Abstract
BackgroundWe previously demonstrated that tumor irradiation potentiates cancer vaccines using genetic modification of tumor cells in murine tumor models. To investigate whether tumor irradiation augments the immune response to MUC1 tumor antigen, we have tested the efficacy of tumor irradiation combined with an MVA-MUC1-IL2 cancer vaccine (Transgene TG4010) for murine renal adenocarcinoma (Renca) cells transfected with MUC1.MethodsEstablished subcutaneous Renca-MUC1 tumors were treated with 8 Gy radiation on day 11 and peritumoral injections of MVA-MUC1-IL2 vector on day 12 and 17, or using a reverse sequence of vaccine followed by radiation. Growth delays were monitored by tumor measurements and histological responses were evaluated by immunohistochemistry. Specific immunity was assessed by challenge with Renca-MUC1 cells. Generation of tumor-specific T cells was detected by IFN-γ production from splenocytes stimulated in vitro with tumor lysates using ELISPOT assays.ResultsTumor growth delays observed by tumor irradiation combined with MVA-MUC1-IL-2 vaccine were significantly more prolonged than those observed by vaccine, radiation, or radiation with MVA empty vector. The sequence of cancer vaccine followed by radiation two days later resulted in 55–58% complete responders and 60% mouse long-term survival. This sequence was more effective than that of radiation followed by vaccine leading to 24–30% complete responders and 30% mouse survival. Responding mice were immune to challenge with Renca-MUC1 cells, indicating the induction of specific tumor immunity. Histology studies of regressing tumors at 1 week after therapy, revealed extensive tumor destruction and a heavy infiltration of CD45+ leukocytes including F4/80+ macrophages, CD8+ cytotoxic T cells and CD4+ helper T cells. The generation of tumor-specific T cells by combined therapy was confirmed by IFN-γ secretion in tumor-stimulated splenocytes. An abscopal effect was measured by rejection of an untreated tumor on the contralateral flank to the tumor treated with radiation and vaccine.ConclusionsThese findings suggest that cancer vaccine given prior to local tumor irradiation augments an immune response targeted at tumor antigens that results in specific anti-tumor immunity. These findings support further exploration of the combination of radiotherapy with cancer vaccines for the treatment of cancer.
Highlights
We previously demonstrated that tumor irradiation potentiates cancer vaccines using genetic modification of tumor cells in murine tumor models
We previously demonstrated that tumor irradiation potentiates cancer vaccines based on in situ genetic modification of tumor cells in Renca renal adenocarcinoma and Murine prostate tumor model (RM-9) prostate carcinoma syngeneic murine tumor models [6,7,8,9]
Titration experiments using radiation doses of 5 and 8 Gy and modified vaccinia Ankara (MVA)-Mucin glycoprotein antigen (MUC1)-IL-2 vaccine doses of 105, 106 and 107 Plaque forming unit (PFU) showed that the combination of 8 Gy tumor irradiation with 107 PFU MVAMUC1-IL-2 was the most effective for the treatment of Renca-MUC1 s.c. tumors (Additional file 1: Figure S1 and Additional file 2: Figure S2)
Summary
We previously demonstrated that tumor irradiation potentiates cancer vaccines using genetic modification of tumor cells in murine tumor models. Renca tumor irradiation combined with intratumoral IL-2 cytokine adenovector gene therapy caused increased tumor destruction and infiltration of immune cells resulting in complete responses in 40– 90% of the mice [6] This combined therapy was more effective than radiation or gene therapy alone and induced specific cytotoxic T cell activity and specific tumor immunity [6]. Irradiation of the tumor nodule on the day preceding initiation of gene therapy showed 50% of mice with complete regression and induction of tumorspecific immunity [7] Both CD4+ helper T cells and CD8+ cytotoxic T cells were essential for induction of an anti-tumor immune response as demonstrated by in vivo depletion of these subsets [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
