LAUSR

The recent past has seen impressive progress in the treatment of various malignancies using immunotherapy. One of the most promising approaches involves immune checkpoint inhibition, mainly relying on monoclonal antibodies or small molecules. With specific relevance to pancreatic cancer, however, checkpoint inhibitors are largely ineffective, in part because of poor T cell infiltration, low tumor mutational burden, an immunosuppressive tumor microenvironment, and the presence of a dense desmoplastic stroma. To overcome these challenges, here we describe the preclinical testing of a new checkpoint inhibitor named MN-siPDL1 in combination with gemcitabine in an aggressive model of PDAC. MN-siPDL1 utilizes the RNA interference mechanism (siRNA) to block the synthesis of the critical immune checkpoint mediator, PD-L1 by tumor cells. The siRNA is delivered by a nanoparticle carrier (MN) that is optimized for oligonucleotide delivery to solid tumors. The efficacy and preliminary safety of MN-siPDL1 were tested in an orthotopic syngeneic model of pancreatic ductal adenocarcinoma generated by implanting Hy15549 murine PDAC cells into the pancreas of C57BL/6J mice. Our studies demonstrated that MN-siPDL1 was successfully delivered and effective even in the highly desmoplastic and hypovascular Hy15549 murine model of PDAC, which has been deemed nonresponsive to antibody-based immune checkpoint blockade. Anatomic MRI showed that in the animals treated with MN-siPDL1 plus gemcitabine, tumor growth rates were lower than in the vehicle control. After two weekly treatments with MN-siPDL1 plus gemcitabine, tumor volumes were four times smaller than in untreated animals. Importantly, animal survival was improved dramatically in animals treated with MN-siPDL1 plus gemcitabine compared to all other groups. Among the animals treated with MN-siPDL1 plus gemcitabine, the hazard ratio for overall survival (OS) relative to PBS was 0.08. Interestingly, even in the absence of gemcitabine, MN-siPDL1 as monotherapy improved survival more dramatically than gemcitabine (HR, 0.24 for MN-siPDL1 vs. 0.42 for gemcitabine). Immunohistology on the tumor tissues post-necropsy indicated that the treatment inhibited PD-L1 and induced a cytotoxic immune response. Finally, as an initial measurement of tissue damage due to the treatment, we analyzed major organs by histopathology and saw no differences from the vehicle-treated controls. Considering the aggressive and fibrous nature of the Hy15549 model and its resistance to traditional checkpoint inhibitors, the described RNAi-based therapeutic approach could be promising against PDAC and could make an impact on one of the most intractable cancers which has long evaded the power of modern medicine to deliver long-term survival. Citation Format: Byunghee Yoo, Mozhdeh Sojoodi, Veronica Clavijo Jordan, Pamela Pantazopoulos, Subrata Ghosh, Peter Caravan, Zdravka Medarova. Cancer immunotherapy based on the RNAi-based PD-L1 inhibitor, MN-siPDL1, demonstrates efficacy in preclinical pancreatic adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5069.