%0 Journal Article
%A Junkuhn, Charlotte
%A Schiele, Phillip
%A Walter, Anna Luzie
%A Hamm, Frederik
%A Obermayer, Benedikt
%A Busch, David
%A Stroux, Andrea
%A Frick, Mareike
%A Penack, Olaf
%A Damm, Frederik
%A Polansky, Julia
%A Bullinger, Lars
%A Künkele, Annette
%A Frentsch, Marco
%A Na, Il-Kang
%T Prior chemotherapy deteriorates T-cell quality for CAR T-cell therapy in B-cell non-Hodgkin's lymphoma.
%J Journal for ImmunoTherapy of Cancer
%V 13
%N 4
%@ 2051-1426
%C London
%I BioMed Central
%M DKFZ-2025-00769
%P e010709
%D 2025
%X Chimeric antigen receptor (CAR) T-cell therapy depends on T cells that are genetically modified to recognize and attack cancer cells. Their effectiveness thus hinges on the functionality of a patient's own T cells. Since CAR T-cell therapy is currently only approved for advanced cancers after at least one line of chemotherapy, we evaluated the potential negative effects of prior exposure to chemotherapy on T-cell functionality.We studied T cells of two B-cell non-Hodgkin's lymphoma patient cohorts, one collected before treatment (pre-therapy) and the other after one or more (median 3) lines of chemotherapy (post-therapy). Leveraging advanced multiparameter flow cytometry, single-cell RNA sequencing (scRNA-seq), whole-genome DNA methylation arrays and in vitro functionality testing of generated CAR T cells, we compared patient samples in their suitability for effective CAR T-cell therapy.We discovered significant modifications in T-cell subsets and their transcriptional profiles secondary to chemotherapy exposure. Our analysis revealed a discernible shift towards phenotypically more differentiated T cells and an upregulation of markers indicative of T-cell exhaustion. Additionally, scRNA-seq and DNA methylation analyses revealed gene expression and epigenetic changes associated with diminished functionality in post-therapy T cells. Cytotoxicity assays demonstrated superior killing efficacy of CAR T cells derived from treatment-naïve patients compared with those with chemotherapy history.These findings corroborate that employing T cells collected prior to frontline chemotherapy could enhance the effectiveness of CAR T-cell therapy and improve patient outcomes.
%K Humans
%K Immunotherapy, Adoptive: methods
%K T-Lymphocytes: immunology
%K T-Lymphocytes: drug effects
%K Lymphoma, B-Cell: therapy
%K Lymphoma, B-Cell: immunology
%K Lymphoma, B-Cell: drug therapy
%K Receptors, Chimeric Antigen: metabolism
%K DNA Methylation
%K Male
%K Female
%K Adoptive cell therapy - ACT (Other)
%K Chimeric antigen receptor - CAR (Other)
%K Lymphoma (Other)
%K Receptors, Chimeric Antigen (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40210237
%R 10.1136/jitc-2024-010709
%U https://inrepo02.dkfz.de/record/300323