초록 ▼

Methods of treating cancer and infectious diseases utilizing a treatment regimen comprising administering a compound that reduces inhibitory signal transduction in T cells, in combination with a potentiating agent, such as cyclophosphamide, to produce potent T cell mediated responses, are described.

Methods of treating cancer and infectious diseases utilizing a treatment regimen comprising administering a compound that reduces inhibitory signal transduction in T cells, in combination with a potentiating agent, such as cyclophosphamide, to produce potent T cell mediated responses, are described. Compositions comprising the PD-1 antagonists and potentiating agents useful in the methods of the invention are also disclosed.

대표청구항 ▼

1. A method of increasing a T cell response in a human comprising administering to the subject an anti-PD-1 antibody or an antigen binding fragment thereof in combination with a potentiating agent selected from the group consisting of cyclophosphamide and an analog of cyclophosphamide, wherein admin

1. A method of increasing a T cell response in a human comprising administering to the subject an anti-PD-1 antibody or an antigen binding fragment thereof in combination with a potentiating agent selected from the group consisting of cyclophosphamide and an analog of cyclophosphamide, wherein administration of the anti-PD-1 antibody or antigen binding fragment thereof in combination with the potentiating agent increases a T cell response,wherein the dose of the potentiating agent is less than 200 mg/kg,wherein the dose of the potentiating agent is not effective to have direct anti-tumor activity,and wherein the T cell response achieved by the combination of anti-PD-1 antibody and the potentiating agent is greater than the T cell response achieved by administering either the anti-PD-1 antibody alone or the potentiating agent alone. 2. The method of claim 1 wherein the anti-PD-1 antibody or antigen binding fragment thereof inhibits, reduces, modulates or abolishes signal transduction mediated by PD-1. 3. The method of claim 1 wherein the anti-PD-1 antibody is a human anti-PD-1 antibody or antigen binding fragment thereof. 4. The method of claim 1 wherein the antigen binding fragment is a Fab, F(ab′)2, or Fv fragment. 5. The method of claim 1 wherein the anti-PD-1 antibody or antigen binding fragment thereof is a humanized, chimeric, or single-chain antibody or fragment thereof. 6. The method of claim 1 wherein the potentiating agent reduces the activity of regulatory T lymphocytes (Tregs). 7. The method of claim 1 wherein the amount of potentiating agent is sub-therapeutic in the absence of the anti-PD-1 antibody or an antigen binding fragment thereof. 8. The method of claim 1 wherein the dose of the potentiating agent is 8 mg/kg of cyclophosphamide or an analog of cyclophosphamide. 9. The method of claim 1 further comprising administering an additional immunomodulatory agent. 10. The method of claim 1 further comprising administering an additional agent selected from the group consisting of an anti-CTLA4 antibody, a mitosis inhibitor, an aromatase inhibitor, an A2a adenosine receptor (A2AR) antagonist, and an angiogenesis inhibitor. 11. The method of claim 10 wherein the angiogenesis inhibitor is a VEGF inhibitor. 12. The method of claim 11 wherein the VEGF inhibitor is bevacizumab or VEGF-Trap. 13. The method of claim 1 wherein the potentiating agent is administered before the anti-PD-1 antibody or antigen binding fragment thereof. 14. The method of claim 13 wherein the potentiating agent is administered at least 1, 2, 3, 5, 10, 15, 20, 24, or 30 hours before the anti-PD-1 antibody or antigen binding fragment thereof. 15. The method of claim 1 wherein the anti-PD-1 antibody or antigen binding fragment thereof and the potentiating agent are administered to a subject having cancer or an infection. 16. The method of claim 15 wherein the cancer is selected from the group consisting of a bladder, brain, breast, cervical, colo-rectal, esophageal, kidney, liver, lung, nasopharangeal, pancreatic, prostate, skin, stomach, uterine, ovarian, testicular, and hematologic cancer. 17. The method of claim 15 wherein the cancer is selected from the group consisting of gastric cancer, glioma, leukemia, melanoma, multiple myeloma, renal cell carcinoma, and urothelial cancer. 18. The method of claim 15 wherein the cancer is melanoma. 19. The method of claim 15 wherein the infection is a viral infection. 20. The method of claim 19 wherein the viral infection is selected from the group consisting of, papilloma, herpes, encephalitis, influenza, hepatitis, and the common cold. 21. The method of claim 19 wherein the viral infection is caused by a virus selected from the group consisting of, human papilloma virus (HPV), herpes simplex virus (HSV), human influenza virus A, hepatitis C virus (HCV), hepatitis B virus (HBV), and human rhinovirus. 22. The method of claim 15 wherein the infection is a non-viral infection. 23. The method of claim 22 wherein the non-viral infection is caused by a microorganism selected from the group consisting of Actinomyces, Anabaena, Bacillus, Bacteroides, Bdellovibrio, Bordetella, Borrelia, Campylobacter, Caulobacter, Chlamydia, Chlorobium, Chromatium, Clostridium, Corynebacterium, Cytophaga, Deinococcus, Escherichia, Francisella, Halobacterium, Heliobacter, Haemophilus, Hemophilus influenza type B (HIB), Hyphomicrobium, Legionella, Leptspirosis, Listeria, Meningococcus A, B and C, Methanobacterium, Micrococcus, Myobacterium, Mycoplasma, Myxococcus, Neisseria, Nitrobacter, Oscillatoria, Prochloron, Proteus, Pseudomonas, Phodospirillum, Rickettsia, Salmonella, Shigella, Spirillum, Spirochaeta, Staphylococcus, Streptococcus, Streptomyces, Sulfolobus, Thermoplasma, Thiobacillus, Treponema, Vibrio, Yersinia, Cryptococcus neoformans, Histoplasma sp. (such as Histoplasma capsulatum), Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi, Leishmania, Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis, Plasmodium sp. (such as Plasmodium falciparum), Trypanosoma brucei, Entamoeba histolytica, Toxoplasma gondii, Trichomonas vaginalis and Schistosoma mansoni. 24. A pharmaceutical dosage unit comprising an anti-PD-1 antibody or an antigen binding fragment thereof and a potentiating agent selected from the group consisting of cyclophosphamide and an analog of cyclophosphamide, wherein administration of the dosage unit to a subject increases a T cell response in the subject,wherein the dose of the potentiating agent is less than 200 mg/kg,wherein the dose of potentiating agent is not effective to have direct anti-tumor activity,and wherein the T cell response achieved by the dosage unit is greater than the T cell response achieved by administering either the anti-PD-1 antibody alone or the potentiating agent alone. 25. A method of increasing T cell response in a human comprising administering to a human the pharmaceutical dosage unit of claim 24. 26. The pharmaceutical dosage unit of claim 24 further comprising an antigen. 27. The method of claim 15 wherein the T cell response against the cancer achieved by the combination of the anti-PD1 antibody and the potentiating agent is greater than the T cell response against the cancer achieved by administering either the anti-PD 1 antibody alone or the potentiating agent alone. 28. The method of claim 1 wherein the dosage of potentiating agent is 5 mg/kg.