A phase 1 and 2 trial evaluated the safety and efficacy of CD19-targeted CAR-NK cells in patients with relapsed or refractory CD19-positive lymphoid cancers. CAR-NK cells were derived from cord blood, transduced with a retroviral vector expressing anti-CD19 CAR, interleukin-15, and inducible caspase 9. These cells were expanded ex vivo and administered after lymphodepleting chemotherapy. The study included 11 patients with non-Hodgkin's lymphoma or chronic lymphocytic leukemia (CLL). No major toxicities such as cytokine release syndrome, neurotoxicity, or graft-versus-host disease were observed. Eight of the 11 patients (73%) had a response, with 7 achieving complete remission. Responses were rapid, occurring within 30 days of infusion. CAR-NK cells persisted at low levels for at least 12 months. The maximum tolerated dose was not reached. CAR-NK cells showed durable antitumor activity, with some patients achieving long-term remission. The study demonstrated that CAR-NK cells could be safely administered without the need for HLA matching, and they exhibited long-term persistence and antitumor activity. The results suggest that CAR-NK cells may offer a safer and more accessible alternative to CAR T-cell therapy for treating CD19-positive cancers. The study was supported by the M.D. Anderson Cancer Center and the National Institutes of Health.A phase 1 and 2 trial evaluated the safety and efficacy of CD19-targeted CAR-NK cells in patients with relapsed or refractory CD19-positive lymphoid cancers. CAR-NK cells were derived from cord blood, transduced with a retroviral vector expressing anti-CD19 CAR, interleukin-15, and inducible caspase 9. These cells were expanded ex vivo and administered after lymphodepleting chemotherapy. The study included 11 patients with non-Hodgkin's lymphoma or chronic lymphocytic leukemia (CLL). No major toxicities such as cytokine release syndrome, neurotoxicity, or graft-versus-host disease were observed. Eight of the 11 patients (73%) had a response, with 7 achieving complete remission. Responses were rapid, occurring within 30 days of infusion. CAR-NK cells persisted at low levels for at least 12 months. The maximum tolerated dose was not reached. CAR-NK cells showed durable antitumor activity, with some patients achieving long-term remission. The study demonstrated that CAR-NK cells could be safely administered without the need for HLA matching, and they exhibited long-term persistence and antitumor activity. The results suggest that CAR-NK cells may offer a safer and more accessible alternative to CAR T-cell therapy for treating CD19-positive cancers. The study was supported by the M.D. Anderson Cancer Center and the National Institutes of Health.