Methods and compositions for treating cancer
Methods for treating cancer are disclosed which comprise administering to a subject T cells which have been pretreated ex vivo or in vitro with a fatty acid catabolism promoter to condition the T cell to use fatty acids rather than glucose for energy production. Still other methods comprise co-administering to a subject having a cancer characterized by a solid tumor (a) an immunotherapeutic composition targeting an antigen or ligand on the tumor cell; and (b) a compound or reagent that promotes the use of fatty acid catabolism by tumor antigen-specific T cells in the tumor microenvironment and/or T cells pretreated ex vivo with the fatty acid catabolism promoter to condition the T cell to use fatty acids rather than glucose for energy production for adoptive cell transfer. Both methods may also employ co-administration of a checkpoint inhibitor.
1. A method for treating a cancer characterized by a tumor with low glucose content in the tumor microenvironment (TME) comprising co-administering to a subject having said cancer
an activated CD8+ T cell or CD8+ T cell population that is pretreated or conditioned ex vivo or in vitro with a compound or reagent that promotes the use of fatty acid catabolism rather than glucose for energy production by the pre-treated T cells, and an immunotherapeutic composition targeting an antigen or ligand on a tumor cell with a hypoglycemic tumor microenvironment (TME) in the subject, wherein said cancer is melanoma.
2. A method for treating a cancer characterized by a tumor with low glucose content in the tumor microenvironment (TME) comprising administering to a subject having said cancer
an activated CD8+ T cell or CD8+ T cell population that is pretreated or conditioned ex vivo or in vitro with a compound or reagent that promotes the use of fatty acid catabolism rather than glucose for energy production by the pre-treated T cells, and
a checkpoint inhibitor in the form of an antibody or a small molecule, and wherein said cancer is melanoma.
3. The method according to claim 2 , wherein the checkpoint inhibitor is an anti-PD-1 antibody or small molecule ligand.
4. A method for treating a cancer characterized by a tumor with low glucose content in the tumor microenvironment (TME) comprising administering to a subject having said cancer an activated CD8+ T cell or CD8+ T cell population that is pretreated or conditioned ex vivo or in vitro with a compound or reagent that promotes the use of fatty acid catabolism rather than glucose for energy production by the pre-treated T cells, wherein the compound or reagent that promotes the use of fatty acid catabolism by T cells is fenofibrate, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, an AMPK activator or 5-aminoimidazole-4-carboxamide riboside, and wherein said cancer is melanoma.
5. The method according to claim 1 , wherein said immunotherapeutic composition is a recombinant virus or virus-like particle that expresses a cancer antigen, a DNA construct that expresses a cancer antigen, a composition comprising cancer antigens or fragments thereof as peptides or proteins, monoclonal antibodies or antigen-binding fragments that specifically bind cancer antigens.
6. The method according to claim 1 , wherein:
(a) the immunotherapeutic composition and the pretreated T cell are administered substantially simultaneously; or
(b) the pretreated T cells are administered once or repeatedly from at least one to 14 days after administration of the immunotherapeutic composition; or
(c) the immunotherapeutic composition is administered in a single dose or as one or more booster doses; or
(d) said composition (a) and (b) are independently administered systemically by intramuscular, intraperitoneal, intravenous, intratumoral or intranodal administration; or
(e) composition (b) is administered orally.
7. The method according to claim 4 , wherein the pretreated T cells are administered once or repeatedly or wherein the pretreated T cells are administered in a single dose or as one or more doses or wherein the pretreated T cells are administered systemically by intravenous injection or infusion.
8. The method according to claim 4 , further comprising
(a) treating the subject with another anti-cancer therapy; or
(b) treating the subject with chemotherapy before administering the pre-treated T cells.
9. The method according to claim 8 , wherein the anti-cancer therapy comprises depleting the subject of lymphocytes and optionally surgically resecting the tumor prior to administration of the pretreated T cells.
10. The method according to claim 4 , wherein the cancer or tumor targeted by the method is characterized by hypoxia or significant infiltration with T lymphocytes.
11. A method for treating a cancer characterized by a tumor with low glucose content in the tumor microenvironment (TME) comprising:
activating a CD8+ T cell and pretreating said activated T cell ex vivo with fenofibrate, clofibrate, gemfibrozil, ciprofibrate, or bezafibrate, thereby promoting the use of fatty acid catabolism rather than glucose for energy production by the pre-treated T cells; and
administering to a subject having said cancer said activated, pretreated T cells, wherein said cancer is melanoma.
12. A method for treating a cancer characterized by a tumor with low glucose content in the tumor microenvironment (TME) comprising:
administering to a subject having said cancer an activated CD8+ T cell or CD8+ T cell population that is pretreated or conditioned ex vivo or in vitro with a compound or reagent that promotes the use of fatty acid catabolism rather than glucose for energy production by the pre-treated T cells; and
administering to said subject an immunotherapeutic composition targeting an antigen ligand on said tumor cell, wherein said cancer is melanoma.
13. The method according to claim 1 , wherein the pretreated T cells are administered once or repeatedly or wherein the pretreated T cells are administered in a single dose or as one or more doses or wherein the pretreated T cells are administered systemically by intravenous injection or infusion.
14. The method according to claim 1 , further comprising
(a) treating the subject with another anti-cancer therapy; or
(b) treating the subject with chemotherapy before administering the pre-treated T cells.
15. The method according to claim 14 , wherein the anti-cancer therapy comprises depleting the subject of lymphocytes and optionally surgically resecting the tumor prior to administration of the pretreated T cells.
16. The method according to claim 2 , wherein the pretreated T cells are administered once or repeatedly or wherein the pretreated T cells are administered in a single dose or as one or more doses or wherein the pretreated T cells are administered systemically by intravenous injection or infusion.
17. The method according to claim 2 , further comprising
(a) treating the subject with another anti-cancer therapy; or
(b) treating the subject with chemotherapy before administering the pre-treated T cells.
18. The method according to claim 17 , wherein the anti-cancer therapy comprises depleting the subject of lymphocytes and optionally surgically resecting the tumor prior to administration of the pretreated T cells.