Background: Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form of pancreatic cancer with poor survival outcomes. Results from the clinic have demonstrated the lack of efficacy when either radiotherapy (RT) or immunotherapy are used as a monotherapy. Recent publications revealed a synergistic effect on RT-induced immune modulation and reduced immune suppression when the immunotherapy was administrated concurrently with RT in mouse models. Other publications demonstrate that immune evasion in PDAC depends on the CCL5/CCR5 axis to recruit immunosuppressive T-regulatory cells (Tregs) into the tumor microenvironment. Therefore, targeting the migration of Tregs through modulation of CCL5/CCR5 axis can potentially inhibit tumor growth in pancreatic cancer.
Aim: This preclinical study is evaluating the impact of fractionated MR-Image Guided Radiotherapy (MR-IGRT) in combination CCR5 inhibitor and simultaneous inhibition of the immune checkpoint axis PD1/PD-L1 on pancreatic cancer.
Methods: For the purpose of this study we generated a syngeneic orthotopic pancreatic mouse model. Tumor cells derived from the Lox-Stop-Lox (LSL)-KrasG12D; LSL-Trp53R172H; Pdx1-cre (KPC) mouse model are injected in the tail of the pancreas. We are able to monitor tumor growth using a respiratory motion desensitized T2-weighted MRI imager, allowing the generation of high-resolution and high-contrast MRI data. Taking advantage of in-house developed technology, the MR-IGRT was delivered using the Small Animal Radiation Research Platform (SARRP) in combination with MRI imaging to deliver MR-guided fractionated radiotherapy. Concurrently with the radiotherapy, CCR5 inhibitor (maraviroc) and PD1 inhibitor were administered at specific time points. To investigate the immunologic microenvironment, we developed a 17-color flow cytometry (FC) panel to immune-phenotype cytotoxic T, T regulatory, NK, NK/T and B cells, M-MDSC, PMN-MDSC, M1 and M2 macrophages in the peripheral blood and tumor infiltrate.
Results/Conclusions: Using the established orthotopic mouse model, our aim is to investigate how the combination of MRI-guided radiotherapy and immune therapies can modulate the tumor microenvironment and the immune response in pancreatic cancer. This project is part of an ongoing preclinical study, and preliminary results will be presented at the meeting.
Citation Format: Simone Lanfredini, Sophie Hughes, Asmita Thapa, Fiona Bangs, Jennifer Morton, Danny Allen, Veerle Kersemans, Paul Kinchesh, Sean Smart, Amy Elliot, James Thompson, Mark Hill, Somnath Mukherjee, Eric O'Neill. Assessment of CCR5i/maraviroc immunotherapy in combination with PD1 and MR-guided radiotherapy for treatment of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B30.