Safety and Efficacy of FT596, a First-in-Class, Multi-Antigen Targeted, Off-the-Shelf, iPSC-Derived CD19 CAR NK Cell Therapy in Relapsed/Refractory B-Cell Lymphoma

Background: The use of a clonal master engineered induced pluripotent stem cell (iPSC) line as a renewable source for the mass production of immune effector cells offers distinct advantages over existing patient (pt)- and donor-derived cell-based cancer immunotherapy approaches, including off-the-shelf availability for broad pt access and multi-dose administration. FT596 is an iPSC-derived, off-the-shelf, CD19-directed chimeric antigen receptor (CAR) natural killer (NK) cell therapy capable of multi-antigen targeting in combination with monoclonal antibody (mAb) therapies. FT596 has three anti-tumor modalities: (1) a proprietary CD19-targeting CAR; (2) a novel high-affinity, non-cleavable CD16 Fc receptor that enables tumor targeting and enhanced antibody-dependent cell cytotoxicity in combination with a therapeutic mAb; and (3) IL-15/IL-15 receptor fusion promoting cytokine-autonomous persistence. Preclinical in vivo models of leukemia and lymphoma demonstrate potent CAR-mediated efficacy of FT596 against CD19+ tumor cells and activity against both CD19+ and CD19- tumor cells when combined with the anti-CD20 agent rituximab (Goodridge et al. 2019). Methods: FT596 is being investigated in a multicenter, Phase I clinical trial in pts with relapsed/refractory (R/R) B-cell lymphomas (BCLs) and chronic lymphocytic leukemia (ClinicalTrials.gov: NCT04245722). Conditioning chemotherapy (fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 on Days -5 to -3) is administered followed by a single dose of FT596 as monotherapy (Regimen A) or combined with rituximab (R) 375 mg/m 2 (Regimen B1) or obinutuzumab 1000 mg/m 2 (Regimen B2) on Day -4. FT596 single-dose levels between 30 and 900 million cells are being tested. Pts experiencing clinical benefit may receive a second cycle of conditioning followed by a single dose of FT596 with FDA approval (Cycle 2). Primary objectives are to determine the recommended Phase II dose of FT596 and safety and tolerability. Additional key objectives include preliminary anti-tumor activity per the Lugano Classification, pharmacokinetics, and anti-product immunogenicity. Results: As of a data cutoff date of 25 June 2021, 20 pts with R/R BCL (12 with aggressive histology, 8 indolent) were treated in dose escalation with FT596, including 10 in Regimen A and 10 in Regimen B1 (3 with 30 million cells, 4 with 90 million cells, and 3 with 300 million cells in each regimen). Pts had received a median of 4 prior therapies, with 7 having receiv