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

Abstract

AbstractChimeric antigen receptor (CAR) natural killer (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 the way for CAR NK cells for safer and more effective off-the-shelf cellular therapy. In this study, CD70-specific (a pan-target of lymphoma) fourth-generation CAR with 4-1BB costimulatory domain and interleukin-15 (IL-15) was constructed and transduced into cord blood–derived NK cells by Baboon envelope pseudotyped lentiviral vector. CD70 CAR NK cells displayed superior cytotoxic activity in vitro and in vivo against CD19-negative B-cell lymphoma when compared with nontransduced NK cells and CD19-specific CAR NK cells. Importantly, mice that received 2 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 with a single dose of CAR NK cells for the treatment of B-cell lymphoma.