Therapeutic tumor immunity requires the presence and appropriate activation of tumor antigen specific CD8+ T cells and migration of activated tumor-antigen specific CD8+ T cells into a tumor microenvironment where immunosuppressive barriers have been eliminated. Antibody mediated blockade of CTLA-4 and PD-1 is a clinically effective strategy to dampen tumor mediated immunosuppression in a minority of patients with advanced cancer, and this approach may be potentiated through vaccination to prime additional CTL clones and through direct stimulation of T cell costimulatory molecules of the TNF superfamily. Here we provide a systematic comparison of anti-tumor vaccination with either heat shock protein gp96-Ig or traditional peptide/adjuvant vaccines given alone or in combination with CTLA-4 or PD-1 blockade and direct T cell costimulation via OX40, 4-1BB and TNFRSF25. Through the tracking of tumor-antigen specific CD4+ and CD8+ T cell responses, these studies demonstrate that both TNFRSF4 and TNFRSF25 independently and additively costimulate vaccine induced CD8+ T cell proliferation following both primary and secondary antigen challenge. In contrast, the activity of TNFRSF4 and TNFRSF25 were observed to be divergent in the costimulation of CD4+ T cell immunity. Interestingly, antigen-specific cellular and humoral responses were uncoupled upon secondary immunization, which was dramatically effected by the presence of OX40, 4-1BB or TNFRSF25 costimulation. When combined with checkpoint inhibition in therapeutic murine orthotopic tumor models, synergistic anti-tumor activity was observed with various triple combinations with vaccine, checkpoint inhibition and T cell costimulation. These studies highlight the complementary activity of vaccination, checkpoint inhibition and direct T cell costimulation, which may guide the application of combination immunotherapy for effective anti-tumor immunity.

Citation Format: Taylor H. Schreiber, Neal Schilling, Vadim Deyev, Eckhard R. Podack. Comparative combination cancer immunotherapy with vaccination, checkpoint inhibition and TNFRSF stimulation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5029. doi:10.1158/1538-7445.AM2014-5029