We have previously demonstrated that tumor irradiation potentiates cancer vaccines using genetic modification of tumor cells in murine tumor models. We showed that prior tumor irradiation enhanced the response of mice to intratumoral gene therapy with an IL-2 adenovector for non-immunogenic tumors. To investigate whether tumor irradiation augments the immune response to a specific tumor antigen, we have now tested the efficacy of tumor irradiation to enhance the therapeutic effect of MVA-MUC1-IL2 cancer vaccine (Transgene TG4010) for the treatment of murine renal adenocarcinoma Renca cells transfected with MUC1. Established subcutaneous (s.c.) Renca-MUC1 tumors (18mm3) were irradiated with 8 Gy on day 11 and peritumoral s.c. injections of MVA-MUC1-IL2 vector were administered at 106- 107 PFU on day 12 and 20. Tumor growth delays were monitored by tumor measurements and histological responses were evaluated following treatment with radiation alone, vector alone, radiation + MVA-MUC1-IL2 vector or radiation + MVA empty vector. Histological evaluation of tumors at an early time point, by 2-3 weeks after radiation and cancer vaccine, revealed that tumors treated with radiation and vaccine showed extensive areas of necrosis due to complete tumor destruction. Intense hemorrhages were observed due to disruption of tumor vasculature. Small areas of remaining tumor showed apoptotic tumor cells and degenerating giant tumor cells typical of radiation-induced changes. At the periphery of the tumor and infiltrating the tumor, we observed large bands of inflammatory cells including lymphocytes and macrophages as well as fibroblasts spindled shaped cells. Immuno-histochemical staining with CD45 leukocyte marker and F4/80 macrophage marker confirmed extensive infiltration of leukocytes and macrophages at the periphery and inside of areas of tumor destruction. These alterations were not as pronounced with radiation alone suggesting a drastic effect of the combined radiation + vaccine therapy on the tumor microenvironment. Radiation induced tumor growth delays for about 15 days but longer tumor growth delays of 30-35 days were observed with radiation + MVA-MUC1-IL2. By day 55, over 30% of the mice treated with radiation + MVA-MUC1-IL2 had a complete response with no sign of tumor whereas no responders were observed with either radiation alone or cancer vaccine alone. Complete responders were immune to rechallenge with Renca-MUC1 cells. These findings suggest that tumor irradiation given prior to cancer vaccine augments a specific immune response targeted at a specific tumor antigen that results in specific tumor immunity. The mechanisms of interaction between tumor irradiation and gene-mediated immunotherapy could include radiation-induced alterations in the tumor microenvironment, as those observed histologically in our studies, which could facilitate a more effective anti-tumor immune response. These include radiation-induced apoptosis and necrosis of tumor cells causing tumor-debulking and release of tumor antigens for APC presentation. Inflammatory cells mobilized in the tumor by radiation-induced tissue damage could subsequently be activated by the immune response triggered by the cancer vaccine. These studies support investing further pre-clinical and clinical efforts to combine radiotherapy with cancer vaccines for the treatment of cancer.
Citation Format: Gilda Gali Hillman, Matthew D. Fountain, Shoshana E. Rothstein, Lyndsey Reich, Lisa Abernathy, Christopher K. Yunker, Fulvio Lonardo, Philippe Slos. Induction of specific immunity to MUC1 antigen by tumor irradiation and cancer vaccines in murine tumor models. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B185.
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