An iPSC-derived CD19 CAR NK therapy expressing a high-affinity CD16 Fc receptor and IL-15/IL-15R was investigated with rituximab in patients with heavily pretreated r/r B-cell lymphoma (BCL). NK cells peaked at day 1 and persisted for up to 15 days. No grade 3+ CRS, neurotoxicity, or GvHD occurred, though grade 3 AEs due to conditioning therapy were common. PFS and mOS were 3.5 and 8.1 months, respectively. ORR and CRR were 100% and 85% in follicular lymphoma, and 38% and 25% in LBCL. 45% of previous CAR T-treated LBCL patients responded. Responders exhibited substantially higher proportions of CD8+ and PD1+ T cells at baseline.
Contributed by Morgan Janes
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 × 107 viable cells as a single dose on day 1 and done independently for individual regimens. A treatment cycle consisted of conditioning chemotherapy with cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) intravenously on days -5 to -3, followed by FT596 administered at various doses and schedules, without (regimen A) or with (regimen B) a single dose of rituximab (375 mg/m2) intravenously on day -4. Supportive care was determined by the treating investigator. Patients were observed for dose-limiting adverse events for 28 days. Patients who tolerated therapy and derived clinical benefit could receive subsequent cycles of study treatment, with modification of conditioning chemotherapy dose if clinically indicated. The dose-expansion phase evaluated additional patients at selected doses and dosing schedules that had been found to be tolerable. The primary endpoints of the study were the incidence and nature of dose-limiting toxicities within each dose-escalation cohort to determine the maximum tolerated dose or maximum assessed dose to establish the RP2D and the incidence, nature, and severity of adverse events, with severity determined according to National Cancer Institute Common Toxicity Criteria and Adverse Events version 5·0. The trial was registered with ClinicalTrials.gov, NCT04245722.
Author Info: (1) Washington University School of Medicine, Saint Louis, MO, USA. Electronic address: arminghobadi@wustl.edu. (2) Masonic Cancer Center, University of Minnesota, Minneapolis, MN,
Author Info: (1) Washington University School of Medicine, Saint Louis, MO, USA. Electronic address: arminghobadi@wustl.edu. (2) Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. (3) Swedish Cancer Institute, Seattle, WA, USA. (4) Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Tennessee Oncology/OneOncology, Nashville, TN, USA. (6) David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, USA. (7) Sarah Cannon Center for Blood Cancer, San Antonio, TX, USA. (8) New York University Langone Health, Perlmutter Cancer Center, New York, NY, USA. (9) Fate Therapeutics, San Diego, CA, USA. (10) Fate Therapeutics, San Diego, CA, USA. (11) Fate Therapeutics, San Diego, CA, USA. (12) Fate Therapeutics, San Diego, CA, USA. (13) Fate Therapeutics, San Diego, CA, USA. (14) Fate Therapeutics, San Diego, CA, USA. (15) Fate Therapeutics, San Diego, CA, USA. (16) Fate Therapeutics, San Diego, CA, USA. (17) The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
