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A preparation of a subset of allogeneic T-lymphocytes that express only gamma chain and delta chain T-cell receptors (TCRs) and that are engineered to express a chimeric antigen receptor (CAR) encoding for human natural-killer group 2, member D receptor protein (NKG2D or KLRK1; natural killer cell activating receptor group 2D), with potential immunomodulating and antineoplastic activities. Upon administration of the NKG2DL-targeting CAR-grafted gamma delta T cells, these cells specifically target and bind to tumor cells expressing NKG2D ligands (NKG2DL). This induces secretion of pro-inflammatory cytokines and results in the lysis of NKG2DL-expressing tumor cells. In addition, these cells target, bind to and kill NKG2DL-expressing tumor-associated endothelial cells in the neovasculature and immunosuppressive cells, such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) that express NKG2D ligands. Gamma/delta T-lymphocytes play a key role in the activation of the immune system and do not require major histocompatibility complex (MHC)-mediated antigen presentation to exert their cytotoxic effect. Ligands for NKG2D, such as MHC class I chain-related protein A (MICA), MICB, and members of the UL16-binding proteins (ULBP)/retinoic acid early transcript 1 (RAET1) family, are overexpressed on infected cells and most cancer cell types, but are not expressed on most normal, healthy cells.
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