Definition

A preparation of autologous T lymphocytes that have been genetically modified and transduced with a retroviral vector to co-express a chimeric antigen receptor (CAR) encoding human natural-killer group 2, member D receptor protein (NKG2D or KLRK1) with a short hairpin RNA (shRNA) targeting MHC class I chain-related protein A (MICA) and MICB, with potential immunostimulating and antineoplastic activities. Upon infusion back into the patient, autologous NKG2D CAR-T cells CYAD-02 specifically recognize and bind to tumor cells expressing NKG2D ligands, resulting in the lysis of NKG2D ligand-expressing tumor cells. In addition, CYAD-02 targets, binds to and kills NKG2D ligand 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. It also activates macrophages within the TME. Ligands for NKG2D, such as 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. NKG2D, a dimeric, type II transmembrane protein expressed on human natural killer (NK) and certain T cells, in association with the natural adaptive protein DAP10, promotes the elimination of NKG2D ligand-expressing cells. The shRNA downregulates the expression of MICA and MICB on the CAR-T cells, which increases in-vitro cell expansion. This may enhance their persistence and increase anti-tumor activity.