title: Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin.
abstract: 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'.
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China ; School of Pharmacy, Liaocheng University, Liaocheng, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
authors.affiliation: School of Bioscience and Bioengneering, South China University of Technology, Guangzhou, China.
authors.forename: Likun
authors.initials: L
authors.lastname: Zhao
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China ; School of Pharmacy, Liaocheng University, Liaocheng, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China ; School of Pharmacy, Liaocheng University, Liaocheng, China.
authors.forename: Kexing
authors.initials: K
authors.lastname: Fan
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China ; School of Pharmacy, Liaocheng University, Liaocheng, China.
authors.forename: Weizhu
authors.initials: W
authors.lastname: Qian
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China ; School of Pharmacy, Liaocheng University, Liaocheng, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Hou
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China ; School of Pharmacy, Liaocheng University, Liaocheng, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, Harborview Medical Center, University of Washington, Seattle, Washington, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Dai
authors.affiliation: Department of Pathology, Harborview Medical Center, University of Washington, Seattle, Washington, United States of America.
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Hellstrom
authors.affiliation: Department of Pathology, Harborview Medical Center, University of Washington, Seattle, Washington, United States of America.
authors.forename: Karl Erik
authors.initials: KE
authors.lastname: Hellstrom
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China ; School of Bioscience and Bioengneering, South China University of Technology, Guangzhou, China ; School of Pharmacy, Liaocheng University, Liaocheng, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology*; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007274:Injections, Intraperitoneal; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D061026:Programmed Cell Death 1 Receptor / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D002945:Cisplatin