Methods and compositions for enhancing the therapeutic effect of anti-tumor T cells
Compositions, e.g., therapeutic agents, and methods are provided for modulating gene and protein expression of Forkhead Box protein 1 (Foxp1). The therapeutic agents include short nucleic acid molecules that modulate gene and protein expression of Forkhead Box protein 1 (Foxp1) expression, viral vectors containing such molecules, T cells transduced with these viruses for adoptive therapies, and any small molecules that bind to and inactivate Foxp1. These compounds and methods have applications in cancer therapy either alone or in combination with other therapies that stimulate the endogenous immune system in the environment of the cancer, e.g., tumor.
1. A method of treating a cancer or enhancing an anti-tumor response in a subject having a cancer characterized by a solid tumor comprising:
administering to a subject in need thereof a therapeutic reagent comprising a short hairpin RNA (shRNA) SEQ ID NO: 5 that inhibits or down-regulates the expression of Foxp1 in tumor-reactive T cells.
2. The method according to claim 1 , wherein the therapeutic reagent is a therapeutic or prophylactic composition comprising a viral vector expressing the shRNA, and a pharmaceutically acceptable carrier or diluent.
3. The method according to claim 2 , wherein the viral vector is selected from the group consisting of adenovirus or lentivirus.
4. The method according to claim 2 , wherein the viral vector is transduced ex vivo into a T cell and said T cell is introduced into the subject.
5. The method according to claim 4 , wherein the T cell is pulsed with tumor antigen prior to transduction with the viral vector.
6. The method according to claim 2 , comprising administering the composition directly into the tumor environment of the subject, or administering the composition by intraperitoneal, intravenous, intratumoral or intranodal administration or said administering is repeated periodically.
7. The method according to claim 2 , further comprising co-administering IL-7 to the subject to promote the in vivo activity of Foxp1-deficient T cells.
8. The method according to claim 6 , wherein T cells in the tumor environment are infected by the vector in vivo and Foxp1 is down regulated in the infected T cells, wherein the vector specifically infects only T cells.
9. The method according to claim 2 , wherein said reagent is administered ex vivo to a T cell selected from the group consisting of (a) a polyclonal/monoclonal tumor-reactive T cell, (b) a tumor-infiltrating lymphocyte generated from aphaeresis samples or isolated from a tumor of a cancer patient, and (c) a T cell conditioned for adoptive transfer.
10. The method according to claim 1 , further comprising administering to the subject a monoclonal antibody, chemotherapy, radiation therapy, a cytokine, or a combination thereof.
11. A method of treating a cancer or enhancing an anti-tumor response in a subject having a cancer characterized by a solid tumor comprising: administering to a subject in need thereof a therapeutic reagent comprising a short hairpin RNA (shRNA) SEQ ID NO: 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, and 50 that inhibits or down-regulates the expression of Foxp1 in tumor-reactive T cells.
12. The method according to claim 11 , wherein the therapeutic reagent is a therapeutic or prophylactic composition comprising a viral vector expressing the shRNA, and a pharmaceutically acceptable carrier or diluent.
13. The method according to claim 11 , wherein the viral vector is selected from the group consisting of adenovirus or lentivirus.
14. The method according to claim 11 , wherein the viral vector is transduced ex vivo into a T cell and said T cell is introduced into the subject.
15. The method according to claim 14 , wherein the T cell is pulsed with tumor antigen prior to transduction with the viral vector.
16. The method according to claim 12 , comprising administering the composition directly into the tumor environment of the subject, or administering the composition by intraperitoneal, intravenous, intratumoral or intranodal administration or said administering is repeated periodically.
17. The method according to claim 12 , further comprising co-administering IL-7 to the subject to promote the in vivo activity of Foxp1-deficient T cells.
18. The method according to claim 17 , wherein T cells in the tumor environment are infected by the vector in vivo and Foxp1 is down regulated in the infected T cells, wherein the vector specifically infects only T cells.
19. The method according to claim 12 , wherein said agent is administered ex vivo to a T cell selected from the group consisting of (a) a polyclonal/monoclonal tumor-reactive T cell, (b) a tumor-infiltrating lymphocyte generated from aphaeresis samples or isolated from a tumor of a cancer patient, and (c) a T cell conditioned for adoptive transfer.
20. The method according to claim 11 , further comprising administering to the subject a monoclonal antibody, chemotherapy, radiation therapy, a cytokine, or a combination thereof.