Abstract 148: In vivo CAR-T T-LNP system (GT801) drives potent B cell depletion and clinical feasibility in hematologic and autoimmune conditions.

Abstract Background: CAR-T therapies have revolutionized hematologic malignancies treatment but remain constrained by complex autologous manufacturing, high cost, and lymphodepletion toxicity. In vivo CAR-T approaches aim to overcome these barriers by engineering T cells directly in patients, which requires targeted delivery, durable CAR expression, potent cytotoxicity, and re-dosing potential. Toward this goal, we present the development, preclinical data, and preliminary clinical results for GT801, a novel anti-CD19 in vivo CAR-T candidate. Methods: GT801 uses T cell-targeted lipid nanoparticles (T-LNPs) encapsulating chemically modified linear mRNA encoding an anti-CD19 CAR. T-LNPs were surface-engineered with a VHH antibody using the CLAMP platform, enabling site-specific antibody attachment, controlled ligand density, and efficient, selective T-cell uptake. Formulation and mRNA design were optimized for targeting specificity, robust CAR expression, and functionality. B-cell depletion, PK, and preliminary toxicology of GT801 were assessed in vitro and in humanized NOG mouse models. Results: With optimized mRNA chemistry, the T-LNP platform achieves robust and durable CAR expression in human PBMCs for >14 days in vitro. Targeted delivery at 0.1 mpk reached receptor-saturating levels across multiple lymphoid tissues, while off-target uptake remained 95% B-cell depletion, and 0.1 mpk achieved near-complete clearance (