2. Academic Validation
  3. Enhanced conversion of T cells into CAR T cells by modulation of the MAPK/ERK pathway

Enhanced conversion of T cells into CAR T cells by modulation of the MAPK/ERK pathway

  • Cell Rep Med. 2025 Feb 18;6(2):101970. doi: 10.1016/j.xcrm.2025.101970.
Elham Adabi 1,  Filippos T Charitidis 1,  Frederic B Thalheimer 2,  Mar Guaza-Lasheras 1,  Colin Clarke 3,  Christian J Buchholz 4
Affiliations

Affiliations

  • 1 Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Hessen, Germany.
  • 2 Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Hessen, Germany; Hematology, Cell and Gene Therapy, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Hessen, Germany; Frankfurt Cancer Institute (FCI), Goethe University, 60590 Frankfurt am Main, Germany.
  • 3 National Institute for Bioprocessing Research and Training, Fosters Avenue, A94 X099 Blackrock, Dublin, Ireland; School of Chemical and Bioprocess Engineering, University College Dublin, D04 V1W8 Belfield, Dublin, Ireland.
  • 4 Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Hessen, Germany; Frankfurt Cancer Institute (FCI), Goethe University, 60590 Frankfurt am Main, Germany; Deutsches Krebsforschungszentrum and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Electronic address: christian.buchholz@pei.de.
PMID: 39938523 DOI: 10.1016/j.xcrm.2025.101970
Abstract

Delivery of chimeric antigen receptors (CARs) to T cells is usually mediated by lentiviral vectors (LVs), which can have broad tropism or be T cell targeted. To better understand the molecular events during CAR T cell generation, T cell transduction with four different LVs is followed by single-cell multi-omics analysis, distinguishing between transduced T cells and T cells with vector signal but no CAR. We find that only a fraction of the T cells that encounter vectors convert into CAR T cells. Single-cell transcriptome data reveal that interferon-stimulated genes are upregulated in non-transduced cells, whereas extracellular signal-regulated kinase (ERK)2 phosphatases are upregulated in CAR T cells. This expression pattern is evident in CAR T cells from healthy donors and patients. The role of the mitogen-activated protein kinase (MAPK)/ERK pathway in CAR T cell generation is confirmed by chemical inhibitors. These data provide molecular insights into T cell transduction with implications for improving CAR T cell generation.

Keywords

CAR T cells, lentiviral vector, adeno-associated vector, interferon-stimulated genes, MAPK/ERK pathway, ERK2 inhibitors.

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