Combining immunotherapy and radiation has emerged as a promising strategy to boost efficacy of diverse immunotherapeutic agents including tumor vaccines. Immuno-radiotherapy uses radiation to increase antigen exposure and, potentially, to amplify and broaden immune responses triggered by tumor vaccines or checkpoint inhibitors. Here we explored the therapeutic potential of combining radiation therapy (RT) and a prostate cancer vaccine (ADXS-PSA) currently in clinical development. ADXS-PSA is a live-attenuated Listeria monocytogenes (Lm)-based vector expressing human PSA (Haas et al., J Immunother Cancer 2015:3(Suppl.2):P153). We confirm and extend earlier observations (Hannan et al., Can Immunol Immunother 61:2227) that the two treatment modalities cooperatively induce regression of syngeneic prostate cancer cells expressing human PSA (TPSA23). The extent of tumor growth inhibition depended on temporal sequencing of vaccine and RT with concurrent administration being superior to other treatment schedules. Using the optimal sequencing protocol, tumors were collected during (day 20) and after treatment (day 38) post-implantation to assess immune infiltrates and function during initial tumor regression and upon resumption of tumor growth. Tumor regression by the RT/vaccine combination was associated with enhanced T cell activation and robust IFNγ signatures in the tumor microenvironment as determined by transcriptome analyses. TCRβ chain sequencing revealed elevated and sustained T cell diversity in tumor tissue of mice receiving the RT/vaccine combination. Transcriptome analysis further revealed that sustained T cell diversity in the RT/vaccine group was accompanied by higher expression levels of resident and/or memory phenotypic markers. Finally, molecular analysis of recurring tumors revealed induction of select immune checkpoints (including PD-L1 and CD137) as a function of treatment, establishing a rationale to test whether therapeutic efficacy can be boosted further by targeting these markers. The results obtained support combining ADXS-PSA with radiation in the clinic and provide a versatile experimental platform to optimize combination immunotherapeutic strategies.
Citation Format: Emily K. Bongiorno, Trevor Baybutt, Carla Portocarrero, Adam Snook, Adam P. Dicker, Sandra M. Hayes, Ulrich Rodeck. Combination immunotherapy of murine prostate cancer using a Listeria-based PSA vaccine: Immune correlates of efficacy and resistance development [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B15.