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PLoS One. 2013 Dec 19;8(12):e84927. doi: 10.1371/journal.pone.0084927. eCollection 2013.

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

Author information

1
International Joint Cancer Institute, Second Military Medical University, Shanghai, China ; School of Pharmacy, Liaocheng University, Liaocheng, China.
2
School of Bioscience and Bioengneering, South China University of Technology, Guangzhou, China.
3
Department of Pathology, Harborview Medical Center, University of Washington, Seattle, Washington, United States of America.
4
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.

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'.

PMID:
24367702
PMCID:
PMC3868659
DOI:
10.1371/journal.pone.0084927
[Indexed for MEDLINE]
Free PMC Article

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