Abstract PO-046: Combining PARP inhibition with radiation to sensitize homologous recombination proficient pancreatic cancer to immunotherapy
Authors: Qiang Zhang, Long Jiang, Yawen Zheng, Theodore Lawrence, Vaibhav Sahai, Michael D. Green, Meredith Morgan
Journal: Clinical Cancer Research (2021)

Abstract Pancreatic cancer is notoriously resistant to most cancer therapeutics including immunotherapy. We have previously shown that inhibition of the DNA damage response (DDR) enhances radiation-induced Type I interferon (T1IFN) and sensitizes pancreatic cancers to immunotherapy. In this study, we investigated the efficacy of radiation in combination with the poly (ADP-ribose) polymerase (PARP)inhibitor olaparib and programmed death ligand 1 (PD-L1) immune checkpoint blockade in otherwise resistant homologous recombination (HR) proficient pancreatic cancer. Initial studies demonstrated, in contrast to olaparib alone, that the combination of olaparib and radiation induced innate immune signaling in HR proficient pancreatic cancer cells marked by increases in pTBK1, T1IFN and pSTAT1. In animal tumor models, we found that the therapeutic efficacy of olaparib and radiation was greater in immune competent versus immune deficient hosts. In addition to the positive immune effects of olaparib and radiation, we also observed increased expression of PD-L1, a negative immune regulatory mechanism that likely restrains T1IFN-mediated innate immunity. We therefore went on to test the combined efficacy of PD-L1 blocking antibody with olaparib and radiation in syngeneic pancreatic tumor models. We found that monotherapy was ineffective in controlling tumor growth while doublet therapy with olaparib and radiation produced an intermediate tumor growth response. Importantly, maximal tumor growth inhibition was achieved following combined treatment with olaparib, radiation, and anti-PD-L1 which was significant relative to doublet therapy with olaparib-radiation or anti-PD-L1-radiation, and associated with a 20% complete response rate. Given that advances in therapy of pancreatic cancer require improvements in both local and systemic disease control, we examined the efficacy of combined therapy against tumors outside of the radiation field. In addition to the effects on tumors in the radiation field, we found that combined therapy with olaparib, radiation and anti-PD-L1 significantly delayed the growth of contralateral tumors outside of the radiation field, suggesting an adaptive immune response. Taken together, these studies illustrate the potential efficacy of combined therapy with olaparib, radiation, and anti-PD-L1 on both local and systemic pancreatic cancer and support our proposed clinical trial in patients with pancreatic cancer. Citation Format: Qiang Zhang, Long Jiang, Yawen Zheng, Theodore Lawrence, Vaibhav Sahai, Michael D. Green, Meredith Morgan. Combining PARP inhibition with radiation to sensitize homologous recombination proficient pancreatic cancer to immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-046.