Research ArticleTransplantation

In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells

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Science Translational Medicine  04 Feb 2015:
Vol. 7, Issue 273, pp. 273ra13
DOI: 10.1126/scitranslmed.3010314

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Sealing T cell fate

Clinical trials are a relatively untapped source of experimental data that can be leveraged to explore both basic and pathological biology in humans. Now, Biasco et al. take advantage of two different gene therapy trials for inherited immunodeficiency to track in the long term T cell fate in humans. They find that the recently described T memory stem cells (TSCM) are able to persist and preserve their precursor potential in human recipients for up to 12 years after genetic correction and infusion into patients. The safety and long-term survival of these cells not only strengthen our knowledge of human immunology but also support the use of TSCM cells for adoptive immunotherapy.


A definitive understanding of survival and differentiation potential in humans of T cell subpopulations is of paramount importance for the development of effective T cell therapies. In particular, uncovering the dynamics in vivo in humans of the recently described T memory stem cells (TSCM) would be crucial for therapeutic approaches that aim at taking advantage of a stable cellular vehicle with precursor potential. We exploited data derived from two gene therapy clinical trials for an inherited immunodeficiency, using either retrovirally engineered hematopoietic stem cells or mature lymphocytes to trace individual T cell clones directly in vivo in humans. We compared healthy donors and bone marrow–transplanted patients, studied long-term in vivo T cell composition under different clinical conditions, and specifically examined TSCM contribution according to age, conditioning regimen, disease background, cell source, long-term reconstitution, and ex vivo gene correction processing. High-throughput sequencing of retroviral vector integration sites (ISs) allowed tracing the fate of more than 1700 individual T cell clones in gene therapy patients after infusion of gene-corrected hematopoietic stem cells or mature lymphocytes. We shed light on long-term in vivo clonal relationships among different T cell subtypes, and we unveiled that TSCM are able to persist and to preserve their precursor potential in humans for up to 12 years after infusion of gene-corrected lymphocytes. Overall, this work provides high-resolution tracking of T cell fate and activity and validates, in humans, the safe and functional decade-long survival of engineered TSCM, paving the way for their future application in clinical settings.

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