient’s peripheral blood and grown under laboratory conditions. In parallel the patients cancer cells are isolated and sequenced to identify and rank neoantigens specific to the tumor.
  • Peptides of the highest-ranking neoantigens are then synthesized and then pulsed with the autologous immature dendritic cells. Then the dendritic cells are allowed to mature, grown in the laboratory in millions, and injected into the patients to activate the CD8 + T cells against tumor.
  • Sipuleucel-T was the first DC-based antitumor vaccine to be approved by the FDA for use against asymptomatic or minimally symptomatic castration-resistant prostate cancer using a single PA2024 antigen.
  • the clinical trial failed to show promising results because the tumor cells could evade the anti- immune response due to a weak use of single antigen.
  • the present invention tries to overcome the problems by using patient’s tumor cells to generate a polyclonal vaccine that will target the tumor against multiple tumor antigens.
  • An object of the present invention is to provide anti-cancer polyclonal vaccine that generally overcomes the deficiencies found in the prior art.
  • Another object of the present invention is to provide anti-cancer polyclonal vaccine that will target the tumor against multiple tumor antigens.
  • Another object of the present invention is to provide polyclonal vaccine that is prepared using patient’s tumor cells, to target the tumor against multiple tumor antigens.
  • Another object of the present invention is to provide anti-cancer polyclonal vaccine that leads to recognition of multiple antigens of cancer cells in the body by its own immune cells.
  • Another object of the present invention is to provide anti-cancer polyclonal vaccine that leads to effective eradication of tumor cells.
  • Another object of the present invention is to provide a method of preparation of anti cancer polyclonal vaccine.
  • the present invention relates to immunotherapy of cancer. Specifically, the present invention relates to polyclonal vaccines and their method of preparation. [0017] In one aspect, the present invention relates to anti-cancer polyclonal vaccine that generally overcomes the deficiencies found in the prior art.
  • the present invention relates to anti-cancer polyclonal vaccine that will target the tumor against multiple tumor antigens.
  • the present invention provides polyclonal vaccine that is prepared using patient’s tumor cells, to target the tumor against multiple tumor antigens.
  • the present invention relates toanti-cancer polyclonal vaccine that leads to recognition of multiple antigens of cancer cells in the body by its own immune cells.
  • the present invention relates to anti-cancer polyclonal vaccine that leads to effective eradication of tumor cells.
  • the present invention relates to a method of preparation of polyclonal vaccines, applicable against all leukemic and solid tumors.
  • the present invention relates to a method of preparation ofpolyclonal vaccine, wherein the method comprises the following steps:
  • the present invention relates to a method of preparation ofpolyclonal vaccine, wherein the method comprises the following steps:
  • the present invention relates to a method of preparation ofpolyclonal vaccine, wherein the method comprises the following steps: a) Transferring a fresh tumor specimen, representative of different metastatic sites from oncology clinic to the laboratory under sterile conditions;
  • the size of fresh tumor specimen is of 0.1 to 5 cubic mm.
  • the size of fresh tumor specimen is of 1 cubic mm.
  • the tumor tissue is dissociated to a single cell suspension using a commercial tumor cell isolation kit.
  • the purity of the tumor cell population is quantified by previously established methods.
  • the purity of the tumor cell population is quantified by flow cytometry.
  • the DNA modifying drugs are FDA approved.
  • DNA modifying drugs can be selected from but not limited to histone deacetlyase inhibitors, DNA methylation inhibitors or platinum based drugs. The choice and concentrations of these drug combinations will be based on the therapeutic regimen the patient is undergoing in the clinic.
  • histone deacetlyase inhibitors can be selected from but not limited to Vorinostat, Romidepsin, Belinostat, Panobinostat, Entinostat and the like.
  • DNA methylation inhibitor can be selected from 5 AZA-CdR and the like.
  • platinum based drugs can be selected from but not limited to Oxaliplatin, Cisplatin, Carboplatin and the like.
  • the xCT inhibitors can be selected from but not limited to Sulfasalazine Sorafenib, Erastin and the like. xCT inhibitors will be only used in tumor cells having higher xCT expression to sensitize cells for subsequent oxidation step.
  • the cells can be exposed to oxidant mixture like hydrogen peroxide (H202) and hypochlorus acid (HOC1).
  • H202 hydrogen peroxide
  • HOC1 hypochlorus acid
  • the concentration range for hydrogen peroxide is 10-100 mM and concentration range for Hypochlorus acid is 10-100 mM.
  • the present invention relates to polyclonal vaccines prepared by the above method and applicable against all leukemic and solid tumors.
  • Figure 1 Schematic overview of steps involved for Polyclonal vaccine preparation.
  • Figure 2 Illustrates the xCT expression in eleven different tumor cell lines with MeWo classified as xCT positive cells.
  • Figure 3 (A) Coomassie staining of protein lysates derived from eight treatment conditions. (B) Quantification of coomassie signals normalized to the control indicate sample 4 and 8 have highest protein load.
  • Figure 4 (A) Co-culture of mDCs (red) pulsed with sample 1, 4 and 8 with MeWo tumor cells (gray). iDCs used as negative control. (B) Quantification of tumor cells (gray) from indicated time points show sample 8+mDCs inhibit tumor growth.
  • the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term“about.’’
  • the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment.
  • the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
  • inventive subject matter provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
  • the term“vaccine” refers to an immunogenic composition for administration to a mammal (such as human) for eliciting a protective immune response against a particular antigen or antigens.
  • the primary active ingredient of a vaccine is the immunogen(s).
  • the term“treating”,“treatment” or“treat” refers to abrogating a disorder, reducing the severity of a disorder, or reducing the severity or occurrence frequency of a symptom of a disorder.
  • the term“immunotherapy” refers to a biological therapy for cancer treatment that helps person’s own immune system fight cancer.
  • the immune system which is made up of white blood cells and organs and tissues of the lymph system, helps the body fight infections and other diseases.
  • polyclonal refers to a collection of different cell lineages within the body.
  • tumor refers toswelling or morbid enlargement thatresults from an overabundance of cell growth and division. Normally, the cells grow and divide to produce new cells in a controlled and orderly manner. Tumor may not be the same as a cancer, although some can develop into cancers.
  • antigen refers to a toxin or other foreign substance which induces an immune response in the body, especially the production of antibodies.
