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 × 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’.

Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

“…By gene-expression analysis, we were able to demonstrate that an active antitumor immune response was induced with increases in the expression of mRNA encoding Cd8a, Ifng, and Eomes. Unlike published data (15,17), our findings did not show changes in myeloid-derived suppressor cells in response to treatment (data not shown).…”

“…1). The combination of anti-4-1BB with anti-PD-1 was also more efficacious than dual combinations of anti-CLTA-4/anti-PD-1 and anti-4-1BB/anti-CTLA-4 in the ID8 model (16,17). Therefore, in at least two of the most aggressive and poorly immunogenic tumor models (ID8 and B16), anti-4-1BB/ anti-PD-1 combination appears to exhibit the strongest antitumor effect among the dual-agent combinations of several widely studied pathways (CTLA-4, PD-1, LAG-3, and 4-1BB).…”

“…Modulation of stimulatory signals by 4-1BB, OX40, or GITR pathway is still in the early stages of clinical evaluation (30). In preclinical studies, combinations of immunomodulators as well as in combination with chemotherapy, targeted agents, vaccination or irradiation, have been evaluated in various models (15)(16)(17)(18)(31)(32)(33). Here, we show that the combination of anti-4-1BB with anti-PD-1 synergistically inhibited the growth of B16F10 melanoma and MC38 colon carcinoma in syngeneic C57BL/6 mice, and that the combination was reasonably well tolerated, supporting the clinical development of an anti-4-1BB/anti-PD-1 combination immunotherapy.…”

“…Synergistic antitumor effects have been observed for combinations of anti-4-1BB with anti-TIM-3 (15) or with anti-PD-1 (16,17) in the ID8 murine ovarian cancer model. Studies on ID8 ovarian carcinoma also indicated that the anti-4-1BB/anti-PD-L1 combination had moderate impact on survival, which could be further improved with additional vaccination (18).…”

Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody

“…Preclinical data suggest that combined targeting of costimulatory and inhibitory immune checkpoint pathways may enhance antitumor immune responses and prolong survival and could reduce the incidence of immune-mediated AEs, including liver inflammation (16,(24)(25)(26). In summary, urelumab at 0.1 mg/kg every 3 weeks is well tolerated with evidence of immunologic activity.…”