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

Abstract 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 received CAR T-cell therapy and 5 with autologous stem cell transplant. Ten of 20 pts were refractory to last prior therapy. No dose-limiting toxicities were reported with either regimen. No graft-versus-host disease (GvHD) or immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Two cases of cytokine release syndrome (CRS) were reported (one Gr 1 and one Gr 2). The most common treatment-emergent adverse events of any grade were neutrophil count decreased (85%), nausea (75%), anemia (50%), WBC count decreased (45%), fatigue and platelet count decreased (40% each), and peripheral edema (35%). No B- or T-cell mediated anti-product responses were observed. Of 17 efficacy-evaluable pts, 5 of 8 in Regimen A and 4 of 9 in Regimen B achieved an objective response after the first FT596 treatment cycle. At single-dose levels of ≥90 million cells, 8 of 11 efficacy-evaluable pts achieved an objective response, including 7 complete responses (CR). Of 4 pts with prior CAR T-cell therapy treated at ≥90 million cells, 2 achieved CR. The FDA approved all requests for FT596 retreatment. Seven of 9 responders received Cycle 2; 1 pt with CR elected not to receive Cycle 2, and 1 pt with partial response (PR) experienced disease progression prior to initiation of Cycle 2. Five pts (4 with CR, 1 with PR after Cycle 1) completed Cycle 2, and 2 pts initiated Cycle 2 after data cutoff. CR was maintained after Cycle 2 in all 4 pts with CR, while the 1 pt with PR experienced a deepening PR after Cycle 2. No CRS, ICANS, or GvHD were reported with Cycle 2. Conclusions: FT596 monotherapy or in combination with R was well tolerated and demonstrated activity in pts with R/R BCL, including in pts previously treated with CAR T-cell therapy. Administration of a second FT596 treatment cycle was well tolerated with evidence of continuing clinical benefit. Dose escalation of FT596 is ongoing. Updated clinical and translational data will be presented at the conference. Disclosures Bachanova: Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobadi: Wugen: Consultancy; Atara: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Patel: Kite Pharma: Consultancy, Speakers Bureau; Janssen: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy; Morphosys: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; MEI Pharma: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; Lilly: Consultancy. Park: Kite Pharma: Consultancy; BMS: Consultancy; Artiva: Consultancy; Minerva: Consultancy; Curocel: Consultancy; Amgen: Consultancy; Affyimmune: Consultancy; Kura Oncology: Consultancy; Servier: Consultancy; Autolus: Consultancy; Intellia: Consultancy; Innate Pharma: Consultancy; PrecisionBio: Consultancy; Novartis: Consultancy. Flinn: Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research