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An AAV variant enables human T cell engineering in vivo

ABSTRACT: Autologous chimeric antigen receptor T (CAR-T) cell therapy has exhibited prominent therapeutic effectiveness in hematologic malignancy and autoimmune disease, but the manufacturing complexity and the required lymphodepletion hindered its wide clinical application. Engineering human T cells in vivo holds promise to conquer these limitations but requires effective T cell-targeted CAR delivery with demonstrated safety. Recombinant adeno-associated virus (rAAV) emerged as a promising vehicle in eight FDA-approved gene therapy drugs and shows attractive potential in tropism redirection via capsid engineering. Here, we showcased that T-cell-tropic rAAV variants successfully enabled CAR expression in human T cells and de-targeted from the liver down to 1% of the parental serotypes. In a humanized mouse model, systematic injection of rAAV-CAR turned up to 8.3% of human T cells into CAR-T cells, which successfully eliminated the number of B cells and controlled tumor progression. Moreover, we identified and verified three cell surface receptors corresponding to the superior transduction efficiencies of the rAAV variants to T cells. This study demonstrated the effectiveness and safety of AAV-based in vivo generation of CAR-T cells in a humanized mouse model, which illustrated a route of in vivo CAR-T therapy via a delivery vector proved in clinics. Furthermore, the identified receptors provide mechanistic insights into the translational potential and guidance to receptor-based capsid engineering.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276034 | GEO | 2026/03/05

REPOSITORIES: GEO

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