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Culture expansion of CAR T cells evokes aberrant DNA methylation that is associated with adverse clinical outcome (Methylation)

ABSTRACT: Culture expansion of CAR T cells evokes aberrant DNA methylation that is associated with adverse clinical outcome (Methylation)

PROVIDER: PRJNA908881 | ENA |

REPOSITORIES: ENA

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Culture expansion of CAR T cells evokes aberrant DNA methylation that is associated with adverse clinical outcome

Project description:Culture expansion of CAR T cells evokes aberrant DNA methylation that is associated with adverse clinical outcome

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Culture expansion of CAR T cells evokes aberrant DNA methylation that is associated with adverse clinical outcome (RNA-Seq)

Project description:Culture expansion of CAR T cells evokes aberrant DNA methylation that is associated with adverse clinical outcome (RNA-Seq)

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Culture expansion of CAR T cells evokes aberrant DNA methylation that is associated with adverse clinical outcome (Methylation)

Project description:Cellular immunotherapy using autologous, genetically modified T cells has delivered remarkable initial response rates in various hematological malignancies, including acute lymphoblastic leukemia (ALL) or lymphoma. Upon treatment with these chimeric antigen receptor (CAR) T cells, approximately 30–40% of patients show long-term remission. There is a growing perception that not only CAR constructs, but also in vitro manufacturing processes may determine therapeutic efficacy. However, little is known about how duration of culture expansion affects molecular and functional features of CAR T cells. A better understanding of molecular signatures, reflecting therapeutic activity of CAR T cells, may help to further optimize the manufacturing process. In this study, we therefore investigated DNAm changes during culture expansion of T cells and CAR T cells during a period of up to three weeks. The results of our current study indicate that culture expansion of CAR T cells leads to DNAm changes that are continuously acquired during culture expansion. Further analysis of culture-associated methylation profiles in CAR T cells from clinical trials support the notion that these chnages are disadvantageous with regards to therapeutic outcome. A shortened cultivation period to avoid dysfunctional methylation programs might be a promising manufacturing strategy to improve therapeutic efficacy of adoptive cell therapies. Our epigenetic signature for culture-associated DNAm may provide a biomarker for quality control of CAR T cell productions and to identify patients at risk for adverse events.

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Culture expansion of CAR T cells evokes aberrant DNA methylation that is associated with adverse clinical outcome (RNA-Seq)

Project description:Cellular immunotherapy using autologous, genetically modified T cells has delivered remarkable initial response rates in various hematological malignancies, including acute lymphoblastic leukemia (ALL) or lymphoma. Upon treatment with these chimeric antigen receptor (CAR) T cells, approximately 30–40% of patients show long-term remission. There is a growing perception that not only CAR constructs, but also in vitro manufacturing processes may determine therapeutic efficacy. However, little is known about how duration of culture expansion affects molecular and functional features of CAR T cells. A better understanding of molecular signatures, reflecting therapeutic activity of CAR T cells, may help to further optimize the manufacturing process. In this study, we therefore investigated DNAm changes during culture expansion of T cells and CAR T cells during a period of up to three weeks. The results of our current study indicate that culture expansion of CAR T cells leads to DNAm changes that are continuously acquired during culture expansion, which is also reflected on gene expression level. Further analysis of culture-associated methylation profiles in CAR T cells from clinical trials support the notion that these chnages are disadvantageous with regards to therapeutic outcome. A shortened cultivation period to avoid dysfunctional methylation programs might be a promising manufacturing strategy to improve therapeutic efficacy of adoptive cell therapies. Our epigenetic signature for culture-associated DNAm may provide a biomarker for quality control of CAR T cell productions and to identify patients at risk for adverse events.

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Culture expansion of CAR T cells evokes aberrant DNA methylation that is associated with adverse clinical outcome

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Culture expansion of CAR T cells results in aberrant DNA methylation that is associated with adverse clinical outcome.

Project description:Chimeric antigen receptor (CAR) T cells provide new perspectives for treatment of hematological malignancies. Manufacturing of these cellular products includes culture expansion procedures, which may affect cellular integrity and therapeutic outcome. In this study, we investigated culture-associated epigenetic changes in CAR T cells and found continuous gain of DNAm, particularly within genes that are relevant for T cell function. Hypermethylation in many genes, such as TCF7, RUNX1, and TOX, was reflected by transcriptional downregulation. 332 CG dinucleotides (CpGs) showed an almost linear gain in methylation with cell culture time, albeit neighboring CpGs were not coherently regulated on the same DNA strands. An epigenetic signature based on 14 of these culture-associated CpGs predicted cell culture time across various culture conditions. Notably, even in CAR T cell products of similar culture time higher DNAm levels at these CpGs were associated with significantly reduced long-term survival post transfusion. Our data demonstrate that cell culture expansion of CAR T cells evokes DNA hypermethylation at specific sites in the genome and the signature may also reflect loss of potential in CAR T cell products. Hence, reduced cultivation periods are beneficial to avoid dysfunctional methylation programs that seem to be associated with worse therapeutic outcome.

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