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Inducible Apoptosisas a Safety Switchfor Adoptive CellTherapy Antonio Di StasiSiok‐Keen TeyGianpietro Dotti2011 год

Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy
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Аннотация: Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct.We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch.Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence.The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.).
Год издания: 2011
Авторы: Antonio Di Stasi, Siok‐Keen Tey, Gianpietro Dotti, Yuriko Fujita, Alana A. Kennedy‐Nasser, Caridad Martinez, Karin Straathof, Enli Liu, April Durett, Bambi Grilley, Hao Liu, Conrad Russell Y. Cruz, Barbara Savoldo, Adrian P. Gee, John Schindler, Robert A. Krance, Helen E. Heslop, David M. Spencer, Cliona M. Rooney, Malcolm K. Brenner
Издательство: Massachusetts Medical Society
Источник: New England Journal of Medicine
Ключевые слова: CAR-T cell therapy research, Virus-based gene therapy research, CRISPR and Genetic Engineering
Другие ссылки: New England Journal of Medicine (PDF)
New England Journal of Medicine (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)