Search

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'.

Monoclonal antibodies (mAbs) to CD137 (a.k.a. 4-1BB) have anti-tumor efficacy in several animal models and have entered clinical trials in patients with advanced cancer. Importantly, anti-CD137 mAbs can also ameliorate autoimmunity in preclinical models. As an approach to better understand the action of agonistic and antagonistic anti-CD137 mAbs we have mapped the binding region of the CD137 ligand (CD137L) to human and mouse CD137. By investigating the binding of CD137L to cysteine rich domain II (CRDII )and CRDIII of CD137, we found that the binding interface was limited and differed between the two species in that mouse CD137L mainly combined with CRDII and human CD137L mainly combined with CRDIII.