Background: Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form of pancreatic cancers with poor survival outcomes, due to late diagnosis, its propensity to metastasize, and lack of therapeutic efficacy under current chemotherapeutic regimens. Despite recent advancements in the field of immunotherapy, results from the clinic have demonstrated lack of efficacy when either radiotherapy (RT) or immunotherapy is used as a monotherapy in PDAC. However, recent publications revealed a synergistic effect on RT-induced immune modulation and reduced immune suppression when administered concurrently. Moreover, these reports demonstrate immune evasion in PDAC is dependent 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 can potentially inhibit tumor growth in pancreatic cancer.
Aim: This preclinical study evaluates 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 in PDAC.
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 administrated 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 and immune monitoring, we are investigating the therapeutic benefit of immunomodulation of the CCL5/CCR5 axis in combination with PD1/PDL1 and radiotherapy.
Citation Format: Sophie Hughes, Simone Lanfredini, Asmita Thappa, Somnath Mukherjee, Eric O’Neill. Assessment of CCR5/maraviroc immunotherapy in combination with PD1 and MR-guided radiotherapy for treatment of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B69.