Universal off-the-shelf combination immunotherapy using oncolytic viruses to redirect T cell engagers to target solid tumors
Background Bispecific T cell engager (BiTE), such as blinatumomab, has demonstrated significant clinical success in treating hematological malignancies like B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, the application of BiTEs in solid tumors has proven challenging,...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-08-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/8/e011051.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849390820289937408 |
|---|---|
| author | Stephen J Forman Wen-Chung Chang Xiuli Wang Anthony K Park Ryan Urak Yuman Fong Monil Shah Colin Cook Yukiko Yamaguchi Saul J Priceman Cathy Lu Shyambabu Chaurasiya Isabel Monroy Yuwei Ren Hannah Valencia Jackson Lent-Koop Seonah Kang Lupita Lopez John P Murad Leslie Mi Ok Chong |
| author_facet | Stephen J Forman Wen-Chung Chang Xiuli Wang Anthony K Park Ryan Urak Yuman Fong Monil Shah Colin Cook Yukiko Yamaguchi Saul J Priceman Cathy Lu Shyambabu Chaurasiya Isabel Monroy Yuwei Ren Hannah Valencia Jackson Lent-Koop Seonah Kang Lupita Lopez John P Murad Leslie Mi Ok Chong |
| author_sort | Stephen J Forman |
| collection | DOAJ |
| description | Background Bispecific T cell engager (BiTE), such as blinatumomab, has demonstrated significant clinical success in treating hematological malignancies like B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, the application of BiTEs in solid tumors has proven challenging, primarily due to the lack of targetable tumor antigens and the immunologically “cold” nature of the tumor microenvironment, which limits immune system activation.Methods We developed a novel oncolytic virus (OV) platform by engineering a chimeric vaccinia virus to express either a truncated non-signaling CD19 antigen (CD19t) or truncated B cell maturation antigen (BCMAt) on the surface of infected tumor cells. Here, we advance a combinatorial platform using an OV to redirect CD19-targeted or BCMA-targeted T cell engagers (TCEs) to drive antitumor responses against multiple solid tumors.Results We found that OV-infected tumor cells in combination with TCEs significantly improved tumor cell killing against solid tumor models, with efficacy comparable to that of chimeric antigen receptor T cells. This combination approach enhanced antitumor responses using in vivo human tumor xenograft models and promoted more effective elimination of solid tumor cells than either therapy alone. Our studies highlight OVs combined with clinically approved TCEs as a readily translatable, tumor-agnostic, off-the-shelf strategy to effectively target solid tumors.Conclusions Our findings demonstrate that the combination of OV and TCEs offers a promising strategy to drive antitumor immune responses against solid tumors. This approach represents a novel and universal platform currently in phase 1 clinical trial combining TCE therapy with oncolytic virotherapy, overcoming antigen heterogeneity and immunological barriers for the effective treatment of solid tumors. |
| format | Article |
| id | doaj-art-d401acd295ee46dbb013b49b3c2ae5c4 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d401acd295ee46dbb013b49b3c2ae5c42025-08-20T03:41:18ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-08-0113810.1136/jitc-2024-011051Universal off-the-shelf combination immunotherapy using oncolytic viruses to redirect T cell engagers to target solid tumorsStephen J Forman0Wen-Chung Chang1Xiuli Wang2Anthony K Park3Ryan Urak4Yuman Fong5Monil Shah6Colin Cook7Yukiko Yamaguchi8Saul J Priceman9Cathy Lu10Shyambabu Chaurasiya11Isabel Monroy12Yuwei Ren13Hannah Valencia14Jackson Lent-Koop15Seonah Kang16Lupita Lopez17John P Murad18Leslie Mi Ok Chong191 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA1 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA1 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA1 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA1 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA3 Department of Surgery, City of Hope National Medical Center, Duarte, California, USA4 Imugene, Sydney, New South Wales, Australia3 Department of Surgery, City of Hope National Medical Center, Duarte, California, USA2 Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA5 KSOM/Norris Center for Cancer Cellular Immunotherapy Research, University of Southern California, Los Angeles, California, USA2 Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA3 Department of Surgery, City of Hope National Medical Center, Duarte, California, USA1 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA2 Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA3 Department of Surgery, City of Hope National Medical Center, Duarte, California, USA1 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA3 Department of Surgery, City of Hope National Medical Center, Duarte, California, USA2 Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA2 Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA4 Imugene, Sydney, New South Wales, AustraliaBackground Bispecific T cell engager (BiTE), such as blinatumomab, has demonstrated significant clinical success in treating hematological malignancies like B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, the application of BiTEs in solid tumors has proven challenging, primarily due to the lack of targetable tumor antigens and the immunologically “cold” nature of the tumor microenvironment, which limits immune system activation.Methods We developed a novel oncolytic virus (OV) platform by engineering a chimeric vaccinia virus to express either a truncated non-signaling CD19 antigen (CD19t) or truncated B cell maturation antigen (BCMAt) on the surface of infected tumor cells. Here, we advance a combinatorial platform using an OV to redirect CD19-targeted or BCMA-targeted T cell engagers (TCEs) to drive antitumor responses against multiple solid tumors.Results We found that OV-infected tumor cells in combination with TCEs significantly improved tumor cell killing against solid tumor models, with efficacy comparable to that of chimeric antigen receptor T cells. This combination approach enhanced antitumor responses using in vivo human tumor xenograft models and promoted more effective elimination of solid tumor cells than either therapy alone. Our studies highlight OVs combined with clinically approved TCEs as a readily translatable, tumor-agnostic, off-the-shelf strategy to effectively target solid tumors.Conclusions Our findings demonstrate that the combination of OV and TCEs offers a promising strategy to drive antitumor immune responses against solid tumors. This approach represents a novel and universal platform currently in phase 1 clinical trial combining TCE therapy with oncolytic virotherapy, overcoming antigen heterogeneity and immunological barriers for the effective treatment of solid tumors.https://jitc.bmj.com/content/13/8/e011051.full |
| spellingShingle | Stephen J Forman Wen-Chung Chang Xiuli Wang Anthony K Park Ryan Urak Yuman Fong Monil Shah Colin Cook Yukiko Yamaguchi Saul J Priceman Cathy Lu Shyambabu Chaurasiya Isabel Monroy Yuwei Ren Hannah Valencia Jackson Lent-Koop Seonah Kang Lupita Lopez John P Murad Leslie Mi Ok Chong Universal off-the-shelf combination immunotherapy using oncolytic viruses to redirect T cell engagers to target solid tumors Journal for ImmunoTherapy of Cancer |
| title | Universal off-the-shelf combination immunotherapy using oncolytic viruses to redirect T cell engagers to target solid tumors |
| title_full | Universal off-the-shelf combination immunotherapy using oncolytic viruses to redirect T cell engagers to target solid tumors |
| title_fullStr | Universal off-the-shelf combination immunotherapy using oncolytic viruses to redirect T cell engagers to target solid tumors |
| title_full_unstemmed | Universal off-the-shelf combination immunotherapy using oncolytic viruses to redirect T cell engagers to target solid tumors |
| title_short | Universal off-the-shelf combination immunotherapy using oncolytic viruses to redirect T cell engagers to target solid tumors |
| title_sort | universal off the shelf combination immunotherapy using oncolytic viruses to redirect t cell engagers to target solid tumors |
| url | https://jitc.bmj.com/content/13/8/e011051.full |
| work_keys_str_mv | AT stephenjforman universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT wenchungchang universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT xiuliwang universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT anthonykpark universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT ryanurak universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT yumanfong universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT monilshah universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT colincook universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT yukikoyamaguchi universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT sauljpriceman universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT cathylu universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT shyambabuchaurasiya universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT isabelmonroy universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT yuweiren universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT hannahvalencia universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT jacksonlentkoop universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT seonahkang universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT lupitalopez universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT johnpmurad universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors AT lesliemiokchong universalofftheshelfcombinationimmunotherapyusingoncolyticvirusestoredirecttcellengagerstotargetsolidtumors |