The development of an off-the-shelf CAR T-cell therapy co-targeting CD19 and CD38 for broad application in autoimmune disease Free

CD19-targeting chimeric antigen receptor (CAR) T-cell therapies have demonstrated profound clinical efficacy in the treatment of a growing list of autoimmune diseases through their ability to target and reset pathogenic B cell immune compartments. The extension of CAR T-cell therapy to additional autoimmune indications offers substantial therapeutic potential, especially for patients with refractory disease and limited treatment options.

Currently approved autologous CAR T-cell therapies face several important limitations including their narrow, single antigen targeting (e.g., CD19) mechanism of action that is unlikely to eliminate all disease-causing immune cell types in complex autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). Moreover, broad patient access to these therapies is limited due to inconsistencies associated with the manufacturing of heterogeneously edited cells, production costs, the inability to be available on-demand, and the need for intense conditioning chemotherapy which requires hospitalization and treatment at specialized centers to monitor adverse events, including the risk of severe infection.

FT839, a next generation off-the-shelf CAR T-cell therapy, is designed to overcome these limitations by expanding CAR T-cell therapy access to a broader pool of autoimmune disease patients. Derived from a clonal, multiplex precision-engineered induced pluripotent stem cell that allows for routine and scaled manufacture, FT839 incorporates novel synthetic functional elements that enable multi-antigen targeting to effectively eliminate a range of pathogenic immune cell types while simultaneously resisting immune rejection in allogeneic patient settings.

FT839 co-expresses two distinct CARs: the first targets the B-cell lineage marker CD19, and the second targets the immune activation marker CD38. Combined with genomic deletion of CD38 to avoid fratricide and T-cell receptor to eliminate the risk of graft-versus-host disease, this multi-antigen targeting approach enables selective elimination across a comprehensive range of disease-causing immune cell subsets. FT839 also expresses a high-affinity, non-cleavable CD16 receptor and a chimeric CD3-fusion receptor, enabling synergistic combinations with standard-of-care monoclonal antibodies and clinically approved T-cell engagers to achieve potentially enhanced therapeutic activity and functional versatility through engagement of one or more activating receptors on separate lineage markers.

In vitro cytotoxicity assays exhibited CAR-mediated targeting of CD19 and/or CD38, resulting in potent elimination of antigen-expressing target cells, including CD19⁺ B cells, CD38⁺ plasma cells, and CD38⁺ alloreactive immune cells. In vivo, FT839 demonstrated potent and specific elimination of xenografts consisting of CD19⁺ and CD38⁺ target cells. Notably, FT839 simultaneously eliminated autoimmune disease driving cell types in vitro, such as B cells, plasma cells, activated Th1 and Th17 CD4⁺ T cells, activated CD8⁺ T cells, and inflammatory macrophages (>90% depletion of all CD19⁺ and CD38⁺ targets), underscoring the broad suitabilityof FT839 for the control of autoreactive immune subsets.

To eliminate the current requirement to administer conditioning chemotherapy alongside CAR T-cell therapy, FT839 incorporates Sword and Shield™ technology engineering with a novel allo-immune defense receptor (ADR), designed to eliminate 4-1BB⁺ alloreactive immune cells, and genetic disruption of the immune synapse adhesion ligand CD58 (CD58^KO) to enable passive evasion from host allogeneic immune cells. In the presence of alloreactive peripheral blood mononuclear cells, FT839 demonstrated sustained cytotoxicity upon serial rechallenge in vitro and maintained tumor growth inhibition and functional persistence in vivo, consistently displaying superior durability and potency compared to controls that lack Sword and Shield™ (p<0.001). These results demonstrate the unique ability of FT839 to functionally persist in an allogeneic and mismatched setting without the need for intensive conditioning chemotherapy.

In summary, FT839 enables the simultaneous and selective elimination of multiple disease-driving immune cells without the need for supportive conditioning chemotherapy. Its scalable, cost-effective manufacturing and off-the-shelf delivery supports broad clinical accessibility across a range of autoimmune disease settings.