Phase I Study of FT538 + Daratumumab for Treatment of r/r AML

Introduction: Relapsed and refractory (r/r) acute myeloid leukemia (AML) remains an unmet need with immune-therapy based treatments such as hematopoietic stem cell transplantation (HSCT) providing the longest relapse-free survival (RFS). Natural Killer (NK cells) have been shown to effect lysis of AML cells, both in vitro and in vivo across multiple platforms. In particular, “adaptive” NK cells induced in vivo in HSCT recipients after CMV reactivation have been shown to confer an RFS advantage. These cells are characterized phenotypically by the expression of NKG2C, CD57, KIR and downregulation of CD38. CD38 is an ectoenzyme broadly expressed on hematopoietic cells, including approximately 60% of AML. It catalyzes the conversion of nicotinamide-adenine dinucleotide (NAD+) and nicotinamide-adenine dinucleotide phosphate (NADP+) to cyclic adenosine diphosphate (cADP) ribosyl. CD38 knock-out NK cells have increased persistence by having enhanced metabolic fitness and resistance to oxidative stress via a reduction of reactive oxygen species. FT538 is an iPSC-derived NK cell product with a non-cleavable CD16 receptor to augment antibody-dependent cytotoxicity (ADCC), IL-15/IL-15R fusion to increase activation and persistence, and CD38 knockout to enhance its metabolic fitness and avoid fratricide when combined with CD38 monoclonal antibodies. Daratumumab (Dara) is a monoclonal antibody targeting CD38 on the surface of AML cells as well as activated lymphocytes. We hypothesized that the addition of Dara to fludarabine and cyclophosphamide would enhance lymphodepletion and augment ADCC for CD38+ AML leading to better response rates when combined with FT538.