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

Autor: Pfeiffer A; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany., Thalheimer FB; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany., Hartmann S; Dr. Senckenberg Institute of Pathology, Goethe-University Frankfurt, Frankfurt am Main, Germany., Frank AM; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany., Bender RR; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany., Danisch S; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Laboratory of Regenerative Immune Therapies Applied, Excellence Cluster REBIRTH and German Centre for Infection Research (DZIF), partner site Hannover, Hannover, Germany., Costa C; CIRI - International Center for Infectiology Research, Team EVIR, Inserm, U1111, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, University of Lyon, Lyon, France., Wels WS; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.; German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, Frankfurt, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Modlich U; Division of Veterinary Medicine, Research Group for Gene Modification in Stem Cells, Paul-Ehrlich-Institut, Langen, Germany., Stripecke R; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Laboratory of Regenerative Immune Therapies Applied, Excellence Cluster REBIRTH and German Centre for Infection Research (DZIF), partner site Hannover, Hannover, Germany., Verhoeyen E; CIRI - International Center for Infectiology Research, Team EVIR, Inserm, U1111, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, University of Lyon, Lyon, France.; INSERM, C3M, Université Côte d'Azur, Nice, France., Buchholz CJ; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany christian.buchholz@pei.de.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK), partner site Heidelberg, Heidelberg, Germany.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2018 Nov; Vol. 10 (11).
DOI: 10.15252/emmm.201809158
Abstrakt: 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.
(© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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