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

• Published in: Nature (London) Vol. 558; no. 7709; pp. 307 - 312
• Main Authors: Fraietta, Joseph A, Nobles, Christopher L, Sammons, Morgan A, Lundh, Stefan, Carty, Shannon A, Reich, Tyler J, Cogdill, Alexandria P, Morrissette, Jennifer J D, 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.06.2018
• Subjects: 5-Methylcytosine - metabolism; Adoptive Transfer; Aged; Alleles; Anticancer properties; Antigens; Antigens, CD19 - immunology; Automobiles; Bioinformatics; Bone marrow; Cancer; Cancer immunotherapy; Cancer research; Cancer treatment; CD19 antigen; Cell Differentiation; Chronic lymphocytic leukemia; Clinical Trials as Topic; Clone Cells - cytology; Clone Cells - immunology; Cloning; Deoxyribonucleic acid; Differentiation (biology); Dioxygenase; Dioxygenases - genetics; Dioxygenases - metabolism; DNA; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Genes; Genetic engineering; Genetic research; Genomes; Genomics; HEK293 Cells; Humans; Immunotherapy; Immunotherapy - methods; Insertion; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemia, Lymphocytic, Chronic, B-Cell - therapy; Lymph nodes; Lymphocytes; Lymphocytes B; Lymphocytes T; Male; Medical research; Medical schools; Mutation; Oxidation; Patients; Peripheral blood; Phenotypes; Progeny; Proteins; Receptors; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Remission; Stem cells; T cell receptors; T cells; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - transplantation; Transgenes; Transposons; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0178-z

Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies . 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 . 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.