Abstract 2941: Local tumor irradiation combined with α-PDL-1 immune checkpoint inhibition results in local and systemic anti-tumor responses: Successful translation of a mouse model to a human case series

Introduction: Tumor irradiation induces innate and adaptive immune responses which, rarely, lead to tumor regression at distant sites, the abscopal effect. We have previously demonstrated that immunotherapy including Toll-like-receptor agonists (CpG) and checkpoint inhibitors (anti-CTLA4) both preclinically and clinically (NCT00185965 & NCT01769222) can significantly increase the rate of systemic, abscopal responses (Kim, Blood 2012 & Brody, JCO 2010). Here we provide the first report of a preclinical murine model and patient case series following local radiation and systemic anti-PD-L1 (NCT01375842). Methods: Preclinical modeling was performed in a two-tumor, syngenic, A20, lymphoma BALB/c model combining fractionated single tumor radiation and systemic (i.p.) anti-PD-L1. Patients receiving MPDL3280A, a human mAb containing an engineered Fc-domain, as part of the phase 1 clinical trial with mixed responses or asymptomatic progression of disease were eligible for the addition of local radiation therapy. Murine and human immune responses including cell phenotype and function, specifically assessing expression of PD-L1 and production of IFNγ were determined by standard flow cytometry and time of flight mass cytometry (CyTOF). Results: Fractionated radiation delayed tumor growth at the treated site only, and systemic anti-PD-L1 reduced tumor growth rate at both sites, however despite prolonged survival all mice died by day 38 following either monotherapy (radiation or anti-PD-L1). In contrast, combination local fractionated radiation and systemic anti-PD-L1 flattened tumor growth at both the irradiated and un-irradiated site, and prolonged survival with 50% survival at day 48 post-tumor inoculation. Modulation of PD-L1 expression post-radiation and tumor-specific augmentation of IFNγ secretion correlated with the enhanced anti-tumor activity. Five patients including four with solid tumors received fractionated, non-definitive dose radiation with at least stabilization of systemic progression in all patients and a RECIST partial response at systemic sites in 1 patient, notably with a synovial sarcoma. Transient, grade 1-2 inflammatory adverse events (fevers, flu-like symptoms) occurred with no DLTs or serious immune-related toxicities. Modulation of PD-L1 expression, T cell phenotype and IFNγ secretion was observed and updated clinical and immune response will be presented. Conclusion: We provide the first report of combination local radiotherapy with anti-PD-