Methods and compositions for treating cancers
The invention relates to a method for treating cancers. Many cancers harbour sternness signature to de-differentiate into immature progenitors confer to tumor clones the re-expression of genes from fetal development. Inventors have obtained mice per group which received two boosts of vaccine 7 and 14 days with 2×106 irradiated hESCs cells that were mixed with 3 different adjuvants: 500 μg of TLR3, 50 μg of TLR9 agonist or 50 μg/ml of Quil A® Saponin vaccine adjuvant. After 14 days 5×104 4T1 cells were injected into the mammary fat pad of the mice and Valproic acid added in the drinking water at the dose of 4 mg/ml. They have shown that in contrast to the non-vaccinated mice, the mice vaccinated with hESC combined with a TLR3 agonist have generated the highest reduction of breast tumor volume (p<0.001) compared to the use of a TLR9 agonist or to Quil-A® Saponin vaccine adjuvant. Accordingly, the invention relates to a method for treating a subject suffering from a cancer with i) an agent that induces MHC-I presentation of antigens, ii) a vaccine composition containing an immunogenic element and iii) an adjuvant.
1 . A method for treating a subject suffering from a cancer, comprising administrating simultaneously, separately, or sequentially to the subject a therapeutically effective amount of:
(i) an agent that induces MHC-I presentation of antigens, wherein the agent is a histone deacetylase inhibitor (HDACi);
(ii) a vaccine composition comprising inactivated pluripotent or fetal stem cells, as an immunogenic element; and
(iii) an adjuvant, wherein the adjuvant is an agonist of toll-like receptor (TLR) 3.
2 . The method of claim 1 , wherein the vaccine composition comprises inactivated fetal stem cells containing a multiplicity of fetal antigens.
3 . The method of claim 1 , wherein the pluripotent or fetal stem cells express one or more antigens also expressed by the cancer cells of the subject.
4 . The method of claim 2 , wherein the inactivated fetal stem cells are obtained by a process comprising:
(a) differentiating a population of pluripotent cells along a pathway specific to the subject's cancer;
(b) expanding the differentiated cells, while optionally exposing the differentiated cells to a mutagenic agent to induce mutagenesis;
(c) verifying that at least 70% of the expanded cells express fetal markers;
(d) optionally, verifying that the expanded cells express at least one tumor associated antigen (TAA) or neo-antigen that is present in the subject's cancer cells; and
(e) inactivating the expanded cells to eliminate their ability to divide.
5 . The method of claim 1 , wherein the pluripotent stem cells are obtained by a process comprising:
(a) expanding pluripotent cells under conditions that maintain their pluripotency, optionally in the presence of an agent that induces MHC-I presentation of antigens during the expansion; and
(b) exposing the expanded cells to an inactivating agent to inactivate the expanded pluripotent cells while maintaining cell envelope integrity.
6 . The method of claim 1 , wherein the histone deacetylase inhibitor is selected from Valproic acid (VPA), Vorinostat, Panobinostat, Givinostat, Belinostat, Levetiracetam, Entinostat, Mocetinostat, Practinostat, Chidamide, Quisinostat, and Abexinostat.
7 . The method of claim 1 , wherein the TLR3 agonist is Poly(A:U) or poly(I:C).
8 . The method of claim 1 , wherein the vaccine composition containing the immunogenic element and the agonist of TLR 3 is initially administered followed by multiple administrations of the histone deacetylase inhibitor.
9 . The method of claim 1 , wherein the cancer is selected from liver cancer, bladder carcinoma, breast carcinoma, cervical carcinoma, cholangiocarcinoma, colorectal carcinoma, gastric sarcoma, glioma, glioblastoma, lung carcinoma, lymphoma, acute lymphoid leukemia, chronic lymphoid leukemia, myeloid leukemias, melanoma, multiple myeloma, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, stomach carcinoma, renal carcinoma, head and neck tumor, hematopoietic malignancies, and RET-mutated endocrine tumors.
10 . The method of claim 1 , wherein the cancer is a hormone-dependent cancer.
11 . The method of claim 10 , wherein the cancer is selected from a breast cancer, a prostate cancer, a uterus cancer, and an ovary cancer.
12 . The method of claim 9 , wherein the RET-mutated endocrine tumor is a medullary thyroid cancer.
13 . The method of claim 4 , wherein the pluripotent cells are exposed to the mutagenic agent during expansion.
14 . The method of claim 5 , wherein the pluripotent cells are exposed to the mutagenic agent during expansion.
15 . The method of claim 13 , wherein the mutagenic agent is N-ethyl-N-nitrosourea (ENU).
16 . The method of claim 14 , wherein the mutagenic agent is N-ethyl-N-nitrosourea (ENU).