In vivo generation of human CD19‐CAR T cells results in B‐cell depletion and signs of cytokine release syndrome

  • Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B‐cell malignancies. Notwithstanding, CAR T‐cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19‐CAR T cells can be generated directly in vivo using the lentiviral vector CD8‐LV specifically targeting human CD8+ cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR expression solely in CD8+ T cells and efficacious elimination of CD19+ B cells. Further, upon injection of CD8‐LV into mice transplanted with human CD34+ cells, induction of CAR T cells and CD19+ B‐cell depletion was observed in 7 out of 10 treated animals. Notably, three mice showed elevated levels of human cytokines in plasma. Tissue‐invading CAR T cells and complete elimination of the B‐lymphocyte‐rich zones in spleen were indicative of a cytokine release syndrome. Our data demonstrate the feasibility of in vivo reprogramming of human CD8+ CAR T cells active against CD19+ cells, yet with similar adverse effects currently notorious in the clinical practice.
Metadaten
Author:Anett Pfeiffer, Frederic Bastian Thalheimer, Sylvia HartmannGND, Annika Frank, Ruben Raphael Bender, Simon Danisch, Caroline Costa, Winfried S. Wels, Ute Modlich, Renata Stripecke, Els Verhoeyen, Christian J. Buchholz
URN:urn:nbn:de:hebis:30:3-473846
DOI:https://doi.org/10.15252/emmm.201809158
ISSN:1757-4684
ISSN:1715-4684
ISSN:1757-4676
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30224381
Parent Title (English):EMBO molecular medicine
Publisher:Wiley-VCH ; EMBO Press
Place of publication:Weinheim ; Heidelberg
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/09/17
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/10/02
Tag:T-cell targeting; cytokine release syndrome; gene delivery; humanized mouse
Volume:10
Issue:e9158
Page Number:11
First Page:1
Last Page:11
Note:
© 2018 The Authors. Published under the terms of the CC BY 4.0 license
HeBIS-PPN:439188741
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0