The development of FT839: An off-the-shelf CD19xCD38 dual-CAR T cell for the treatment of multiple myeloma

Abstract Following autologous chimeric antigen receptor (CAR) T-cell therapy, approximately 50% of multiple myeloma (MM) patients relapse within two years of treatment. Relapses can occur for many reasons, but ultimately it is the result of tumor re-growth caused by the underlying attribute of tumor heterogeneity. FT839 is an induced pluripotent stem cell (iPSC) derived CAR T cell product specifically designed to address tumor heterogeneity while enabling broad patient access. To uniquely address tumor heterogeneity, FT839 was engineered to contain two unique CARs, i) a lineage-antigen CD19 shown to be associated with MM initiating cancer stem cells and ii) an activated state-antigen CD38 broadly associated with MM. To further enable tertiary antigen targeting and synergies with other therapeutic agents, FT839 can also be combined with monoclonal antibodies (mAbs) through a modified high affinity and protease resistant CD16 receptor (hnCD16), and T cell engagers (TCEs) through a novel CD3-chimeric fusion receptor (CD3-CFR). In vitro cytotoxicity assays against MM cell lines RPMI-8226, OPM2, MM1.s and H929 demonstrated durable and potent cell cytotoxicity at low effector:target ratios, as a monotherapy with further deepening of response when combined with mAbs such as daratumumab or sarclisa, or T cell engagers such as teclistamab or talquetamab (exceeding 90% cytotoxicity in each case). These data demonstrate that FT839, via combinatorial dual-CAR, hnCD16, and/or CD3-CFR targeting, can circumvent antigen loss to successfully eliminate MM target cells with diverse and heterogenous antigen expression. FT839 has also been specifically engineered to support functional persistence without the need for intense conditioning chemotherapy through Sword and ShieldTM engineering which confers resistance to potent pre-existing and de novo host immune cell-mediated rejection, at the same time preserving anti-tumor responses. In mixed lymphocyte co-cultures, FT839 maintained functional persistence and prevented expansion of pre-existing alloreactive T cells by 20.7x compared to control. Notably, FT839 demonstrated durable anti-tumor activity over multiple rounds of tumor challenge with repeat exposure to alloreactive T cells primed to specifically target FT839 and create a supraphysiological allogeneic environment. Collectively, FT839 is engineered to eliminate cancer cells with broad and heterogenous antigen expression by a unique dual-CAR system and in combination with standard of care therapeutics, including mAbs and TCEs via hnCD16 and CD3-CFR transgenes, to overcome multiple challenges that have limited autologous CAR T-cell therapies in treating MM. Moreover, as an off-the-shelf CAR T-cell therapy, FT839 is intended for broad and on-demand access without the need for complicated and variable manufacturing processes or intense conditioning chemotherapy.