Engineered NKG2C ⁺ NK-like T cells exhibit superior antitumor efficacy 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 have, however, been 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 an NK-like TCRαβ ⁺ CD8 T cell subset, identified and expanded ex vivo through its expression of the activating receptor NKG2C (NKG2C ⁺ NK-like T cells), can be transduced to express a second-generation CD19 CAR (1928z), resulting in superior tumor clearance, longer persistence and decreased exhaustion compared to conventional 1928z CAR ⁺ CD8 T cells and 1928z CAR+ NK cells. Moreover, CAR-modified NKG2C ⁺ NK-like T cells resulted in significantly reduced CRS compared to conventional CAR ⁺ CD8 T cells. Similarly, NKG2C ⁺ NK-like T cells engineered with a TCR targeting the NY-ESO-1 antigen exhibit robust tumor control and minimal exhaustion compared to TCR-engineered conventional CD8 T cells. These data establish NKG2C ⁺ NK-like T cells as a robust platform for cell engineering, and offer a safer, more durable alternative to conventional CAR-T and CAR-NK therapies.