CBU-derived allogeneic CD19-specific CAR-NK cells for CD19+ B cell malignancies
Marin D, Li Y, Basar R, et al. Safety, Efficacy and Determinants of Response of Allogeneic CD19-Specific CAR-NK Cells in CD19+ B Cell Tumors: A Phase 1/2 Trial. Nature Medicine. 2024; (doi: 10.1038/s41591-023-02785-8).
Off-the-shelf chimeric antigen receptor natural killer (CAR-NK) cells are a more affordable and safer alternative to autologous anti-CD19 CAR T cells for the treatment of CD19+ B cell malignancies. NK cells can be designed to express a CAR, but because they do not rely on human leukocyte antigen matching, cells do not have to be manufactured specifically for each individual patient. In this case, they were derived from cord blood from healthy donors and engineered to express anti-CD19 CAR, interleukin-15 (CAR19/IL-15). Although a single cord blood unit (CBU) can yield hundreds of doses of CAR-NK cells, researchers used contributions from different donors for each of the 37 study participants in order to distinguish which CBU properties promote the desired clinical response. Each patient underwent lymphodepletion and a CAR-NK cell infusion. Based on overall response at 30 days, researchers found CAR 19/IL-15 CBU-NK cells to be as effective as autologous CAR19 T cells but even safer, with no patients developing neurotoxicity or graft-versus-host disease and only one experiencing cytokine release syndrome. Optimal CBUs had nucleated red blood cells ≤8×107 and a collection-to-cryopreservation time ≤24 hours; NK cells derived from this environment were highly functional and enriched in effector-related genes. The finding, validated in murine tumor models, highlights the advantages in identifying and selecting allogeneic donors with this CBU profile.