Dataset Information

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

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 potency-enhancing effect of TET2 dysfunction in this patient's CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies.

SUBMITTER: Fraietta JA

PROVIDER: S-EPMC6320248 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Fraietta Joseph A JA Nobles Christopher L CL Sammons Morgan A MA Lundh Stefan S Carty Shannon A SA Reich Tyler J TJ Cogdill Alexandria P AP Morrissette Jennifer J D JJD DeNizio Jamie E JE Reddy Shantan S Hwang Young Y Gohil Mercy M Kulikovskaya Irina I Nazimuddin Farzana F Gupta Minnal M Chen Fang F Everett John K JK Alexander Katherine A KA Lin-Shiao Enrique E Gee Marvin H MH Liu Xiaojun X Young Regina M RM Ambrose David D Wang Yan Y Xu Jun J Jordan Martha S MS Marcucci Katherine T KT Levine Bruce L BL Garcia K Christopher KC Zhao Yangbing Y Kalos Michael M Porter David L DL Kohli Rahul M RM Lacey Simon F SF Berger Shelley L SL Bushman Frederic D FD June Carl H CH Melenhorst J Joseph JJ

Nature 20180530 7709

Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies<sup>1-3</sup>. 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 cells<sup>4,5</sup>. Here we report mechanistic insights from studies of a patient with chronic lymphoc ...[more]

PMID: 29849141

Similar Datasets

Project description:Epstein-Barr virus (EBV) latently infects normal B cells and contributes to the development of certain human lymphomas. Newly infected B cells support a highly transforming form (type III) of viral latency; however, long-term EBV infection in immunocompetent hosts is limited to B cells with a more restricted form of latency (type I) in which most viral gene expression is silenced by promoter DNA methylation. How EBV converts latency type is unclear, although it is known that type I latency is associated with a germinal center (GC) B cell phenotype, and type III latency with an activated B cell (ABC) phenotype. In this study, we have examined whether expression of TET2, a cellular enzyme that initiates DNA demethylation by converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates EBV latency type in B cells. We found that TET2 expression is inhibited in normal GC cells and GC type lymphomas. In contrast, TET2 is expressed in normal naive B cells and ABC type lymphomas. We also demonstrate that GC type cell lines have increased 5mC levels and reduced 5hmC levels in comparison to those of ABC type lines. Finally, we show that TET2 promotes the ability of the EBV transcription factor EBNA2 to convert EBV-infected cells from type I to type III latency. These findings demonstrate that TET2 expression is repressed in GC cells independent of EBV infection and suggest that TET2 promotes type III EBV latency in B cells with an ABC or naive phenotype by enhancing EBNA2 activation of methylated EBV promoters.IMPORTANCE EBV establishes several different types of viral latency in B cells. However, cellular factors that determine whether EBV enters the highly transforming type III latency, versus the more restricted type I latency, have not been well characterized. Here we show that TET2, a cellular enzyme that initiates DNA demethylation by converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates EBV latency type in B cells by enhancing the ability of the viral transcription factor EBNA2 to activate methylated viral promoters that are expressed in type III (but not type I) latency. Furthermore, we demonstrate that (independent of EBV) TET2 is turned off in normal and malignant germinal center (GC) B cells but expressed in other B cell types. Thus, restricted TET2 expression in GC cells may promote type I EBV latency.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure