iPSC-derived NK cell therapy induces durable responses in glioblastoma and overcomes resistance via a B7-H3–targeted tri-specific killer engager

Background Glioblastoma is the most aggressive primary brain tumor, with poor prognosis and limited treatment options. Natural killer (NK) cell therapy is a promising immunotherapeutic strategy, yet its efficacy remains limited. We evaluated FT538, a clinical-grade NK product derived from induced pluripotent stem cells (iPSCs), in glioblastoma models. Methods FT538, engineered with a high-affinity non-cleavable CD16 Fc receptor, a membrane-bound IL-15/IL-15Rα fusion protein, and CD38 knockout, was tested against 13 patient-derived glioblastoma stem-like cells (GSCs) in vitro and in orthotopic xenograft models. Intracranial persistence and neurotoxicity were assessed in mice. Surface proteomics identified therapeutic targets, and a B7-H3–targeted tri-specific killer engager (TriKE) was evaluated with FT538 and NKG2C+ adaptive NK cells. Results GSCs were classified as sensitive (38%), moderately sensitive (38%), or resistant (23%) to FT538. Intracranial administration in mice was well tolerated, persisted for at least 35 days, and caused no neurotoxicity. A single intratumoral dose induced complete regression in sensitive xenografts. Surface profiling identified B7-H3 as a target to overcome resistance. Combination therapy with FT538 and a B7-H3 TriKE enhanced antitumor efficacy in resistant models, an effect also observed with adaptive NK cells. Conclusions FT538 exhibits potent tumoricidal activity in 77% of GSC lines (NK-sensitive and moderately sensitive), with curative potential in sensitive models, and demonstrates favorable persistence and tolerability in vivo. B7-H3–targeted TriKE restores NK sensitivity in resistant tumors. These findings provide a strong preclinical rationale for further clinical evaluation of FT538, alone or combined with B7-H3–targeted TriKE, for glioblastoma and other solid tumors.