Off-the-shelf induced pluripotent stem-cell-derived natural killer-cell therapy in relapsed or refractory B-cell lymphoma: a multicentre, open-label, phase 1 study.

Abstract

Background: Natural killer-cell therapies are limited by donor cell sourcing and dose-to-dose variability. FT516 is an induced pluripotent stem cell (iPSC)-derived natural killer-cell therapy expressing high-affinity, non-cleavable CD16 to optimise antibody-dependent cellular cytotoxicity in combination with therapeutic monoclonal antibody. We aimed to assess the safety of FT516 in patients with relapsed or refractory B-cell lymphoma.

Methods: This multicentre, open-label, phase 1 study was conducted at eight research centres in the USA. Eligible patients were aged 18 years or older, had B-cell lymphoma expected to express CD20, with relapsed or refractory disease following at least one previous systemic therapy including anti-CD20 antibody, had measurable disease, and had no treatment options expected to improve survival. Participants received fludarabine (30 mg/m² for 3 days on days -5 to -3) and cyclophosphamide (500 mg/m² for 3 days on days -5 to -3) or bendamustine (90 mg/m² for 2 days on days -4 and -3) combined with rituximab at 375 mg/m² on day -4 or obinutuzumab 1000 mg replaced rituximab in patients with follicular lymphoma during dose expansion. FT516 was administered intravenously at escalating doses, ranging from 3 × 10⁷ to 9 × 10⁸ cells per dose on days 1, 8, and 15, with IL-2 (6 million units) administered subcutaneously 2-4 h after each FT516 dose. The primary endpoint was safety, including dose-limiting toxicity and maximum tolerated dose. Safety was analysed in all patients who received at least one dose of FT516. Patients with acute myeloid leukaemia were also enrolled and will be reported elsewhere. This study was registered with ClinicalTrials.gov, NCT04023071, and is completed.

Findings: From Oct 11, 2019, to Nov 28, 2022, 56 patients were enrolled, 55 of whom received FT516. 32 (58%) patients were male, 23 (42%) were female, and 43 (78%) were White. The maximum FT516 cell dose (9 × 10⁸ cells per dose for three doses per 28-day cycle) was tolerated and identified as the recommended phase 2 dose. No dose-limiting toxicities were reported. Cytokine release syndrome was reported in one (2%) patient and was grade 1; neurotoxicity was not observed. Most common adverse events grade 3 or worse were neutropenia (in 46 [84%] patients), thrombocytopenia (20 [36%]), and anaemia (15 [27%]). There were no treatment-related deaths. Objective response was observed in 32 (58%) of 55 patients.

Interpretation: Our findings suggest that cell therapy using iPSC-derived, gene-modified natural killer cells in combination with monoclonal antibody and IL-2 is safe and active in B-cell malignancies and might address limitations of currently available immune-cell therapies, including manufacturing time, heterogeneity, access, and cost.

Funding: Fate Therapeutics.