  • the present invention relates to immunotherapy of cancer. Specifically, the present invention relates to polyclonal vaccines and their method of preparation.
  • the present invention relates to anti-cancer polyclonal vaccine that generally overcomes the deficiencies found in the prior art.
  • the present invention relates to anti-cancer polyclonal vaccine that will target the tumor against multiple tumor antigens.
  • the present invention provides polyclonal vaccine that is prepared using patient’s tumor cells, to target the tumor against multiple tumor antigens.
  • the present invention relates toanti-cancer polyclonal vaccine that leads to recognition of multiple antigens of cancer cells in the body by its own immune cells.
  • the present invention relates to anti-cancer polyclonal vaccine that leads to effective eradication of tumor cells.
  • the present invention relates to a method of preparation of polyclonal vaccines, applicable against all leukemic and solid tumors.
  • the present invention relates to a method of preparation ofpolyclonal vaccine, wherein the method comprises the following steps:
  • the present invention relates to a systematic method to generate polyclonal tumor vaccines as shown in Figure 1.
  • the present invention relates to a method of preparation ofpolyclonal vaccine, wherein the method comprises the following steps:
  • the present invention relates to a method of preparation ofpolyclonal vaccine, wherein the method comprises the following steps:
  • the size of fresh tumor specimen is of 0.1 to 5 cubic mm.
  • the size of fresh tumor specimen is of 1 cubic mm.
  • the tumor tissue is dissociated to a single cell suspension using a commercial tumor cell isolation kit.
  • the purity of the tumor cell population is quantified by previously established methods. [0080] In another embodiment, the purity of the tumor cell population is quantified by flow cytometry.
  • DNA modifying drugs are the drugs approved by FDA.
  • FDA approved DNA modifying drugs can be selected from but not limited to histone deacetlyase inhibitors, DNA methylation inhibitors or platinum based drugs. The choice and concentrations of these drug combinations will be based on the therapeutic regimen the patient is undergoing in the clinic.
  • histone deacetlyase inhibitors can be selected from but not limited to Vorinostat, Romidepsin, Belinostat, Panobinostat, Entinostat and the like.
  • DNA methylation inhibitor can be 5 AZA-CdR and the like.
  • platinum based drugs can be selected from but not limited to Oxaliplatin, Cisplatin, Carboplatin and the like.
  • the xCT inhibitors can be selected from but not limited to Sulfasalazine Sorafenib, Erastin and the like. xCT inhibitors will be only used in tumor cells having higher xCT expression to sensitize cells for subsequent oxidation step.
  • the cells can be exposed to oxidant mixture like hydrogen peroxide (H2O2) and hypochlorus acid (HOC1).
  • H2O2 hydrogen peroxide
  • HAC1 hypochlorus acid
  • the concentration range for hydrogen peroxide is 10-100 mM and concentration range for Hypochlorus acid is 10-100 pM.
  • Sub toxic concentrations of oxidants are known to enhance gene expression patterns and immunogenic cell death in multiple tumor cells.
  • the induction of gene expression is greatly amplified upon incubating cells with oxidants.
  • the oxidation step is performed to enhance the antigenic/immunogenic profile of the tumor cells, which has been previously suppressed in the patient’s body.
  • repeated freeze thaw cycle is process of isolating and fragmenting proteins and other biological molecules in the most efficient way.
  • the immunogenic proteins derived from the tumor cells will be fragmented into a high-grade antigen mixture that can be used in as vaccine in DC therapy.
  • the present invention relates to polyclonal vaccines prepared by the above method and applicable against all leukemic and solid tumors.
  • Example 1 Generation of tumor cell lysates
  • Tumor lysates were prepared as described below. These are used as a polyclonal vaccine starting from a pure commercially available population of a melanoma tumor cell line MeWo(ATCC) as a model. Hence, this method does not require steps for isolation and quantification of purity of the tumor cells. However, if the tumor is obtained from a cancer patient from the clinic then pure population of tumor cells will be obtained using commercially available Tumor Cell Isolation kit (MiltenyiBiotec) according to manufacturer’s instructions.
  • Tumor Cell Isolation kit MiltenyiBiotec
  • the lysates were prepared using different conditions and the optimal condition for high yield and high antigenicity was identified.
  • the FDA approved drug Voronistat (VOR) was used as DNA modifying agent, hydrogen peroxide (H202) as an oxidizing agent, and 5 cycles of freeze thaw (FT) in liquid nitrogen for fragmentation.
  • the cell lysates were generated from eight different conditions to identify the best condition resulting in higher protein yield.
  • Melanoma tumor cell line MeWo was grown in DMEM (Dulbecco’s Minimal Essential Media; Sigma Aldrich) media supplemented with 10% FCS (Fetal Calf Serum; Gibco) and 1 % penicillin/streptomycin (Gibco) solution.
  • MeWo cells were then treated with 500 mM of xCT inhibitor sulfasalazine (Santa Cruz).
  • MeWo cells were then divided into eight treatment conditions(lxl0 6 /condition) as
  • Example 2 Determination of anti-tumor response of the tumor lysates in vitro.
  • THP1 monocytes purchased from cell repository ATCC, were grown in RPMI 1640 (Roswell Park Memorial Institute 1640; Thermo Scientific) media with 10% FCS (Fetal Calf serum; Gibco) and 1% penicillin/streptomycin (Thermo Scientific).
  • THP1 monocytes were incubated with rhIL-4 (Interleukin-4) and rhGMCSF (human Granulocyte Macrophage Colony Stimulating Factor) for five days to induce differentiation to iDCs.
  • rhIL-4 Interleukin-4
  • rhGMCSF human Granulocyte Macrophage Colony Stimulating Factor
  • the iDCs were isolated and split in to three wells with lxlO 6 cells/well. 100 m ⁇ of the lysates from samples 1, 4 and 8 were mixed to these cells and incubated for another 24 hours.
  • the mDCs was then isolated and washed with Cell Trace RedTM dye, which labels cells red for fluorescent microscopy.
  • mDCs (Red) and MeWo tumor cell line (gray) were co-cultured and time-lapse microscopy was initiated to determine whether the mDCs inhibit the growth of the tumor cell line MeWo.
  • iDCs that were not treated with any lysate was used as a control for specificity.
  • the present invention provides anti-cancer polyclonal vaccine that generally overcomes the deficiencies found in the prior art.
  • the present invention provides a method of preparation of anti-cancer polyclonal vaccine that generally overcomes the deficiencies found in the prior art.
  • the present invention provides anti-cancer polyclonal vaccine that will target the tumor against multiple tumor antigens.
  • the present invention provides anti-cancer polyclonal vaccine that leads to recognition of multiple antigens of cancer cells in the body by its own immune cells.
  • the present invention provides anti-cancer polyclonal vaccine that leads to effective eradication of tumor cells.

