Abstract B061: Harnessing stem cell-engineered CAR-NKT cells for universal low-toxicity autoimmune therapy
Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disease of the central nervous system with no curative therapy and limited treatment options for progressive disease. While autologous CAR-T cell therapies targeting pathogenic B cells have shown early clinical promise, their efficacy is constrained by incomplete control of pro-inflammatory myeloid populations, safety concerns including cytokine release syndrome (CRS) and neurotoxicity, and challenges in scalability and manufacturing. Here, we present a next-generation, allogeneic “off-the-shelf” CAR-NKT cell platform engineered from cord blood–derived CD34+ hematopoietic stem and progenitor cells (HSPCs) for the treatment of MS. Using a clinically guided, feeder-free culture system, we generated high-yield, pure, and clonal Allo15CAR19-NKT cells that co-express an invariant NKT TCR, a CD19-targeting CAR, and IL-15. These cells demonstrated robust and reproducible manufacturing across multiple donors, long-term stability, and favorable safety characteristics. Functionally, Allo15CAR19-NKT cells exhibited potent cytotoxic activity against CD19+ B cells and uniquely enabled dual targeting of CD19+ B cells and CD1d+ pro-inflammatory myeloid cells derived from MS patient samples. In vivo, Allo15CAR19-NKT cells achieved superior disease control compared to conventional CAR-T cells, including enhanced tumor clearance, reduced neuroinflammation, and improved survival. Mechanistically, this dual activity is mediated by CAR-dependent B cell depletion and invariant NKT TCR–mediated targeting of myeloid cells. Importantly, Allo15CAR19-NKT cells displayed a favorable safety profile, with minimal risk of graft-versus-host disease, reduced susceptibility to host allorejection, and significantly attenuated CRS in humanized mouse models. Collectively, these findings establish HSPC-engineered allogeneic CAR-NKT cells as a promising, scalable, and safer immunotherapy platform for MS, supporting their advancement toward clinical translation. Yan-Ruide Li, Yichen Zhu, Yuning Chen. Harnessing stem cell-engineered CAR-NKT cells for universal low-toxicity autoimmune therapy [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B061.