Title |
Combinatorial PD-1 Blockade and CD137 Activation Has Therapeutic Efficacy in Murine Cancer Models and Synergizes with Cisplatin
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Published in |
PLOS ONE, December 2013
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DOI | 10.1371/journal.pone.0084927 |
Pubmed ID | |
Authors |
Huafeng Wei, Likun Zhao, Wei Li, Kexing Fan, Weizhu Qian, Sheng Hou, Hao Wang, Min Dai, Ingegerd Hellstrom, Karl Erik Hellstrom, Yajun Guo |
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'. |
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United States | 1 | 33% |
Unknown | 1 | 33% |
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Mendeley readers
Geographical breakdown
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Iran, Islamic Republic of | 1 | <1% |
Netherlands | 1 | <1% |
Unknown | 138 | 97% |
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Readers by professional status | Count | As % |
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Researcher | 47 | 33% |
Student > Ph. D. Student | 25 | 18% |
Other | 14 | 10% |
Student > Bachelor | 10 | 7% |
Student > Master | 10 | 7% |
Other | 14 | 10% |
Unknown | 22 | 15% |
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Pharmacology, Toxicology and Pharmaceutical Science | 5 | 4% |
Other | 9 | 6% |
Unknown | 25 | 18% |