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Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia.
Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia.
- Source :
-
Frontiers in immunology [Front Immunol] 2020 Jul 02; Vol. 11, pp. 1347. Date of Electronic Publication: 2020 Jul 02 (Print Publication: 2020). - Publication Year :
- 2020
-
Abstract
- Autologous T cells engineered to express a chimeric antigen receptor (CAR) against the CD19 antigen are in the frontline of contemporary hemato-oncology therapies, leading to high remission rates in B-cell malignancies. Although effective, major obstacles involve the complex and costly individualized manufacturing process, and CD19 target antigen loss or modulation leading to resistant and relapse following CAR therapy. A potential solution for these limitations is the use of donor-derived γδT cells as a CAR backbone. γδT cells lack allogenecity and are safely used in haploidentical transplants. Moreover, γδT cells are known to mediate natural anti-tumor responses. Here, we describe a 14-day production process initiated from peripheral-blood mononuclear cells, leading to a median 185-fold expansion of γδ T cells with high purity (>98% CD3+ and >99% γδTCR+). CAR transduction efficacy of γδ T cells was equally high when compared to standard CAR-T cells (60.5 ± 13.2 and 65.3 ± 18.3%, respectively). CD19-directed γδCAR-T cells were effective against CD19+ cell lines in vitro and in vivo, showing cytokine production, direct target killing, and clearance of bone marrow leukemic cells in an NSG model. Multiple injections of γδCAR-T cells and priming of mice with zoledronate lead to enhanced tumor reduction in vivo . Unlike standard CD19 CAR-T cells, γδCAR-T cells were able to target CD19 antigen negative leukemia cells, an effect that was enhanced after priming the cells with zoledronate. In conclusion, γδCAR-T cell production is feasible and leads to highly pure and efficient effector cells. γδCAR-T cell may provide a promising platform in the allogeneic setting, and may target leukemic cells also after antigen loss.<br /> (Copyright © 2020 Rozenbaum, Meir, Aharony, Itzhaki, Schachter, Bank, Jacoby and Besser.)
- Subjects :
- Animals
Genetic Engineering methods
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Transduction, Genetic methods
Xenograft Model Antitumor Assays
Cell Culture Techniques methods
Immunotherapy, Adoptive methods
Leukemia
Receptors, Antigen, T-Cell, gamma-delta immunology
Receptors, Chimeric Antigen immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 11
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 32714329
- Full Text :
- https://doi.org/10.3389/fimmu.2020.01347