 Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cellsJoseph A. Fraietta,
Christopher L. Nobles,
Morgan A. Sammons,
Stefan Lundh,
Shannon A. Carty,
Tyler J. Reich,
Alexandria P. Cogdill,
Jennifer J. D. Morrissette,
Jamie E. DeNizio,
Shantan Reddy,
Young Hwang,
Mercy Gohil,
Irina Kulikovskaya,
Farzana Nazimuddin,
Minnal Gupta,
Fang Chen,
John K. Everett,
Katherine A. Alexander,
Enrique Lin-Shiao,
Marvin H. Gee,
Xiaojun Liu,
Regina M. Young,
David Ambrose,
Yan Wang,
Jun Xu,
Martha S. Jordan,
Katherine T. Marcucci,
Bruce L. Levine,
K. Christopher Garcia,
Yangbing Zhao,
Michael Kalos,
David L. Porter,
Rahul M. Kohli,
Simon F. Lacey,
Shelley L. Berger,
Frederic D. Bushman,
Carl H. June () and
J. Joseph Melenhorst ()
Nature, 2018, vol. 558, issue 7709, 307-312 Abstract: 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. Date: 2018 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:558:y:2018:i:7709:d:10.1038_s41586-018-0178-z Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-018-0178-z Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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