IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors
Background Oncofetal splice variants of extracellular matrix (ECM) proteins present a unique group of target antigens for the immunotherapy of pediatric cancers. However, limited data is available if these splice variants can be targeted with T cells expressing chimeric antigen receptors (CARs).Meth...
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| Language: | English |
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BMJ Publishing Group
2024-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/11/e009743.full |
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| author | Jessica Wagner Stephen Gottschalk Giedre Krenciute Jinghui Zhang Shannon Lange Jason Chiang Liqing Tian Deanna Langfitt Peter Vogel Heather Sheppard Timothy I Shaw Jorge Ibanez Selene C Koo Elizabeth Wickman Meifen Lu Matthew Bell S Scott Perry Raghuvaran Shanmugam |
| author_facet | Jessica Wagner Stephen Gottschalk Giedre Krenciute Jinghui Zhang Shannon Lange Jason Chiang Liqing Tian Deanna Langfitt Peter Vogel Heather Sheppard Timothy I Shaw Jorge Ibanez Selene C Koo Elizabeth Wickman Meifen Lu Matthew Bell S Scott Perry Raghuvaran Shanmugam |
| author_sort | Jessica Wagner |
| collection | DOAJ |
| description | Background Oncofetal splice variants of extracellular matrix (ECM) proteins present a unique group of target antigens for the immunotherapy of pediatric cancers. However, limited data is available if these splice variants can be targeted with T cells expressing chimeric antigen receptors (CARs).Methods To determine the expression of the oncofetal version of tenascin C (TNC) encoding the C domain (C.TNC) in pediatric brain and solid tumors, we used quantitative reverse transcription PCR and immunohistochemistry. Genetically modified T cells were generated from human peripheral blood mononuclear cells and evaluated in vitro and in vivo.Results We demonstrate that C.TNC is expressed on a protein level in pediatric tumors, including diffuse intrinsic pontine glioma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. We generate C.TNC-CAR T cells and establish that these recognize and kill C.TNC-positive tumor cells. However, their antitumor activity in vivo is limited. To improve the effector function of C.TNC-CAR T cells, we design a leucine zipper-based chimeric cytokine receptor that activates interleukin-18 signaling pathways (Zip18R). Expression of Zip18R in C.TNC-CAR T cells improves their ability to secrete cytokines and expand in repeat stimulation assays. C.TNC-CAR.Zip18R T cells also have significantly greater antitumor activity in vivo compared with unmodified C.TNC-CAR T cells.Conclusions Our study identifies the C domain of the ECM protein TNC as a promising CAR T-cell therapy for pediatric solid tumors and brain tumors. While we focus here on pediatric cancer, our work has relevance to a broad range of adult cancers that express C.TNC. |
| format | Article |
| id | doaj-art-8507f7b85407469dbd101d8fe85f0108 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-8507f7b85407469dbd101d8fe85f01082025-08-20T01:52:49ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-11-01121110.1136/jitc-2024-009743IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumorsJessica Wagner0Stephen Gottschalk1Giedre Krenciute2Jinghui Zhang3Shannon Lange4Jason Chiang5Liqing Tian6Deanna Langfitt7Peter Vogel8Heather Sheppard9Timothy I Shaw10Jorge Ibanez11Selene C Koo12Elizabeth Wickman13Meifen Lu14Matthew Bell15S Scott Perry16Raghuvaran Shanmugam17Department of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Computational Biology, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Pathology, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Pathology, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Pathology, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USADepartment of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Pathology, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Pathology, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Host Microbe Interactions, St. Jude Children`s Research Hospital, Memphis, Tennessee, USABackground Oncofetal splice variants of extracellular matrix (ECM) proteins present a unique group of target antigens for the immunotherapy of pediatric cancers. However, limited data is available if these splice variants can be targeted with T cells expressing chimeric antigen receptors (CARs).Methods To determine the expression of the oncofetal version of tenascin C (TNC) encoding the C domain (C.TNC) in pediatric brain and solid tumors, we used quantitative reverse transcription PCR and immunohistochemistry. Genetically modified T cells were generated from human peripheral blood mononuclear cells and evaluated in vitro and in vivo.Results We demonstrate that C.TNC is expressed on a protein level in pediatric tumors, including diffuse intrinsic pontine glioma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. We generate C.TNC-CAR T cells and establish that these recognize and kill C.TNC-positive tumor cells. However, their antitumor activity in vivo is limited. To improve the effector function of C.TNC-CAR T cells, we design a leucine zipper-based chimeric cytokine receptor that activates interleukin-18 signaling pathways (Zip18R). Expression of Zip18R in C.TNC-CAR T cells improves their ability to secrete cytokines and expand in repeat stimulation assays. C.TNC-CAR.Zip18R T cells also have significantly greater antitumor activity in vivo compared with unmodified C.TNC-CAR T cells.Conclusions Our study identifies the C domain of the ECM protein TNC as a promising CAR T-cell therapy for pediatric solid tumors and brain tumors. While we focus here on pediatric cancer, our work has relevance to a broad range of adult cancers that express C.TNC.https://jitc.bmj.com/content/12/11/e009743.full |
| spellingShingle | Jessica Wagner Stephen Gottschalk Giedre Krenciute Jinghui Zhang Shannon Lange Jason Chiang Liqing Tian Deanna Langfitt Peter Vogel Heather Sheppard Timothy I Shaw Jorge Ibanez Selene C Koo Elizabeth Wickman Meifen Lu Matthew Bell S Scott Perry Raghuvaran Shanmugam IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors Journal for ImmunoTherapy of Cancer |
| title | IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors |
| title_full | IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors |
| title_fullStr | IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors |
| title_full_unstemmed | IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors |
| title_short | IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors |
| title_sort | il 18r supported car t cells targeting oncofetal tenascin c for the immunotherapy of pediatric sarcoma and brain tumors |
| url | https://jitc.bmj.com/content/12/11/e009743.full |
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