Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells

Nature
Joseph A FraiettaJ Joseph Melenhorst

Abstract

Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies1-3. In this strategy, the T cell genome is modified by integration of viral vectors or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells4,5. Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient's second TET2 allele. TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the pot...Continue Reading

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Datasets Mentioned

BETA
SRP136348
GSE112494

Methods Mentioned

BETA
PCR
dot blotting
leukapheresis
flow cytometry
electrophoresis
Assay

Clinical Trials Mentioned

NCT01029366

Software Mentioned

Bioconductor
Genome browser
BLAT
Metascape
Morpheus
Bioconductor Oligo
MACS
SAS
FlowJo
Bowtie

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