Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin

• Published in: PloS one Vol. 8; no. 12; p. e84927
• Main Authors: Wei, Huafeng, Zhao, Likun, Li, Wei, Fan, Kexing, Qian, Weizhu, Hou, Sheng, Wang, Hao, Dai, Min, Hellstrom, Ingegerd, Hellstrom, Karl Erik, Guo, Yajun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.12.2013; Public Library of Science (PLoS)
• Subjects: Analysis; Analysis of Variance; Animal models; Animals; Antibodies, Monoclonal, Murine-Derived - administration & dosage; Antibodies, Monoclonal, Murine-Derived - pharmacology; Antibodies, Monoclonal, Murine-Derived - therapeutic use; Antigens; Antineoplastic Combined Chemotherapy Protocols - immunology; Apoptosis; Cancer; Cancer therapies; Cancer treatment; CD137 antigen; CD8 antigen; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Clinical trials; Combinatorial analysis; Combined treatment; Cytolytic activity; Dendritic cells; Deoxyribonucleic acid; DNA; Drug Synergism; Enzyme-Linked Immunosorbent Assay; Female; Immune response; Immune system; Immunological memory; Immunology; Immunomodulation; Immunotherapy; Injections, Intraperitoneal; Interferon; Kaplan-Meier Estimate; Ligands; Lung cancer; Lungs; Lymphocytes; Lymphocytes T; Melanoma; Mice; Mice, Inbred C57BL; Monoclonal antibodies; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - drug therapy; Pathology; PD-1 protein; Peritoneum; Pharmacy; Programmed Cell Death 1 Receptor - administration & dosage; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Survival; T cells; Tumor Necrosis Factor Receptor Superfamily, Member 9 - administration & dosage; Tumor Necrosis Factor Receptor Superfamily, Member 9 - antagonists & inhibitors; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumors; γ-Interferon; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0084927

There is an urgent need for improved therapy for advanced ovarian carcinoma, which may be met by administering immune-modulatory monoclonal antibodies (mAbs) to generate a tumor-destructive immune response. Using the ID8 mouse ovarian cancer model, we investigated the therapeutic efficacy of various mAb combinations in mice with intraperitoneal (i.p.) tumor established by transplanting 3 × 10(6) ID8 cells 10 days previously. While most of the tested mAbs were ineffective when given individually or together, the data confirm our previous finding that 2 i.p. injections of a combination of anti-CD137 with anti-PD-1 mAbs doubles overall survival. Mice treated with this mAb combination have a significantly increased frequency and total number of CD8(+) T cells both in the peritoneal lavage and spleens, and these cells are functional as demonstrated by antigen-specific cytolytic activity and IFN-γ production. While administration of anti-CD137 mAb as a single agent similarly increases CD8(+) T cells, these have no functional activity, which may be attributed to up-regulation of co-inhibitory PD-1 and TIM-3 molecules induced by CD137. Addition of the anti-cancer drug cisplatin to the 2 mAb combination increased overall survival >90 days (and was probably curative) by a mechanism which included a systemic CD8(+) T cell response with tumor specificity and immunological memory. Strikingly, combined treatment of cisplatin and CD137/PD-1 mAb also gave rise to the long-term survival of mice with established TC1 lung tumors. A similar combination of the 2 mAbs and cisplatin should be considered for clinical 'translation'.