CD70-specific CAR-NK cells expressing IL-15 for the treatment of CD19-negative B cell malignancy.

Chimeric antigen receptor (CAR)-NK cells can eliminate tumors not only through the ability of the CAR molecule to recognize antigen expressed cancer cells but also through NK cell receptors themselves. This overcomes some of the limitations of CAR-T cells, paving CAR-NK cells for safer and more effective off-the-shelf cellular therapy. In this study, CD70, a pan-target of lymphoma, specific fourth-generation CAR with 4-1BB co-stimulatory domain and IL-15 was constructed and transduced into cord blood-derived NK cells by Baboon envelope pseudotyped lenti-vector. CD70-CAR NK cells displayed superior cytotoxic activity in vitro and in vivo against CD19 negative B-cell lymphoma when compared to non-transduced NK cells and CD19-specific CAR-NK cells. Importantly, mice received two doses of CD70-CAR NK cells showed effective eradication of tumors, accompanied by increased concentration of plasma IL-15 and enhanced CAR-NK cell proliferation and persistence. Our study suggests that repetitive administration-based CAR NK-cell therapy has clinical advantage compared to single dose of CAR-NK cells for the treatment of B-cell lymphoma.