Abstract 4232: TLR2 agonist as a novel therapeutic approach to treat pancreatic adenocarcinoma

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with an overall 5-year survival rate of <10% due to late stage diagnosis and poor clinical outcome with existing therapies. PDAC displays a high degree of tumor heterogeneity and immunosuppressive tumor microenvironment with lower tumor infiltrating lymphocytes (TIL). These factors contribute to resistance against chemotherapies and immunotherapies. Immunotherapies have shown activities across different tumor types including chemotherapy or targeted therapy resistant cancers however these options have little efficacy in the PDAC tumor. Here, in this study we tested the efficacy of gemcitabine in combination with Cadi-05 (TLR2 agonist) against established murine PDAC tumor models (Pan02 in C57/BL6 and 688M in B6129SF1/J). Animals were randomized to receive gemcitabine, Cadi-05, their combination or no treatment when they had tumor size ≈ 50 mm3, 65mm3 and 100 mm3. The weekly treatment of gemcitabine, Cadi-05 and their combination inhibited the tumor progression across all tumor sizes. At the end of study, PBMC and tumors were collected and analyzed for different immune parameters. Results revealed that Cadi-05 treatment alone was associated with increase in CD4+ and CD8+ T cells in PBMC as well as amongst TIL with significant decrease in their expression of immunosuppressive markers like FOXP3 and PD-1. Its combination with gemcitabine synergized the effect of each other. There was further increase in absolute TIL as well as TIL expressing CD4+ and CD8+ markers with decrease in FOXP3 and PD-1 expressing CD4+ and CD8+ TIL. Inhibition of tumor progression was associated with improved effector function of PBMC. Synergy between Cadi-05 and gemcitabine was also evident in effector function. In presence of established tumor, TLR2 agonist Cadi-05 improves effector function, increases CD4+ and CD8+ expressing TIL, decreases immune suppressive TIL and retards tumor growth. Our study suggests that combination of gemcitabine and Cadi-05 inhibits the tumor growth irrespective of its size and it is coupled with increased anti-tumor response and decreased immunosuppressive function Citation Format: Arpit Dheeraj, Chandreshwar Shukla, Dhanir Tailor, Nayan K. Jain, Kirsten Stefan, Chintan D. Patel, Rajiv Modi, Bakulesh M. Khamar, Sanjay V. Malhotra. TLR2 agonist as a novel therapeutic approach to treat pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4232.