Abstract 3976: PD-1 blockade combined with TEGVAX (TLR agonists-enhanced GVAX) can induce regression of established palpable tumors.

Abstract

Abstract Background: Cell-based vaccines have been developed for several types of tumors, but these vaccines have two critical shortcomings that weaken their clinical efficacy. The first of which is a limited capability to activate antigen presenting cells. Second, they fail to address critical immune checkpoint molecules that dampen the subsequent T-cell response against the established tumor. In order to optimize the activation of antigen presenting cells capable of marshaling both an innate and adaptive immune response against the tumor, we formulated a GM-CSF secreting tumor cell vaccine with multiple TLR agonists. To address the immune checkpoint signaling pathway, we combined our formulated vaccine with a blocking αPD-1 antibody in two mouse models of established tumor - one with melanoma and the other with tongue cancer. Methods: To optimize in vivo efficacy of anti-tumor T-cell response, we engineered TEGVAX, a GM-CSF secreting cell-based tumor vaccine formulated with GLA (TLR4 agonist) and R848 (TLR7/8 agonists), molecules that are amenable for clinical translation. We then combined TEGVAX with αPD-1 blocking antibody (G4 clone) in the murine B16 melanoma and SCCFVII tongue cancer model. Furthermore, we studied immunological parameters that correlated with in vivo anti-tumor response. Results: In both B16 and SCCFVII treatment models, TEGVAX demonstrated statistically significantly (p<0.01) enhanced anti-tumor responses in comparison to the parental cell vaccine in vivo. For tumor bearing mice treated with TEGVAX, these potent anti-tumor responses were correlated with a statistically significant increase in CD4+ and CD8+ T-cells that secrete IFNγ in the tumor microenvironment. TEGVAX treated mice also had significantly higher levels of tumor antigen p15E-specific cell mediated killing in vivo. Blockade of the PD-1 immune checkpoint pathway further augmented the therapeutic potential of TEGVAX and induced the regression of established B16 and SCCFVII tumors. Conclusion: When combined with αPD-1 antibody, TEGVAX was able to induce regression of established B16 and SCCFVII tumors. Our results with these combinatorial immunotherapeutic strategies provide preclinical evidence to support the translation of these reagents for HNSCC or melanoma patients that are refractory to standard treatment modalities. Citation Format: Ian-James Malm, Juan Fu, Drew Pardoll, Young J. Kim. PD-1 blockade combined with TEGVAX (TLR agonists-enhanced GVAX) can induce regression of established palpable tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3976. doi:10.1158/1538-7445.AM2013-3976