Alpha Omega Alpha Honor Medical Society

2012 Research Abstract

PD-1 Blockade Combined with TEGVAX (TLR Agonists-Enhanced GVAX) Can Induce Regression of Established Palpable Tumors

Investigators: Ian-James Malm, Juan Fu, Deepak K. Kadayakkara, Emilia Albesiano, Hy Levitsky, Drew Pardoll, Young J. Kim, Department of Otolaryngology, Johns Hopkins University School of Medicine

Mentor: Young J. Kim, MD, Department of Otolaryngology, Johns Hopkins University School of Medicine

Background: Cell-based vaccines have been developed for several types of tumors, but these vaccines have two critical shortcomings. 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 an adaptive immune response against the tumor, we formulated a GM-CSF secreting tumor cell vaccine with multiple toll-like receptor agonists. To address the immune checkpoint signaling pathway, we combined our formulated vaccine with a blocking αPD-1 antibody.

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 tested this vaccine in two mouse models of established tumor – one with melanoma (B16) and the other with tongue cancer (SCCFVII). We then combined TEGVAX with αPD-1 blocking antibody (G4 clone) in our preclinical 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. TEGVAX treated mice also had significantly higher levels of tumor antigen p15E specific cell mediated killing in vitro. Furthermore, TEGVAX treatment was correlated with a statistically significant increase in CD4 and CD8 T-cells. These tumor-infiltrating lymphocytes secreted IFNγ in the tumor microenvironment, leading to upregulation of PD-L1 on the surface of tumor cells. Blockade of the PD-1 immune checkpoint pathway further augmented the therapeutic potential of TEGVAX and induced complete regression of established B16 tumors in a 50% of mice.

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 patients that are refractory to standard treatment modalities.

Updated on July 25, 2013.

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