CD62L as target receptor for specific gene delivery into less differentiated human T lymphocytes

Frontiers in Immunology

Immunology

Frederic B. Thalheimer¹  Arezoo Jamali¹  Naphang Ho¹  Annika M. Frank¹  Jessica Hartmann¹  Thomas Kerzel¹  Laura Kapitza²  Christian J. Buchholz³  Thomas Schaser⁴ 

[1] Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany;Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany;German Cancer Consortium (DKTK), Heidelberg, Germany;Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany;German Cancer Consortium (DKTK), Heidelberg, Germany;Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany;Research & Development, Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany;

关键词: L-selectin;    receptor-targeted viral vectors;    LV;    chimeric antigen receptor;    CAR T cells;    ΔLNGFR;    naïve T lymphocytes;   

DOI  :  10.3389/fimmu.2023.1183698

 received in 2023-03-10, accepted in 2023-07-24,  发布年份 2023

来源: Frontiers

【 摘 要 】

Chimeric antigen receptor (CAR)-expressing T cells are a complex and heterogeneous gene therapy product with variable phenotype compositions. A higher proportion of less differentiated CAR T cells is usually associated with improved antitumoral function and persistence. We describe in this study a novel receptor-targeted lentiviral vector (LV) named 62L-LV that preferentially transduces less differentiated T cells marked by the L-selectin receptor CD62L, with transduction rates of up to 70% of CD4+ and 50% of CD8+ primary T cells. Remarkably, higher amounts of less differentiated T cells are transduced and preserved upon long-term cultivation using 62L-LV compared to VSV-LV. Interestingly, shed CD62L neither altered the binding of 62L-LV particles to T cells nor impacted their transduction. The incubation of 2 days of activated T lymphocytes with 62L-LV or VSV-LV for only 24 hours was sufficient to generate CAR T cells that controlled tumor growth in a leukemia tumor mouse model. The data proved that potent CAR T cells can be generated by short-term ex vivo exposure of primary cells to LVs. As a first vector type that preferentially transduces less differentiated T lymphocytes, 62L-LV has the potential to circumvent cumbersome selections of T cell subtypes and offers substantial shortening of the CAR T cell manufacturing process.

【 授权许可】

Unknown   
Copyright © 2023 Kapitza, Ho, Kerzel, Frank, Thalheimer, Jamali, Schaser, Buchholz and Hartmann