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Anti-CD19 CARs Displayed at the Surface of Lentiviral Vector Particles Promote Transduction of Target-expressing Cells
Nicole Cordes
Carolin Kolbe
Dominik Lock
Tatjana Holzer
Deborah Althoff
Daniel Schäfer
Franziska Blaeschke
Bettina Kotter
Sandra Karitzky
Claudia Rössig
Anton Cathomen
Tobias F. Feuchtinger
Iris Bürger
Mario Assenmacher
Thomas Schaser
Andrew Kaiser
出版
Universität
, 2021
URL
http://books.google.com.hk/books?id=qId2zgEACAAJ&hl=&source=gbs_api
註釋
Abstract: Recently, a rare type of relapse was reported upon treating a B cell acute lymphoblastic leukemia (B-ALL) patient with anti-CD19 chimeric antigen receptor (CAR)-T cells caused by unintentional transduction of residual malignant B cells (CAR-B cells). We show that anti-CD19 and anti-CD20 CARs are presented on the surface of lentiviral vectors (LVs), inducing specific binding to the respective antigen. Binding of anti-CD19 CAR-encoding LVs containing supernatant was reduced by CD19-specific blocking antibodies in a dose-dependent manner, and binding was absent for unspecific LV containing supernatant. This suggests that LVs bind via displayed CAR molecules to CAR antigen-expressing cells. The relevance for CAR-T cell manufacturing was evaluated when PBMCs and B-ALL malignant B cells were mixed and transduced with anti-CD19 or anti-CD20 CAR-displaying LVs in clinically relevant doses to mimic transduction conditions of unpurified patient leukapheresis samples. Malignant B cells were transduced at higher levels with LVs displaying anti-CD19 CARs compared to LVs displaying non-binding control constructs. Stability of gene transfer was confirmed by applying a potent LV inhibitor and long-term cultures for 10 days. Our findings provide a potential explanation for the emergence of CAR-B cells pointing to safer manufacturing procedures with reduced risk of this rare type of relapse in the future