Engineered NKG2C+ CD8+ TKLR cells exhibit effective antitumor control in mice while mitigating cytokine release syndrome

Engineered T and NK cell therapies have widely been used to treat hematologic malignancies and solid tumors, with promising clinical results. Current chimeric antigen receptor (CAR) T cell therapeutics are, however, associated with treatment-related adverse events such as cytokine release syndrome (CRS) and are prone to immunologic exhaustion. CAR-NK therapeutics, while not associated with CRS, have limited in vivo persistence. We now demonstrate that a population of NK-like TCRαβ ⁺ CD8 T cells (T _KLR ), identified and expanded ex vivo through its expression of the activating receptor NKG2C, can be transduced to express a second-generation CD19 CAR (1928z). These CAR+ T _KLR demonstrates superior tumor clearance and longer persistence compared to 1928z CAR ⁺ conventional CD8 T cells (T _Conv ) and 1928z CAR+ NK cells in mouse xenograft models. Moreover, CAR-modified T _KLR had decreased expression of PD-1, TIM-3, and LAG-3 and elicited significantly reduced CRS compared to CAR ⁺ CD8 T _Conv in mouse xenograft models. Similarly, NKG2C ⁺ T _KLR engineered with a TCR targeting the NY-ESO-1 antigen exhibited robust tumor control compared to TCR-engineered CD8 T _Conv in a mouse xenograft model. These data establish NKG2C+ T _KLR as a promising platform for cell engineering, and offer a safer, more durable alternative to conventional CAR-T and CAR-NK therapies.