BACKGROUND: FT596 is an induced pluripotent stem-cell (iPSC)-derived chimeric antigen receptor (CAR) natural killer (NK) cell therapy with three antitumour modalities: a CD19 CAR
a high-affinity, non-cleavable CD16 Fc receptor
and interleukin-15-interleukin-15 receptor fusion. In this study, we aimed to determine the recommended phase 2 dose (RP2D) and evaluate the safety and tolerability of FT596 as monotherapy and in combination with rituximab. We also aimed to evaluate the antitumour activity and characterise the pharmacokinetics of FT596 as monotherapy and in combination with rituximab. METHODS: In this phase 1, first-in-human trial, we evaluated FT596 in patients with relapsed or refractory B-cell lymphoma at nine sites in the USA. Patients who had received at least one previous systemic therapy and had no curative treatment options were eligible for inclusion. FT596 was administered after conditioning chemotherapy without rituximab (regimen A) or combined with rituximab (regimen B). The study consisted of a dose-escalation phase using a 3 + 3 design, with dose escalation commencing at 3 × 10 FINDINGS: Between March 19, 2020, and Jan 12, 2023, 86 patients with B-cell lymphoma received FT596 on regimen A (n=18) or regimen B (n=68). 22 (26%) of 86 patients were female and 72 (84%) of 86 patients were White. Patients had received a median of four previous lines of therapy (range 1-11) and 33 (38%) of 86 patients had received previous CAR T-cell therapy. The maximum tolerated dose was not reached. Cytokine release syndrome was reported in one (6%) of 18 patients (maximum grade 1) on regimen A and nine (13%) of 68 patients on regimen B (six with maximum grade 1 and three with grade 2). Neurotoxicity was not observed. INTERPRETATION: FT596 was well tolerated as monotherapy or with rituximab and induced deep and durable responses in patients with indolent and aggressive lymphomas and the RP2D was preliminarily identified to be 1·8 × 10 FUNDING: Fate Therapeutics.