The immunosuppressive prostate cancer microenvironment renders most infiltrating effector immune cells anergic or regulatory. Immunotherapeutic agents localized to the prostate can break this immune tolerance, leading to greater efficacy and less toxicity than systemically administered drugs. We have previously shown that cytotopic modification of interleukin-15 (cyto-IL-15) can activate NK and CD8+ T-cells in the presence of prostate cancer cells. In the present study, we used this cyto-IL-15 and two immuno-checkpoint blocking antibodies modified in a similar approach (these antibodies have previously exhibited antitumor response in clinical trials) to investigate their efficacy when used alone or in combination in a syngeneic murine model of prostate cancer. IL-15 and antibodies were modified by conjugation to a myristoylated peptide that enables them to adhere to cell membranes (patents pending), and thus localize to any potential site of injection. The cytotopically modified IL-15 and antibodies were injected intratumorally either alone (cyto-IL-15 or cyto-abs) or in combination (cyto-combo) in subcutaneous TRAMP C2 prostate tumors in C57BL/6 mice and compared with their nonmodified equivalents and with a vehicle-treated control group. Histopathologic analysis and immunohistochemistry were performed on sections from excised frozen tumors in order to quantify necrosis (haematoxylin and eosin staining) and immune cell infiltration. Intratumoral injection of cyto-IL15, combo or cyto-combo significantly delayed tumor growth at day 14 post-treatment by 50%. However, only cyto-IL15 and cyto-combo significantly increased median survival after treatment to 28 (p < 0.05) and 24 days (p < 0.05) respectively, compared with 17 days in the vehicle group. Nonmodified IL15 or antibodies alone had no effect on tumor growth or survival. Mice showed no adverse effects or weight loss with either of the treatments. Moreover, histologic analysis showed that cyto-IL-15 increased necrosis and infiltration of NK cells and CD8+ T cells in the tumors compared with the vehicle- and nonmodified-IL-15-treated groups. We have demonstrated that cytotopically modified immunotherapeutic agents can lead to tumor growth delay in an in vivo murine model of prostate cancer, induce tumor cell death and increase mouse survival. Hence, cytotopic modification in combination with direct injection of the agents directly into the tumor site appears to be a promising novel approach for prostate cancer immunotherapy.
Citation Format: Efthymia Papaevangelou, Dorota Smolarek, Oussama Elhage, Richard A. Smith, Prokar Dasgupta, Christine Galustian. Targeting prostate cancer using novel cytotopically modified immunotherapies intratumorally in a syngeneic murine model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A11.