Abstract 4708: Imprime (beta-1,3/1,6 glucan) synergizes with a CD40 agonist to stimulate T cell-dependent antitumor activity in a poorly immunogenic model of pancreatic carcinoma

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Abstract Introduction: While some solid tumors show remarkable sensitivity to immunotherapy, pancreatic ductal adenocarcinoma (PDAC) has demonstrated impressive resistance. This poor responsiveness to immunotherapy may reflect multiple mechanisms necessary for generating productive T-cell immunosurveillance, including ineffective tumor antigen presentation by myeloid cells. Here, we hypothesized that combining two immune agonists capable of “licensing” myeloid cells with enhanced T-cell stimulatory properties would synergize to reverse the poorly immunogenic state of pancreatic cancer and, in doing so, drive productive T cell-dependent antitumor immunity. Methods: C57BL/6 mice were challenged subcutaneously with a syngeneic PDAC cell line (7940B.PDA) derived from a tumor arising spontaneously in the KrasG12D/+; Trp53R172H/+; Pdx-1 Cre (KPC) mouse model. Mice with tumors measuring approximately 5 mm3 in diameter were treated with defined combinations of gemcitabine chemotherapy, a CD40 agonist (FGK45), and Imprime (a yeast β-1,3/1,6 glucan that coordinately activates innate and adaptive immune responses through pattern recognition receptors). CD4 and CD8 T cells were depleted in vivo using GK1.5 and 2.43 antibodies, respectively. Tumor growth curves and overall survival were determined. Results: Monotherapy with Imprime or a CD40 agonist only modestly delayed tumor outgrowth compared to chemotherapy alone. Delivering chemotherapy 48 hours prior to Imprime administration produced a two-fold increase in the median overall survival, but responses were not durable and all mice relapsed. In contrast, concurrent single administration of Imprime and a CD40 agonist induced complete and durable regressions in 60% of mice. Tumor-free mice resisted tumor rechallenge and therapeutic efficacy was completely abrogated with CD4/CD8 cell depletion. Conclusions: The combination of two myeloid-directed immune agonists (Imprime and a CD40 agonist) shows promising activity for stimulating T cell-dependent antitumor immunity against PDAC, a poorly immunogenic cancer. Citation Format: Mingen Liu, Kathleen Graham, Anissa S. Chan, Nadine R. Ottoson, Nandita Bose, Gregory L. Beatty. Imprime (beta-1,3/1,6 glucan) synergizes with a CD40 agonist to stimulate T cell-dependent antitumor activity in a poorly immunogenic model of pancreatic carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4708.