Abstract
Abstract
PDAC is typically resistant to chemotherapy and immunotherapy; therefore, novel strategies are needed to enhance therapeutic response. BXCL701 is a well-studied inhibitor of dipeptidyl peptidases 4, 8, 9, and Fibroblast Activation Protein, and has been postulated to work through cytokine induction and macrophage pyroptosis. We examined the effects of BXCL701 and/or PD1 therapy in murine models of PDAC. In the mT3-2D PDAC model, combination therapy of established (~75mm3) sc tumors reduced tumor growth to a greater extent (PBS: 1349±230 mm3 on day 42 vs B + PD1: 355±161mm3, p<0.0001) following a 28-day treatment program of PBS, B (1mg/kg by daily oral gavage), PD1 (10mg/kg ip weekly) or the combination of B + PD1. Treatment with either B or PD1 alone had minimal anti-tumor effects. B + PD1 therapy was accompanied by significant tumor infiltration of NK cells by IHC, flow cytometry and Nanostring analysis. A dramatic reduction of tumor stromal fibrosis by Masson's trichrome staining was found in tumors treated with B alone or B + PD1. These findings suggest that the combination of BXCL701 with anti-PD1 antibody therapy can exert anti-tumor effects associated with increased intratumoral NK cell content and the loss of fibrosis that may facilitate immunotherapy efficacy.
Citation Format: Shangzi Wang, Allison Fitzgerald, Reham Ajina, Sandra A. Jablonsk, Louis M. Weiner, John MacDougall, Veena Agarwal, Vince J. O'Neill. Therapy with BXCL701 (B), a DPP8, DPP9, DPPIV and FAP inhibitor, in combination with anti-PD1 antibody (PD1) in a syngeneic murine pancreatic ductal adenocarcinoma (PDAC) model improves treatment outcomes and induces intratumoral NK cell infiltrates and a marked reduction in tumor stromal fibrosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6636.