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Abstract

La présente invention concerne une immunothérapie contre le cancer. Plus particulièrement, la présente invention concerne des vaccins polyclonaux et leur procédé de préparation. La présente invention concerne en outre un procédé de préparation de vaccins polyclonaux, applicables contre toutes les tumeurs leucémiques et solides. La présente invention concerne un procédé de préparation d'un vaccin polyclonal, le procédé comprenant les étapes suivantes : a) purification et classification de cellules tumorales; b) induction de l'expression génique; c) oxydation; et d) fragmentation.
PCT/IB2019/058411 2019-02-04 2019-10-03 Préparation d'un vaccin polyclonal contre le cancer pour une immunothérapie personnalisée Ceased WO2020161535A1 (fr)

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Cited By (2)

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CN111109248A (zh) * 2019-12-24 2020-05-08 武汉博士德生物工程有限公司 一种杂交瘤细胞冻存液及96孔板冻存复苏方法
CN115791354A (zh) * 2022-11-29 2023-03-14 苏州贝康医疗器械有限公司 一种精子dna碎片化检测用质控品及其制备方法和应用

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111109248A (zh) * 2019-12-24 2020-05-08 武汉博士德生物工程有限公司 一种杂交瘤细胞冻存液及96孔板冻存复苏方法
CN115791354A (zh) * 2022-11-29 2023-03-14 苏州贝康医疗器械有限公司 一种精子dna碎片化检测用质控品及其制备方法和应用

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