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Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells

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Science Translational Medicine  25 Jan 2017:
Vol. 9, Issue 374, eaaj2013
DOI: 10.1126/scitranslmed.aaj2013

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Chimeric antigen receptor (CAR) T cells can be very effective in treating acute lymphocytic leukemia. Unfortunately, these therapeutic cells have to be custom-made for each patient, and this is not always feasible, especially for patients who do not have sufficient healthy T cells. Qasim et al. demonstrate that there may be another option for these patients. By using gene editing to simultaneously introduce the CAR and disrupt TCR and CD52 in T cells, the authors generated functional CAR T cells that could evade host immunity for use in unmatched recipients. These “off-the-shelf” CAR T cells were then used to treat two infants with relapsed refractory acute lymphocytic leukemia and bridge them to allogeneic stem cell transplantation.

Abstract

Autologous T cells engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) are achieving marked leukemic remissions in early-phase trials but can be difficult to manufacture, especially in infants or heavily treated patients. We generated universal CAR19 (UCART19) T cells by lentiviral transduction of non–human leukocyte antigen–matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)–mediated gene editing of T cell receptor α chain and CD52 gene loci. Two infants with relapsed refractory CD19+ B cell acute lymphoblastic leukemia received lymphodepleting chemotherapy and anti-CD52 serotherapy, followed by a single-dose infusion of UCART19 cells. Molecular remissions were achieved within 28 days in both infants, and UCART19 cells persisted until conditioning ahead of successful allogeneic stem cell transplantation. This bridge-to-transplantation strategy demonstrates the therapeutic potential of gene-editing technology.

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