A Phase I Study of FT538, an Off-the-Shelf, Multiplexed-Engineered, iPSC-Derived NK Cell Therapy in Combination with Daratumumab in Relapsed/Refractory Multiple Myeloma

Introduction: Allogeneic natural killer (NK) cell therapies have been well tolerated with documented anti-tumor activity in patients with relapsed/refractory (R/R) multiple myeloma (MM) (Lupo et al. 2019). However, limited availability of suitable donors, relatively short in vivo persistence, and manufacturing constraints that affect the ability to administer >1 dose of cells sufficient to achieve clinical activity are major barriers to maximizing the clinical benefit of allogeneic NK cell therapy. Induced pluripotent stem cell (iPSC)-derived immune effector cells offer distinct advantages over existing patient- and donor-derived therapeutic approaches, notably the use of a clonal master engineered iPSC line as a renewable source for the mass production of multiplexed-engineered immune cells of uniform composition for off-the-shelf availability, repeated dosing, and broad patient access.

FT538 is an off-the-shelf, multiplexed-engineered NK cell therapy generated from a clonal master engineered iPSC line. FT538 incorporates 3 functional modalities for enhanced innate immunity: (1) high-affinity 158V, non-cleavable CD16 Fc receptor for augmented antibody-dependent cellular cytotoxicity (ADCC); (2) IL-15/IL-15 receptor fusion that promotes NK cell persistence; and (3) CD38 knockout to mitigate NK cell fratricide by CD38-directed monoclonal antibodies and to promote higher rates of glycolysis with improved metabolic fitness and resistance to oxidative stress within the tumor microenvironment. In preclinical studies, FT538 displays increased persistence without the need for exogenous cytokine support and, when combined with daratumumab against MM targets, demonstrates avoidance of daratumumab-mediated fratricide and significantly enhanced ADCC in vitro in a serial stimulation cytotoxicity assay compared with peripheral blood NK cells. The combination of FT538 and daratumumab led to highly effective tumor control compared with daratumumab alone in an in vivo MM xenograft model (Bjordahl et al. 2019).

Methods: This is a multicenter, Phase I clinical trial of FT538 as monotherapy in R/R acute myelogenous leukemia (Regimen A) or in combination with daratumumab in R/R MM (Regimen B) (ClinicalTrials.gov: NCT04614636). In Regimen B, conditioning chemotherapy (fludarabine 30 mg/m² and cyclophosphamide 300 mg/m²) followed by 3 once-weekly doses of FT538 (Days 1, 8, 15 of a 28-d cycle), ranging from 100 million cells/dose up to 1.5 billion cells/dose, are being evaluated using a standard 3 + 3 dose-escalation design. Daratumumab is first administered on Day -11 and given per prescribing information. A second cycle of therapy (daratumumab, conditioning chemotherapy, FT538) may be administered with FDA approval in subjects who have derived clinical benefit from their first cycle of therapy. The primary objectives are to evaluate safety and tolerability and to determine the recommended Phase II dose. Additional key objectives include anti-tumor activity, pharmacokinetics, and anti-product immunogenicity.

Results: As of a data cutoff date of 05 Jul 2022, 6 patients with R/R MM were treated and evaluable in the first 2 dose cohorts (100 and 300 million cells/dose) of Regimen B. No dose-limiting toxicities, and no events of any grade of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD), were observed. No B- or T-cell mediated anti-product responses were observed.

Conclusions: Administration of up to 3 doses of FT538 cells at 100 or 300 million cells/dose in combination with daratumumab is safe and well tolerated without CRS, neurotoxicity, or GvHD. Interim clinical data, including safety and tolerability and initial anti-tumor activity from the ongoing Phase I dose-escalation study of FT538 in combination with daratumumab in R/R MM, will be presented at the conference.

References: Bjordahl R, Gaidarova S, Woan K, et al. FT538: Preclinical development of an off-the-shelf adoptive NK cell immunotherapy with targeted disruption of CD38 to prevent anti-CD38 antibody-mediated fratricide and enhance ADCC in multiple myeloma when combined with daratumumab. Blood. 2019;134 (Supplement_1):133.

Lupo KB, Matosevic S. Natural killer cells as allogeneic effectors in adoptive cancer immunotherapy. Cancers (Basel). 2019;11(6):769.

Mailankody:OncLive: Honoraria; Plexus Communication: Honoraria; Fate Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Juno Therapeutics: Research Funding; Takeda Oncology: Research Funding; Allogene Therapeutics: Research Funding; Optum Oncology: Consultancy; BioAscend: Consultancy; Janssen Oncology: Consultancy, Research Funding; Evicore: Consultancy; Legend Biotech: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Physician Education Resource: Honoraria. Bickers:Fate Therapeutics, Inc.: Current Employment. Zong:Fate Therapeutics: Current Employment. Wong:Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Ly:Fate Therapeutics, Inc.: Current Employment. Byon:Fate Therapeutics, Inc.: Current Employment. Cooley:Fate Therapeutics, Inc.: Current Employment. Valamehr:Fate Therapeutics: Current Employment. Chu:Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company. Vij:BMS, Takeda, Sanofi, GSK, Janssen, Pfizer, Oncopeptides, Legend, Biegene, Harpoon, Adaptive: Consultancy; BMS, Sanofi, Takeda: Research Funding.