Chimeric Antigen Receptor-Engineered Human Gamma Delta T Cells: Enhanced Cytotoxicity with Retention of Cross Presentation

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.

Targeting the interleukin-17 immune axis for cancer immunotherapy

“…Vγ9Vδ2 T cells are the most abundant γδ T cells in human blood (Poupot and Fournié, 2004) and have been the major focus of ACT immunotherapy. Polarization and ACT of γδ T cells using IL-2 and zalendronate (which mimics TLR ligation) has shown some efficacy in prostate cancer (Dieli et al, 2007), advanced renal cell carcinoma (Bennouna et al, 2008;Fisher et al, 2014b), non-small cell lung cancer (Nakajima et al, 2010), and neuroblastoma (Capsomidis et al, 2018). Notably, γδ TCRs do not require an antigen to be complexed to an MHC receptor in order to generate an immune response, enabling them to rapidly respond to foreign peptides in concert with the innate immune system.…”

γδ T cells in cancer: a small population of lymphocytes with big implications

“…124,125 An additional perquisite of using cd T cells for immunotherapy lies in their ability to crosspresent processed tumor antigen to ab T cells, and this process is retained in CAR-cd T cells, further enhancing their antitumor effects. 124,125 An additional perquisite of using cd T cells for immunotherapy lies in their ability to crosspresent processed tumor antigen to ab T cells, and this process is retained in CAR-cd T cells, further enhancing their antitumor effects.…”

“…Recently, cd T cells have been incorporated into CAR therapy, producing sufficient cells from Vd1 + and Vd2 + subsets for clinical studies. 124,125 An additional perquisite of using cd T cells for immunotherapy lies in their ability to crosspresent processed tumor antigen to ab T cells, and this process is retained in CAR-cd T cells, further enhancing their antitumor effects. 124…”

Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions

“…To date, numerous preclinical studies have evaluated CAR-modified γδ T cells targeting neuroblastoma [152,153], melanoma [154], B cell malignancies [153,155], and epithelial cell adhesion molecule (epCAM)-positive adenocarcinomas [156]. GD2-CAR-modified γδ T cells expressing the RQR8 suicide gene were shown to expand 2.5-fold upon antigen exposure [152].…”