Non-signaling Chimeric Antigen Receptors Enhance Antigen-Directed Killing by γδ T Cells in Contrast to αβ T Cells
Chimeric antigen receptor (CAR)-modified T cells have demonstrated efficacy against B cell leukemias/lymphomas. However, redirecting CAR T cells to malignant T cells is more challenging due to product-specific cis- and trans-activation causing fratricide. Other challenges include the potential for p...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770520300826 |
| _version_ | 1818884462220410880 |
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| author | Lauren C. Fleischer Scott A. Becker Rebecca E. Ryan Andrew Fedanov Christopher B. Doering H. Trent Spencer |
| author_facet | Lauren C. Fleischer Scott A. Becker Rebecca E. Ryan Andrew Fedanov Christopher B. Doering H. Trent Spencer |
| author_sort | Lauren C. Fleischer |
| collection | DOAJ |
| description | Chimeric antigen receptor (CAR)-modified T cells have demonstrated efficacy against B cell leukemias/lymphomas. However, redirecting CAR T cells to malignant T cells is more challenging due to product-specific cis- and trans-activation causing fratricide. Other challenges include the potential for product contamination and T cell aplasia. We expressed non-signaling CARs (NSCARs) in γδ T cells since donor-derived γδ T cells can be used to prevent product contamination, and NSCARs lack signaling/activation domains, but retain antigen-specific tumor cell-targeting capability. As a result, NSCAR targeting requires an alternative cytotoxic mechanism, which can be achieved through utilization of γδ T cells that possess major histocompatibility complex (MHC)-independent cytotoxicity. We designed two distinct NSCARs and demonstrated that they do not enhance tumor-killing by αβ T cells, as predicted. However, both CD5-NSCAR- and CD19-NSCAR-modified γδ T cells enhanced cytotoxicity against T and B cell acute lymphoblastic leukemia (T-ALL and B-ALL) cell lines, respectively. CD5-NSCAR expression in γδ T cells resulted in a 60% increase in cytotoxicity of CD5-expressing T-ALL cell lines. CD19-NSCAR-modified γδ T cells exhibited a 350% increase in cytotoxicity against a CD19-expressing B-ALL cell line compared to the cytotoxicity of naive cells. NSCARs may provide a mechanism to enhance antigen-directed anti-tumor cytotoxicity of γδ T cells through the introduction of a high-affinity interaction while avoiding self-activation. |
| first_indexed | 2024-12-19T15:49:56Z |
| format | Article |
| id | doaj.art-57c3a61041d34dbe85e0bb0f4d7cdf17 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-19T15:49:56Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-57c3a61041d34dbe85e0bb0f4d7cdf172022-12-21T20:15:14ZengElsevierMolecular Therapy: Oncolytics2372-77052020-09-0118149160Non-signaling Chimeric Antigen Receptors Enhance Antigen-Directed Killing by γδ T Cells in Contrast to αβ T CellsLauren C. Fleischer0Scott A. Becker1Rebecca E. Ryan2Andrew Fedanov3Christopher B. Doering4H. Trent Spencer5Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Program in Molecular and Systems Pharmacology, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University School of Medicine, Atlanta, GA, USAAflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Program in Molecular and Systems Pharmacology, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University School of Medicine, Atlanta, GA, USAAflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Program in Molecular and Systems Pharmacology, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University School of Medicine, Atlanta, GA, USAAflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USAAflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Program in Molecular and Systems Pharmacology, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University School of Medicine, Atlanta, GA, USAAflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Program in Molecular and Systems Pharmacology, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University School of Medicine, Atlanta, GA, USA; Corresponding author: H. Trent Spencer, Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.Chimeric antigen receptor (CAR)-modified T cells have demonstrated efficacy against B cell leukemias/lymphomas. However, redirecting CAR T cells to malignant T cells is more challenging due to product-specific cis- and trans-activation causing fratricide. Other challenges include the potential for product contamination and T cell aplasia. We expressed non-signaling CARs (NSCARs) in γδ T cells since donor-derived γδ T cells can be used to prevent product contamination, and NSCARs lack signaling/activation domains, but retain antigen-specific tumor cell-targeting capability. As a result, NSCAR targeting requires an alternative cytotoxic mechanism, which can be achieved through utilization of γδ T cells that possess major histocompatibility complex (MHC)-independent cytotoxicity. We designed two distinct NSCARs and demonstrated that they do not enhance tumor-killing by αβ T cells, as predicted. However, both CD5-NSCAR- and CD19-NSCAR-modified γδ T cells enhanced cytotoxicity against T and B cell acute lymphoblastic leukemia (T-ALL and B-ALL) cell lines, respectively. CD5-NSCAR expression in γδ T cells resulted in a 60% increase in cytotoxicity of CD5-expressing T-ALL cell lines. CD19-NSCAR-modified γδ T cells exhibited a 350% increase in cytotoxicity against a CD19-expressing B-ALL cell line compared to the cytotoxicity of naive cells. NSCARs may provide a mechanism to enhance antigen-directed anti-tumor cytotoxicity of γδ T cells through the introduction of a high-affinity interaction while avoiding self-activation.http://www.sciencedirect.com/science/article/pii/S2372770520300826chimeric antigen receptorCARnon-stimulating chimeric antigen receptorNSCARanti-CD5CARgamma delta T cells |
| spellingShingle | Lauren C. Fleischer Scott A. Becker Rebecca E. Ryan Andrew Fedanov Christopher B. Doering H. Trent Spencer Non-signaling Chimeric Antigen Receptors Enhance Antigen-Directed Killing by γδ T Cells in Contrast to αβ T Cells Molecular Therapy: Oncolytics chimeric antigen receptor CAR non-stimulating chimeric antigen receptor NSCAR anti-CD5CAR gamma delta T cells |
| title | Non-signaling Chimeric Antigen Receptors Enhance Antigen-Directed Killing by γδ T Cells in Contrast to αβ T Cells |
| title_full | Non-signaling Chimeric Antigen Receptors Enhance Antigen-Directed Killing by γδ T Cells in Contrast to αβ T Cells |
| title_fullStr | Non-signaling Chimeric Antigen Receptors Enhance Antigen-Directed Killing by γδ T Cells in Contrast to αβ T Cells |
| title_full_unstemmed | Non-signaling Chimeric Antigen Receptors Enhance Antigen-Directed Killing by γδ T Cells in Contrast to αβ T Cells |
| title_short | Non-signaling Chimeric Antigen Receptors Enhance Antigen-Directed Killing by γδ T Cells in Contrast to αβ T Cells |
| title_sort | non signaling chimeric antigen receptors enhance antigen directed killing by γδ t cells in contrast to αβ t cells |
| topic | chimeric antigen receptor CAR non-stimulating chimeric antigen receptor NSCAR anti-CD5CAR gamma delta T cells |
| url | http://www.sciencedirect.com/science/article/pii/S2372770520300826 |
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