Methods of treating cancer using PD-1 axis binding antagonists and TIGIT inhibitors
The present invention describes combination treatment comprising a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and/or activity and methods for use thereof, including methods of treating conditions where enhanced immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer or chronic infection.
1. A method for treating or delaying progression of a cancer in an individual, the method comprising administering to the individual an effective amount of (i) a PD-L1 binding antagonist that inhibits the binding of PD-L1 to PD-1 and/or B7-1, a PD-1 binding antagonist that inhibits the binding of PD-1 to PD-L1 and/or PD-L2, or a PD-L2 binding antagonist that inhibits the binding of PD-L2 to PD-1 and (ii) an antagonist of TIGIT expression and/or activity.
2. A method for treating or delaying progression of a viral infection in an individual, the method comprising administering to the individual an effective amount of (i) a PD-L1 binding antagonist that inhibits the binding of PD-L1 to PD-1 and/or B7-1, a PD-1 binding antagonist that inhibits the binding of PD-1 to PD-L1 and/or PD-L2, or a PD-L2 binding antagonist that inhibits the binding of PD-L2 to PD-1 and (ii) an antagonist of TIGIT expression and/or activity.
3. A method of increasing, enhancing, or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of (i) a PD-L1 binding antagonist that inhibits the binding of PD-L1 to PD-1 and/or B7-1, a PD-1 binding antagonist that inhibits the binding of PD-1 to PD-L1 and/or PD-L2, or a PD-L2 binding antagonist that inhibits the binding of PD-L2 to PD-1 and (ii) an antagonist of TIGIT expression and/or activity.
4. The method of any one of claims 1 , 2 , and 3 , wherein the antagonist of TIGIT expression and/or activity is an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, or an inhibitory polypeptide.
5. The method of claim 4 , wherein the inhibitory antibody or antigen-binding fragment thereof is an anti-TIGIT antibody or antigen-binding fragment thereof.
6. The method of any one of claims 1 , 2 , and 3 , further comprising administering at least one chemotherapeutic agent.
7. The method of claim 3 , wherein the individual has a cancer.
8. The method of claim 1 or 7 , wherein the cancer has elevated levels of T cell infiltration.
9. The method of claim 5 , wherein the anti-TIGIT antibody or antigen-binding fragment thereof is a humanized antibody, a chimeric antibody, a bispecific antibody, a heteroconjugate antibody, or an immunotoxin.
10. The method of any one of claims 1 , 2 , and 3 , wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.
11. The method of claim 10 , wherein the anti-PD-L1 antibody comprises a heavy chain comprising HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:17), HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:18), and HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:19); and a light chain comprising HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:20), HVR-L2 sequence of SASFLYS (SEQ ID NO:21), and HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:22).
12. The method of claim 1 or 7 , wherein the cancer is selected from the group consisting of a non-small cell lung cancer, a small cell lung cancer, a renal cell cancer, a colorectal cancer, an ovarian cancer, a breast cancer, a pancreatic cancer, a gastric carcinoma, a bladder cancer, an esophageal cancer, a mesothelioma, a melanoma, a head and neck cancer, a thyroid cancer, a sarcoma, a prostate cancer, a glioblastoma, a cervical cancer, a thymic carcinoma, a leukemia, a lymphomas, a myelomas, a mycosis fungoides, a Merkel cell cancer, and a hematologic malignancy.
13. The method of claim 1 or 7 , wherein tumor growth is substantially reduced.
14. The method of claim 1 or 7 , wherein tumor volume is substantially reduced.
15. The method of claim 1 or 7 , wherein the individual exhibits a sustained response.
16. The method of claim 1 or 7 , wherein the individual exhibits a complete remission.
17. The method of claim 1 or 7 , wherein tumor-infiltrating CD8+ T cells of the individual produce IFNγ and/or TNFα following administration.
18. The method of claim 1 or 7 , wherein the function of tumor-infiltrating CD8+ T cells is enhanced.
19. The method of claim 1 or 7 , wherein the effector function of chronically stimulated or exhausted CD8+ T cells in a tumor of the individual is restored.
20. The method of claim 1 or 7 , wherein the effector function of chronically stimulated or exhausted tumor-infiltrating CD8+ T cells of the individual is restored.
21. The method of claim 1 or 7 , wherein TIGIT is expressed on tumor-infiltrating CD8+ T cells of the individual.
22. The method of any one of claims 1 , 2 , and 3 , wherein the antagonist of TIGIT expression and/or activity does not impact PVR-CD226 interaction.