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American Head & Neck Society
Annual Meeting, April 10-11, 2013
JW Marriott Grande Lakes
Orlando, Florida

During the
Combined Otolaryngology Spring Meeting
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PD-1 BLOCKADE COMBINED WITH TEGVAX (TLR AGONISTS-ENHANCED GVAX) CAN INDUCE REGRESSION OF ESTABLISHED PALPABLE TUMORS

Presentation: P002
Topic: Basic Science - Immunology
Type: Poster
Date: Wednesday - Thursday, April 10 - 11, 2013
Session: Designated Poster viewing times
Authors: Ian-James Malm, BA, Juan Fu, MD, PhD, Qi Zheng, MD, PhD, Drew Pardoll, MD, PhD, Young J Kim, MD, PhD
Institution(s): Johns Hopkins Medical Institutions

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 marshalling 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 in the 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 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 and other Th1 cytokines 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 translate these reagents for HNSCC patients that are refractory to standard treatment modalities.

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