Abstract
Gamma delta T (γδT) lymphocytes are primed for rapid function, including cytotoxicity toward cancer cells, and are a component of the immediate stress response. Following activation, they can function as professional antigen-presenting cells. Chimeric antigen receptors (CARs) work by focusing T cell function on defined cell surface tumor antigens and provide essential costimulation for robust activation. Given the natural tropism of γδT cells for the tumor microenvironment, we hypothesized that their transduction with CARs might enhance cytotoxicity while retaining their ability to migrate to tumor and act as antigen-presenting cells to prolong the intratumoral immune response. Using a GD2-targeting CAR as a model system, we showed that γδT cells of both Vδ1 and Vδ2 subsets could be expanded and transduced to sufficient numbers for clinical studies. The CAR added to the cells’ innate cytotoxicity by enhancing GD2-specific killing of GD2-expressing cancer cell lines. Migration toward tumor cells in vitro was not impaired by the presence of the CAR. Expanded CAR-transduced Vδ2 cells retained the ability to take up tumor antigens and cross presented the processed peptide to responder alpha beta T (αβT) lymphocytes. γδ CAR-T cell products show promise for evaluation in clinical studies of solid tumors.
Highlights
Adoptive cellular therapy with T cells engineered to express chimeric antigen receptors (CARs) combines the antigen specificity of a monoclonal antibody with potent T cell activation, proliferative potential, and cytotoxic function
Cells from Peripheral Blood To evaluate a potential role of human peripheral blood Gamma delta T (gdT) cells as vehicles for CARs, we first evaluated different activation methods to facilitate both transduction and expansion to sufficient numbers for adoptive transfer
concanavalin A (ConA) led to expansion of both Vd1 and Vd2 cells (Figures 1D and 1G), most cultured cells remained ab T cells by day 13 despite significantly greater fold expansion of Vd1 and Vd2 cells compared to ab (Figures 1D and 1G)
Summary
Adoptive cellular therapy with T cells engineered to express chimeric antigen receptors (CARs) combines the antigen specificity of a monoclonal antibody with potent T cell activation, proliferative potential, and cytotoxic function. First-generation CARs typically had a single CD3-z intracellular signaling domain; they were shown to have poor persistence in vivo.[1] Second-generation and third-generation CARs were created by the addition of one or two costimulatory endodomains to the CD3-z motif to provide tailored signals with the aim of enhancing activation and survival. Alternative approaches, including the use of unconventional lymphocytes that might be naturally tumoricidal and capable of enhanced tumor trafficking, should be evaluated.[7] Gamma delta T (gdT) cells are intriguing given their capacity to differentiate following activation into cells with professional antigen presentation function
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