Disruption of TET2 Promotes the Therapeutic Efficacy of CD19-targeted T-cells

By J. Fraietta, C. Nobles, Morgan A. Sammons, Stefan Lundh, Shannon A. Carty, Tyler J. Reich, Alexandria P. Cogdill, J. Morrissette, J. Denizio, Shantan Reddy and 28 more. Nature, 2018

771 citations recorded by the source corpus.

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. Genetically engineered T cells that induced remission in a patient with chronic lymphocytic leukaemia were found to have disruption of the TET2 gene, which caused T cell changes that potentiated their anti-tumour effects.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/57ea95b62f55d17a748c3a1418b0e45faef50178

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In Immunology

1. Christopher S. Hackett
2. S. Rafiq
3. R. Brentjens

In Oncology

1. Christopher S. Hackett
2. S. Rafiq
3. R. Brentjens

Citations in the corpus

• Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, methodology): “Specifically, the CAR gene was inserted into the TET2 loci and led to a clonal expansion of T cells 248 ; this clonal T cell population eventually contracted spontaneously, but this event highlights the risk of treating patients with genetically modified cells.”
• Clonal hematopoiesis in human aging and disease (2019, neutral): “There is also a report of an exceptional response in a patient with CLL treated by infusion of chimeric antigen receptor (CAR)– T cells in which the CAR construct disrupted one copy of TET2, while the other copy had been previously mutated somatically (97).”