Chimeric antigen receptor natural killer (CAR-NK) cell therapy has rapidly progressed in early-phase clinical trials for hematologic cancers over the past five years. We systematically reviewed all published human studies (2019–2025) on CAR-NK therapy in leukemia, lymphoma, and myeloma. Eight clinical trials (Phase I/II) encompassing both autologous and allogeneic “off-the-shelf” CAR-NK products were identified. These trials targeted B-cell antigens (mostly CD19) in relapsed/refractory lymphoid malignancies and myeloid antigens (e.g., CD33, NKG2D-ligands) in acute myeloid leukemia. Results demonstrate that CAR-NK cells can induce meaningful response rates (overall response rates ~50–80% in B-cell cancers, with complete remissions in 30–70% of patients). Durable remissions up to 1 year have been observed in indolent lymphoma, though remissions in aggressive disease are often shorter (median ~2–5 months). Notably, CAR-NK therapy exhibited a favorable safety profile across all studies, with no cases of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GvHD) and only infrequent low-grade cytokine release syndrome (CRS). Taking this information into account, CAR-NK cell therapy shows promising anti-tumor activity in hematologic malignancies with substantially reduced toxicity compared to CAR-T cells. Ongoing trials are refining CAR-NK dosing, persistence, and multi-antigen targeting to improve durability of remission. These early results support the continued development of CAR-NK platforms as a safe, off-the-shelf immunotherapy for blood cancers, potentially broadening patient access and paving the way for applications in solid tumors and immune disorders.

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2025
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