Abstract 4023: Combination therapy with immune checkpoint inhibitor and CCK-receptor blockade increases survival of pancreatic cancer

Abstract

Abstract Introduction: Advanced pancreatic ductal adenocarcinoma (PDAC) has typically been resistant to chemotherapy and immune therapy; therefore, novel strategies are needed to enhance therapeutic response. Cholecystokinin receptors (CCKRs) are present on pancreatic cancer epithelial cells, fibroblasts of the microenvironment, and lymphocytes. We hypothesized that CCK receptor blockade would improve response to immune checkpoint blockade and survival by promoting influx of tumor infiltrating lymphocytes (TILs) and reducing fibrosis. Methods: Subcutaneous tumors were established using Panc02 murine pancreatic cancer cells (1.0- or 2.0 x10E6) in a syngeneic immune competent mouse model. Three separate experiments were performed with 40 mice each. Mice (C57BL/6) were divided into 4 groups (N = 10 mice each) and treated with PBS (control), a CCKR antagonist (L364,718 or proglumide), an immune checkpoint blockade antibody (PD-1 or CTLA-4; Im-Ab), or the combination of CCKR antagonist and immune checkpoint blockade antibody (combination). Tumor growth and animal survival were evaluated. Tumors were subjected to immunohistochemical staining for TILs, trichrome staining, and flow cytometry. Results: On day 50 after inoculation of 10E6 cells all control mice had died while 42%, 42% and 71% of L364,718, CTLA-4 mice, or combination-treated mice, respectively were alive (p = 0.02). By day 90 all mice died except one in the combination-treated group. In the experiment where mice were injected with 2×10E6 Panc02 cells, survival was also increased in mice receiving a proglumide and PD-1 antibody combination (p = 0.0009). CD8+TILs increased by 3-,6.3-,and 7.5-fold in CCKR antagonist, Im-Ab, and combination therapy, respectively compared to controls (p<0.0001). CD4+ TILs also significantly increased (p = 0.001) in the tumors of mice treated with the combination. Trichrome stain analysis revealed 50% less fibrosis in mice treated with CCKR antagonist compared to PBS controls (p = 0.017). Conclusions: The combination of CCKR antagonism and immune checkpoint blockade antibodies significantly improve survival in a murine model of PDAC. The mechanism is associated with decreased fibrosis in the microenvironment and an accompanying influx of CD8+ and CD4+ TILs. Supported by NCI CA50633, CA51008, and CA194745 Citation Format: Jill P. Smith, Shangzi Wang, Ajina Reham, Sandra A. Jablonski, Louis M. Weiner. Combination therapy with immune checkpoint inhibitor and CCK-receptor blockade increases survival of pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4023.