Natural Killer (NK) cells and CD8+ cytotoxic T cells are two types of immune cells that can kill target cells through similar cytotoxic mechanisms. With the remarkable success of chimeric antigen receptor -engineered T (CAR-T) cells for treating hematological malignancies, there is a rapidly growing interest in developing CAR-engineered NK (CAR-NK) cells for cancer therapy. Compared to CAR-T cells, CAR-NK cells could offer some significant advantages, including (1) better safety, such as a lack of or minimal cytokine release syndrome and neurotoxicity in autologous setting and graft-versus-host disease in allogeneic setting, (2) multiple mechanisms for activating cytotoxic activity, and (3) high feasibility for “off-the-shelf” manufacturing. We have developed tumor-specific CAR for acute myeloid leukemia (AML) and other tumors. We are developing CAR-NK cells using cytokine-induced memory-like NK cells for AML, evaluating their efficacy in preclinical models and in humans. We are also developing the next generation of CAR-NK cells to target diverse antigens, enhance proliferation and persistence in vivo, increase infiltration into solid tumors, overcome the suppressive tumor microenvironment, and ultimately achieve an effective, durable anti-tumor response in patients.
- NK cell responses to tumor microenvironment
- Development of single chain variable fragments (scFv) specific for tumor-driver mutations
- Development and evaluation of novel CAR-NK cells in vitro and in vivo
- Optimization of biomanufacturing process for the production of CAR-NK cells
NK cell activation is controlled by a complex system of germline-encoded activating and inhibitory receptors. This figure highlights some potential interactions between NK cells and tumor cells (Xie et al. 2020).