Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells
Advancing chimeric antigen receptor (CAR)-engineered T cells for the treatment of solid tumors is a major focus in the field of cellular immunotherapy. Several hurdles have hindered similar CAR T cell clinical responses in solid tumors as seen in hematological malignancies. These challenges include...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-06-01
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| Series: | Molecular Therapy: Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950329924000316 |
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| author | Kelly T. Kennewick Yukiko Yamaguchi Jackson Gibson Ethan A. Gerdts Brook Jeang Dileshni Tilakawardane John P. Murad Wen-Chung Chang Sarah L. Wright Michalina S. Thiel Stephen J. Forman Lawrence A. Stern Saul J. Priceman |
| author_facet | Kelly T. Kennewick Yukiko Yamaguchi Jackson Gibson Ethan A. Gerdts Brook Jeang Dileshni Tilakawardane John P. Murad Wen-Chung Chang Sarah L. Wright Michalina S. Thiel Stephen J. Forman Lawrence A. Stern Saul J. Priceman |
| author_sort | Kelly T. Kennewick |
| collection | DOAJ |
| description | Advancing chimeric antigen receptor (CAR)-engineered T cells for the treatment of solid tumors is a major focus in the field of cellular immunotherapy. Several hurdles have hindered similar CAR T cell clinical responses in solid tumors as seen in hematological malignancies. These challenges include on-target off-tumor toxicities, which have inspired efforts to optimize CARs for improved tumor antigen selectivity and overall safety. We recently developed a CAR T cell therapy targeting prostate stem cell antigen (PSCA) for prostate and pancreatic cancers, showing improved preclinical antitumor activity and T cell persistence by optimizing the intracellular co-stimulatory domain. Similar studies were undertaken to optimize HER2-directed CAR T cells with modifications to the intracellular co-stimulatory domain for selective targeting of breast cancer brain metastasis. In the present study, we evaluate various nonsignaling extracellular spacers in these CARs to further improve tumor antigen selectivity. Our findings suggest that length and structure of the extracellular spacer can dictate the ability of CARs to selectively target tumor cells with high antigen density, while sparing cells with low antigen density. This study contributes to CAR construct design considerations and expands our knowledge of tuning solid tumor CAR T cell therapies for improved safety and efficacy. |
| format | Article |
| id | doaj-art-a79a3384ba0b4c218c73e5547bdf3cf8 |
| institution | Kabale University |
| issn | 2950-3299 |
| language | English |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-a79a3384ba0b4c218c73e5547bdf3cf82024-11-24T04:15:33ZengElsevierMolecular Therapy: Oncology2950-32992024-06-01322200789Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cellsKelly T. Kennewick0Yukiko Yamaguchi1Jackson Gibson2Ethan A. Gerdts3Brook Jeang4Dileshni Tilakawardane5John P. Murad6Wen-Chung Chang7Sarah L. Wright8Michalina S. Thiel9Stephen J. Forman10Lawrence A. Stern11Saul J. Priceman12Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA; Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USADepartment of Chemical, Biological, and Materials Engineering, University of South Florida, Tampa, FL 33620, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA; Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Corresponding author: Saul J. Priceman, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA.Advancing chimeric antigen receptor (CAR)-engineered T cells for the treatment of solid tumors is a major focus in the field of cellular immunotherapy. Several hurdles have hindered similar CAR T cell clinical responses in solid tumors as seen in hematological malignancies. These challenges include on-target off-tumor toxicities, which have inspired efforts to optimize CARs for improved tumor antigen selectivity and overall safety. We recently developed a CAR T cell therapy targeting prostate stem cell antigen (PSCA) for prostate and pancreatic cancers, showing improved preclinical antitumor activity and T cell persistence by optimizing the intracellular co-stimulatory domain. Similar studies were undertaken to optimize HER2-directed CAR T cells with modifications to the intracellular co-stimulatory domain for selective targeting of breast cancer brain metastasis. In the present study, we evaluate various nonsignaling extracellular spacers in these CARs to further improve tumor antigen selectivity. Our findings suggest that length and structure of the extracellular spacer can dictate the ability of CARs to selectively target tumor cells with high antigen density, while sparing cells with low antigen density. This study contributes to CAR construct design considerations and expands our knowledge of tuning solid tumor CAR T cell therapies for improved safety and efficacy.http://www.sciencedirect.com/science/article/pii/S2950329924000316MT: Regular Issuechimeric antigen receptorCARprostate cancerbreast cancerPSCA |
| spellingShingle | Kelly T. Kennewick Yukiko Yamaguchi Jackson Gibson Ethan A. Gerdts Brook Jeang Dileshni Tilakawardane John P. Murad Wen-Chung Chang Sarah L. Wright Michalina S. Thiel Stephen J. Forman Lawrence A. Stern Saul J. Priceman Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells Molecular Therapy: Oncology MT: Regular Issue chimeric antigen receptor CAR prostate cancer breast cancer PSCA |
| title | Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells |
| title_full | Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells |
| title_fullStr | Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells |
| title_full_unstemmed | Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells |
| title_short | Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells |
| title_sort | nonsignaling extracellular spacer regulates tumor antigen selectivity of car t cells |
| topic | MT: Regular Issue chimeric antigen receptor CAR prostate cancer breast cancer PSCA |
| url | http://www.sciencedirect.com/science/article/pii/S2950329924000316 |
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