Lee, Dunn, Guo, et al. found that CD16hi Vδ2 T cells expanded from selected donors displayed enhanced cytotoxicity in vitro. Mesothelin (MSLN)-targeting CAR-engineered Vδ2 T cells further engineered to produce IL-15 were developed from CD16hi donors (MCAR15-Vδ2T). MCAR15-Vδ2T were cytotoxic to ovarian cancer cells in vitro. Additionally, these cells could induce tumor killing through ADCC, and were able to kill M2 macrophages in vitro. In intraperitoneal and subcutaneous models for ovarian cancer in NSG mice, MCAR15-Vδ2 T cells showed enhanced tumor control and induction of complete remissions, without causing GvHD.
Contributed by Maartje Wouters
ABSTRACT: Allogeneic Vγ9Vδ2 (Vδ2) T cells have emerged as attractive candidates for developing cancer therapy due to their established safety in allogeneic contexts and inherent tumor-fighting capabilities. Nonetheless, the limited clinical success of Vδ2 T cell-based treatments may be attributed to donor variability, short-lived persistence, and tumor immune evasion. To address these constraints, we engineer Vδ2 T cells with enhanced attributes. By employing CD16 as a donor selection biomarker, we harness Vδ2 T cells characterized by heightened cytotoxicity and potent antibody-dependent cell-mediated cytotoxicity (ADCC) functionality. RNA sequencing analysis supports the augmented effector potential of Vδ2 T cells derived from CD16 high (CD16Hi) donors. Substantial enhancements are further achieved through CAR and IL-15 engineering methodologies. Preclinical investigations in two ovarian cancer models substantiate the effectiveness and safety of engineered CD16Hi Vδ2 T cells. These cells target tumors through multiple mechanisms, exhibit sustained in vivo persistence, and do not elicit graft-versus-host disease. These findings underscore the promise of engineered CD16Hi Vδ2 T cells as a viable therapeutic option for cancer treatment.
Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. (2) Department of Microbiology, Immunology & Molecular Genetics, Un
Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. (2) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA. (3) Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA. (4) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. (5) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. (6) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. (7) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. (8) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. (9) Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA, USA. (10) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. (11) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. (12) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. (13) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. (14) Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA, USA. (15) Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA. Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA. (16) Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA. (17) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. liliyang@ucla.edu. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA. liliyang@ucla.edu. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. liliyang@ucla.edu. Molecular Biology Institute, University of California, Los Angeles, CA, USA. liliyang@ucla.edu.
