TY  - JOUR
AU  - Junkuhn, Charlotte
AU  - Schiele, Phillip
AU  - Walter, Anna Luzie
AU  - Hamm, Frederik
AU  - Obermayer, Benedikt
AU  - Busch, David
AU  - Stroux, Andrea
AU  - Frick, Mareike
AU  - Penack, Olaf
AU  - Damm, Frederik
AU  - Polansky, Julia
AU  - Bullinger, Lars
AU  - Künkele, Annette
AU  - Frentsch, Marco
AU  - Na, Il-Kang
TI  - Prior chemotherapy deteriorates T-cell quality for CAR T-cell therapy in B-cell non-Hodgkin's lymphoma.
JO  - Journal for ImmunoTherapy of Cancer
VL  - 13
IS  - 4
SN  - 2051-1426
CY  - London
PB  - BioMed Central
M1  - DKFZ-2025-00769
SP  - e010709
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Immunotherapy, Adoptive: methods
KW  - T-Lymphocytes: immunology
KW  - T-Lymphocytes: drug effects
KW  - Lymphoma, B-Cell: therapy
KW  - Lymphoma, B-Cell: immunology
KW  - Lymphoma, B-Cell: drug therapy
KW  - Receptors, Chimeric Antigen: metabolism
KW  - DNA Methylation
KW  - Male
KW  - Female
KW  - Adoptive cell therapy - ACT (Other)
KW  - Chimeric antigen receptor - CAR (Other)
KW  - Lymphoma (Other)
KW  - Receptors, Chimeric Antigen (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40210237
DO  - DOI:10.1136/jitc-2024-010709
UR  - https://inrepo02.dkfz.de/record/300323
ER  -