Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigen
Background We 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 com...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2017-11-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/5/1/4.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849724123063779328 |
|---|---|
| author | Philippe Slos Gilda G. Hillman Lyndsey A. Reich Shoshana E. Rothstein Lisa M. Abernathy Matthew D. Fountain Kali Hankerd Christopher K. Yunker Joseph T. Rakowski Eric Quemeneur |
| author_facet | Philippe Slos Gilda G. Hillman Lyndsey A. Reich Shoshana E. Rothstein Lisa M. Abernathy Matthew D. Fountain Kali Hankerd Christopher K. Yunker Joseph T. Rakowski Eric Quemeneur |
| author_sort | Philippe Slos |
| collection | DOAJ |
| description | Background We 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.Methods Established 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.Results Tumor 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.Conclusions These 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. |
| format | Article |
| id | doaj-art-fe030e74722946d4a38f0b5332c2c2f3 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2017-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-fe030e74722946d4a38f0b5332c2c2f32025-08-20T03:10:50ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262017-11-015110.1186/s40425-016-0204-3Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigenPhilippe Slos0Gilda G. Hillman1Lyndsey A. Reich2Shoshana E. Rothstein3Lisa M. Abernathy4Matthew D. Fountain5Kali Hankerd6Christopher K. Yunker7Joseph T. Rakowski8Eric Quemeneur9Aff5 Present address: Oncodesign 20, rue Jean Mazen 21076 Dijon Cedex FranceAff1 grid.254444.70000000114567807Department of OncologyWayne State University School of Medicine, Karmanos Cancer Institute Hudson Webber Cancer Research Center, room 515, 4100 John R 48201 Detroit MI USAAff2 grid.254444.70000000114567807Radiation Oncology Division, Immunology & MicrobiologyWayne State University School of Medicine, Karmanos Cancer Institute 48201 Detroit MI USAAff1 grid.254444.70000000114567807Department of OncologyWayne State University School of Medicine, Karmanos Cancer Institute Hudson Webber Cancer Research Center, room 515, 4100 John R 48201 Detroit MI USAAff1 grid.254444.70000000114567807Department of OncologyWayne State University School of Medicine, Karmanos Cancer Institute Hudson Webber Cancer Research Center, room 515, 4100 John R 48201 Detroit MI USAAff1 grid.254444.70000000114567807Department of OncologyWayne State University School of Medicine, Karmanos Cancer Institute Hudson Webber Cancer Research Center, room 515, 4100 John R 48201 Detroit MI USAAff1 grid.254444.70000000114567807Department of OncologyWayne State University School of Medicine, Karmanos Cancer Institute Hudson Webber Cancer Research Center, room 515, 4100 John R 48201 Detroit MI USAAff1 grid.254444.70000000114567807Department of OncologyWayne State University School of Medicine, Karmanos Cancer Institute Hudson Webber Cancer Research Center, room 515, 4100 John R 48201 Detroit MI USAAff1 grid.254444.70000000114567807Department of OncologyWayne State University School of Medicine, Karmanos Cancer Institute Hudson Webber Cancer Research Center, room 515, 4100 John R 48201 Detroit MI USA3Transgene, Illkirch-Graffenstaden, FranceBackground We 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.Methods Established 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.Results Tumor 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.Conclusions These 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.https://jitc.bmj.com/content/5/1/4.full |
| spellingShingle | Philippe Slos Gilda G. Hillman Lyndsey A. Reich Shoshana E. Rothstein Lisa M. Abernathy Matthew D. Fountain Kali Hankerd Christopher K. Yunker Joseph T. Rakowski Eric Quemeneur Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigen Journal for ImmunoTherapy of Cancer |
| title | Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigen |
| title_full | Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigen |
| title_fullStr | Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigen |
| title_full_unstemmed | Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigen |
| title_short | Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigen |
| title_sort | radiotherapy and mva muc1 il 2 vaccine act synergistically for inducing specific immunity to muc 1 tumor antigen |
| url | https://jitc.bmj.com/content/5/1/4.full |
| work_keys_str_mv | AT philippeslos radiotherapyandmvamuc1il2vaccineactsynergisticallyforinducingspecificimmunitytomuc1tumorantigen AT gildaghillman radiotherapyandmvamuc1il2vaccineactsynergisticallyforinducingspecificimmunitytomuc1tumorantigen AT lyndseyareich radiotherapyandmvamuc1il2vaccineactsynergisticallyforinducingspecificimmunitytomuc1tumorantigen AT shoshanaerothstein radiotherapyandmvamuc1il2vaccineactsynergisticallyforinducingspecificimmunitytomuc1tumorantigen AT lisamabernathy radiotherapyandmvamuc1il2vaccineactsynergisticallyforinducingspecificimmunitytomuc1tumorantigen AT matthewdfountain radiotherapyandmvamuc1il2vaccineactsynergisticallyforinducingspecificimmunitytomuc1tumorantigen AT kalihankerd radiotherapyandmvamuc1il2vaccineactsynergisticallyforinducingspecificimmunitytomuc1tumorantigen AT christopherkyunker radiotherapyandmvamuc1il2vaccineactsynergisticallyforinducingspecificimmunitytomuc1tumorantigen AT josephtrakowski radiotherapyandmvamuc1il2vaccineactsynergisticallyforinducingspecificimmunitytomuc1tumorantigen AT ericquemeneur radiotherapyandmvamuc1il2vaccineactsynergisticallyforinducingspecificimmunitytomuc1tumorantigen |