Methods and compositions for treating cancers

Abstract

The inventors have developed a metastatic 4T1 breast tumor model in BALB/c mice. They have shown that the vaccination with xenogeneic embryonic stem cells in combination with valproic acid (VPA) generates a higher anti-tumoral response against breast cancer and inhibits metastasis development. They established that these responses are achieved only by the addition of valproic acid in the therapeutic regimen in comparison to the use ESCs or iPSCs alone. Thus, the inventors provide a new therapeutic strategy to treat cancers expressing embryonic antigens. Accordingly, the present invention relates to i) a population of pluripotent cells and ii) a compound selected from a group which activates MHC expression, as a combined preparation for use in a method for treating a subject suffering from a cancer, comprising a step of administering simultaneously, separately or sequentially to said subject a therapeutically amount thereof.

1 . A method for producing a population of pluripotent cells comprising:
 (i) expanding pluripotent cells under conditions that maintain pluripotent ability of the cells, in the presence of an agent that induces MHC-I presentation of antigens in the cells during the expanding;   (ii) exposing the expanded cells to an inactivating agent that inactivates the expanded cells while maintaining cell envelope integrity; and   (iii) recovering and conditioning the expanded inactivated cells.   
     
     
         2 . The method of  claim 1 , wherein the population of pluripotent cells is selected from human embryonic stem cells, induced pluripotent stem cells (iPS), allogeneic stem cells, xenogeneic stem cells, autologous stem cells and syngeneic stem cells. 
     
     
         3 . The method of  claim 1 , wherein the pluripotent cells are exposed to a mutagenic agent during expansion to induce mutagenesis of genes in the cells. 
     
     
         4 . The method of  claim 3 , wherein the mutagenic agent is a physical mutagen selected from ionizing radiation and UV radiation. 
     
     
         5 . The method of  claim 3 , wherein the mutagenic agent is a chemical mutagen selected from alkylating agents, reactive oxygen species, deaminating agents, polycyclic aromatic hydrocarbons, aromatic amines, bleomycin, bromine, benzene, base analogs, DNA intercalating agents, metals, psoralen combined with ultraviolet radiation, and sodium azide. 
     
     
         6 . The method of  claim 3 , wherein the mutagenic agent is an alkylating agent, preferably ENU, and the pluripotent cells are exposed to the alkylating agent for a duration of at least 15 days, more preferably at least 30 days, more preferably at least 45 days, more preferably at least 60 days. 
     
     
         7 . The method of  claim 1 , wherein the agent that induces MHC-I presentation of antigens is a histone deacetylase inhibitor (HDACi), preferably selected from the group consisting of Valproic acid (VPA), Vorinostat, Panobinostat, Givinostat, Belinostat, Entinostat, Mocetinostat, Practinostat, Chidamide, Quisinostat and Abexinostat. 
     
     
         8 . The method of  claim 1 , wherein a DNA methyltransferase inhibitor, preferably 5-azacytidine, is present in (i). 
     
     
         9 . The method of  claim 1 , wherein the inactivating agent is a lethal dose of radiation. 
     
     
         10 . The method of  claim 1 , wherein the recovery includes washing and resuspending the cells in an appropriate buffer. 
     
     
         11 . The method of  claim 1 , wherein the conditioning includes freezing or lyophilizing the cells. 
     
     
         12 . A cancer vaccine composition comprising:
 (a) a population of inactivated pluripotent cells; and   (b) a histone deacetylase inhibitor.   
     
     
         13 . The vaccine composition of  claim 12 , wherein the pluripotent cells contain mutagenized pluripotent cells. 
     
     
         14 . The vaccine composition of  claim 12 , wherein the cancer expresses embryonic antigens and is preferably selected from the group consisting of bladder carcinoma, breast carcinoma, cervical carcinoma, cholangiocarcinoma, colorectal carcinoma, gastric sarcoma, glioma, lung carcinoma, lymphoma, acute and chronic lymphoid and myeloid leukemias, melanoma, multiple myeloma, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, stomach carcinoma, kidney carcinoma, head and neck tumor, and a solid tumor. 
     
     
         15 . A kit comprising the vaccine composition of  claim 12  and an information leaflet providing instructions for immunization. 
     
     
         16 . A method of treating a subject suffering from a cancer comprising administrating simultaneously, separately or sequentially to the subject a therapeutically effective amount of (i) a population of inactivated pluripotent cells and (ii) a compound which activates MHC expression and/or an immune response, preferably a histone deacetylase inhibitor, in particular valproic acid or a DNA methyltransferase inhibitor, as a combined preparation. 
     
     
         17 . The method of  claim 16  wherein the population of pluripotent cells is selected from human embryonic stem cells, induced pluripotent stem cells (iPS), allogeneic stem cells, xenogeneic stem cells, autologous stem cells, and syngeneic stem cells. 
     
     
         18 . The method of  claim 16 , wherein the cancer is selected from cancers expressing embryonic antigens and is preferably selected from the group consisting of bladder carcinoma, breast carcinoma, cervical carcinoma, cholangiocarcinoma, colorectal carcinoma, gastric sarcoma, glioma, lung carcinoma, lymphoma, acute and chronic lymphoid and myeloid leukemias, melanoma, multiple myeloma, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, stomach carcinoma, kidney carcinoma, head and neck tumor, and a solid tumor. 
     
     
         19 . The method of  claim 16 , wherein the pluripotent cells are genetically modified to over-express compounds that stimulate MHC-I expression and/or immune response, wherein the compound that stimulates MHC-I expression and/or the immune response is preferably selected from Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), Granulocyte Colony Stimulating Factor (G-CSF), Interferon gamma (IFN-gamma), Interleukin 2 (IL-2) and combination thereof. 
     
     
         20 . The method of  claim 16 , wherein the inactivated pluripotent cells have been treated with a mutagenic agent. 
     
     
         21 . The method of  claim 16 , further comprising administering an immune checkpoint inhibitor to the subject or performing one or more of radiation therapy, targeted therapy, immunotherapy, or chemotherapy to the subject. 
     
     
         22 . The method of  claim 16 , wherein the administering of the pluripotent cells is performed by intradermal, intravenous, subcutaneous, or intramuscular injection. 
     
     
         23 . The method of  claim 16 , further comprising administering a histone deacetylase inhibitor for a period of time after the administering of the population of pluripotent cells, in particular between three days and three weeks.