Abstract 4284: FT839: A next-generation, off-the-shelf CAR T cell uniquely engineered with a dual CAR system targeting CD19 and CD38 for the treatment of hematological malignancies and autoimmune diseases without conditioning chemotherapy

Abstract Autologous chimeric antigen receptor (CAR) T cell therapies have revolutionized treatment of hematological malignancies and are showing promising results in autoimmune settings. Despite these successes, widespread accessibility to autologous CAR T-cell therapy is challenged by manufacturing complexities, high cost, lack of on-demand drug product availability and the requirement for intensive conditioning-chemotherapy. Moreover, single antigen targeting often fails to address the complex and heterogenous nature of such diseases. FT839 is an off-the-shelf, uniformly engineered, 13-point edited iPSC-derived CAR T cell therapy that overcomes these challenges, delivering potent and flexible multi-antigen targeting with broad patient accessibility.Mediated by its dual CAR system targeting CD19 and CD38 to eliminate malignant and aberrant immune cells, in preclinical studies FT839 exhibited selective elimination of autoimmune disease drivers like B cells, plasma cells and activated T cells as well as hematological cancer cells of lymphoma/leukemia and myeloma origin with profound potency (p0.01). The comprehensive targeting strategy and the depth of activity was further extended when combined with the monoclonal antibody (mAb) rituximab or the T cell engager (TCE) epcoritamab facilitated through the expression of high affinity/non-cleavable Fc receptor (hnCD16) and CD3ε fusion receptor (CD3FR), respectively (p0.01). Furthermore, FT839 features Sword and ShieldTM technology, designed to promote functional persistence by directly targeting and evading alloreactive host immune cells. In allogeneic settings with HLA-mismatched donor PBMCs or primed allogeneic T cells designed to quickly eliminate non-host cells, FT839 showed enhanced persistence (21x, p0.0001 vs control), limited alloreactive cell expansion (0.25x, p0.0005 vs control), and durable tumor control (18x greater cytotoxicity vs control). FT839 has also been engineered with the chemokine receptor CXCR2, and a TGFβ signal redirection receptor to improve trafficking to sites of pathological activity and to counter the suppressive effect of TGFβ, respectively (6.5x greater tissue potency, p0.005). With Sword and ShieldTM technology, FT839 obviates the need for conditioning chemotherapy, reducing patient burden and maximizing access. Armed with CD19 and CD38 targeting CARs and the ability to functionally combine with approved therapeutic mAbs and TCEs, FT839 selectively and uniquely eliminates heterogeneously populated disease-driving immune cells. Collectively, FT839 is a scalable, cost-effective, and uniform off-the-shelf CAR T-cell therapy for the broad treatment of hematological malignancies and autoimmune diseases. Citation Format: Alex J. Garcia, Shilpi Chandra, Soheila Shirinbak, Mark Jelcic, Brian Groff, Spas Markov, Alma Gutierrez, Angela Gentile, Miguel Meza, Karina Palomares, Carissa Dege, Bjoern Gaertner, Ramzey Abujarour, John Goulding, Tom Lee, Karl-Johan Malmberg, Maksim Mamonkin, Jode Goodridge, Martin Hosking. FT839: A next-generation, off-the-shelf CAR T cell uniquely engineered with a dual CAR system targeting CD19 and CD38 for the treatment of hematological malignancies and autoimmune diseases without conditioning chemotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4284.