Engineered chimeric antigen receptors (CARs) that are expressed in cytotoxic T cells and natural killer (NK) cells have been used to specifically target tumor cells. However, CAR-T and CAR-NK cells are still subject to down regulation by their inhibitory receptors after injection into patients.
Scientists at NIAID have developed CAR constructs that overcome inhibition of NK cells by receptors for human major histocompatibility complex molecules HLA-E and HLA-C, based on in vitro studies. The CAR contains an antigen binding domain of receptor CD28 homolog (CD28H), a CD28H transmembrane domain (TM), a CD28H signaling domain, and other intracellular signaling domains, such as 2B4 (CD244) and CD3 zeta chain (CD3zeta). A variant of this CAR, in which the antigen binding domain of CD28H is replaced by a single-chain antibody variable region (scFv) that binds to CD19, rendered NK cells resistant to inhibition by HLA-E and HLA-C on CD19+ tumor cells.
- Method of adoptive therapy where CAR-NK cell or CAR-T cell is the effector cell
- Resistant to inhibition of NK cells or T cells by HLA-E and HLA-C
- Manufacturing efficiency
- CAR-NK can be developed without the need to genetic silencing of TCR