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

H Wei, L Zhao, W Li, K Fan, W Qian, S Hou, H Wang… - PloS one, 2013 - journals.plos.org
H Wei, L Zhao, W Li, K Fan, W Qian, S Hou, H Wang, M Dai, I Hellstrom, KE Hellstrom, Y Guo
PloS one, 2013journals.plos.org
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 (ip) tumor established by transplanting 3× 106 ID8 cells 10 days previously.
While most of the tested mAbs were ineffective when given individually or together, the data …
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 × 106 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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