Fraietta, Joseph A, Nobles, Christopher L, Sammons, Morgan A, Lundh, Stefan, Carty, Shannon A, Reich, Tyler J, Cogdill, Alexandria P, Morrissette, Jennifer JD, DeNizio, Jamie E, Reddy, Shantan, Hwang, Young, Gohil, Mercy, Kulikovskaya, Irina, Nazimuddin, Farzana, Gupta, Minnal, Chen, Fang, Everett, John K, Alexander, Katherine A, Lin-Shiao, Enrique, Gee, Marvin H, Liu, Xiaojun, Young, Regina M, Ambrose, David, Wang, Yan, Xu, Jun, Jordan, Martha S, Marcucci, Katherine T, Levine, Bruce L, Garcia, K Christopher, Zhao, Yangbing, Kalos, Michael, Porter, David L, Kohli, Rahul M, Lacey, Simon F, Berger, Shelley L, Bushman, Frederic D, June, Carl H, Melenhorst, J Joseph (June 2018) Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature, 558 (7709). pp. 307-312. ISSN 0028-0836
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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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > drugs and therapies > Immunotherapy diseases & disorders > cancer > cancer types > leukemia diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Alexander lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | June 2018 |
| Date Deposited: | 16 Jul 2024 17:27 |
| Last Modified: | 16 Jul 2024 17:27 |
| PMCID: | PMC6320248 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41617 |
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