Treatment of renal cell carcinoma
This disclosure provides methods for treating a subject afflicted with a tumor derived from a renal cell carcinoma. The methods comprise administering a first dose to a subject of an anti-PD-1 antibody or antigen-binding portion thereof and/or an anti-PD-L1 antibody or antigen-binding portion thereof, and administering a second dose to the subject, wherein the subject exhibited differential expression in one or more biomarker genes, e.g., CTLA-4, TIGIT, and/or PD-L2, following administration of the first dose.
1. A method for treating a subject afflicted with a tumor derived from a renal cell carcinoma comprising:
(i) administering a first dose of an anti-PD-1 antibody or an anti-PD-L1 antibody to the subject who exhibits an increased expression level of MICB, PVRIG, SPI1, CLEC2B, and NKG7 in a tumor biopsy obtained from the subject, relative to a reference expression level of MICB, PVRIG, SPI1, CLEC2B, and NKG7, wherein the reference expression level corresponds to the average expression level of MICB, PVRIG, SPI1, CLEC2B, and NKG7 as measured in tumor biopsies from a patient population affected with a tumor derived from a renal cell carcinoma; and
(ii) administering a second dose of the anti-PD-1 antibody or the anti-PD-L1 antibody to the subject, wherein a tumor sample obtained from the subject exhibits an increased expression level of PVRIG, NKG7, CD244, NKTR, TNFSF8, TNFSF13B, TNFRSF14, SPI1, CLEC2B, CTLA-4, TIGIT, PD-L2, or any combination thereof on about day 8 after the administration of the first dose of the anti-PD-1 antibody or the anti-PD-L1 antibody, relative to the expression level of PVRIG, NKG7, CD244, NKTR, TNFSF8, TNFSF13B, TNFRSF14, SPI1, CLEC2B, CTLA-4, TIGIT, PD-L2, or any combination thereof in a tumor sample prior to the administration of the first dose of the anti-PD-1 antibody or the anti-PD-L1 antibody.
2. The method of claim 1 , wherein the first dose of the anti-PD-1 antibody is administered at a flat dose of at least about 240 mg.
3. The method of claim 1 , wherein the first dose of the anti-PD-1 antibody comprises more than one dose, and wherein the first dose of the anti-PD-1 antibody is administered at a flat dose of at least about 240 mg once about every 2 weeks.
4. The method of claim 1 , which further comprises administering one or more additional anti-cancer agents.
5. The method of claim 4 , wherein the anti-cancer agent is selected from the group consisting of an antibody or antigen-binding portion thereof that binds specifically to CTLA-4 and inhibits CTLA-4 activity (“anti-CTLA-4 antibody”), a chemotherapy, a platinum-based doublet chemotherapy, a tyrosine kinase inhibitor, an anti-VEGF inhibitor, and any combination thereof.
6. The method of claim 5 , wherein the anti-cancer agent is ipilimumab.
7. The method of claim 5 , wherein the first dose of the anti-PD-1 antibody comprises more than one dose, and wherein the first dose of the anti-PD-1 antibody is administered at a dose of about 1 mg/kg body weight once about every three weeks.
8. The method of claim 1 , wherein the first dose of the anti-PD-L1 antibody is administered at a flat dose of at least about 1200 mg.
9. The method of claim 1 , wherein after the administration of the first dose, the subject further exhibits an increased T cell count in the tumor.
10. The method of claim 1 , wherein:
(i) the expression level of MICB, PVRIG, SPI1, CLEC2B, NKG7, or any combination thereof is a protein expression level measured by an immunohistochemistry, an ELISA, a western blot, a protein array or any combination thereof; or
(ii) the expression level of MICB, PVRIG, SPI1, CLEC2B, NKG7, or any combination thereof is a polynucleotide expression level measured by an in situ hybridization, a DNA or RNA array or polynucleotide hybridization technique, a tumor sequencing technique, a quantitative polymerase chain reaction (PCR), or any combination thereof.
11. The method of claim 1 , wherein the anti-PD-1 antibody is nivolumab or pembrolizumab.
12. The method of claim 1 , wherein the anti-PD-L1 antibody is BMS-936559, MPDL3280A, MEDI4736, or MSB0010718C.
13. The method of claim 1 , wherein the first dose of the anti-PD-1 antibody is administered at a flat dose of at least about 480 mg.
14. The method of claim 1 , wherein the first dose comprises more than one dose, and wherein the first dose of the anti-PD-1 antibody is administered at a flat dose of at least about 480 mg once about every 4 weeks.
15. The method of claim 1 , wherein the second dose of the anti-PD-1 antibody is administered as a flat dose of at least 240 mg.
16. The method of claim 1 , wherein the second dose of the anti-PD-1 antibody comprises more than one dose, and wherein the second dose of the anti-PD-1 antibody is administered at a flat dose of at least about 240 mg once about every 2 weeks.
17. The method of claim 1 , wherein the second dose of the anti-PD-1 antibody is administered as a flat dose of at least 480 mg.
18. The method of claim 1 , wherein the second dose of the anti-PD-1 antibody comprises more than one dose, and wherein the second dose of the anti-PD-1 antibody is administered at a flat dose of at least about 480 mg once about every 4 weeks.