strategies reduce control and may lead to excessive activation.Improving CAR-NK killing capacity while sustaining persistence remains a key challenge. Methods:We developed NK-Next, a CAR-NK approach in which cells secrete CAR-Enhancers (CAR-E), antigen-directed cytokine fusion proteins composed of tumor antigens (BCMA, CD19, or EGFR) linked to low-affinity IL-2 or IL-15 variants.CAR-E were expressed using a T2A-linked cassette, enabling localized cytokine delivery in proximity to CAR engagement.CAR-NK cells containing CD28 or 4-1BB costimulatory domains were evaluated in hematologic malignancy models and patient-derived glioblastoma (GBM) cell lines.Results: CAR-E secretion led to a marked increase in both CAR-dependent and NK receptors-mediated mechanisms, accompanied by improved expansion and prolonged persistence.Enhanced cytotoxicity was observed across multiple targets and was particularly pronounced in 4-1BB-based CAR-NK cells, which showed sustained activity compared with CD28-based constructs.NK-Next preserved killing capacity in tumors with heterogeneous antigen expression, including patient-derived GBM models.Mechanistic analyses indicated reduced exhaustion and sustained effector signaling through the non-canonical NF-B pathway, supporting durable function without excessive activation.Conclusions: NK-Next enhances CAR-NK antitumor killing and persistence through localized, antigen-coupled cytokine support, enabling sustained cytotoxic activity across hematologic malignancies and patient-derived GBM.
Alisher et al. (Wed,) studied this question.
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