Inducible apoptosis as a safety switch for adoptive cell therapy.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.).

• Authors: Antonio Di Stasi, Siok-Keen Tey, Gianpietro Dotti, Yuriko Fujita, Alana Kennedy-Nasser, Caridad Martinez, Karin Straathof, Enli Liu, April G Durett, Bambi Grilley, Hao Liu, Conrad R Cruz, Barbara Savoldo, Adrian P Gee, John Schindler, Robert A Krance, Helen E Heslop, David M Spencer, Cliona M Rooney, Malcolm K Brenner
• Journal: The New England journal of medicine (N Engl J Med) Vol. 365 Issue 18 Pg. 1673-83 (Nov 03 2011) ISSN: 1533-4406 [Electronic] United States
• PMID: 22047558 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Organic Chemicals
• Caspase 9
• Tacrolimus Binding Proteins
• AP 1903 reagent

Topics

• Adolescent
• Apoptosis
• Caspase 9 (genetics, metabolism)
• Child
• Child, Preschool
• Female
• Gene Transfer Techniques
• Genes, Transgenic, Suicide
• Graft vs Host Disease (therapy)
• Humans
• Immunotherapy, Adoptive
• Leukemia (therapy)
• Male
• Organic Chemicals (therapeutic use)
• Recurrence
• Stem Cell Transplantation
• T-Lymphocytes (immunology, transplantation)
• Tacrolimus Binding Proteins (genetics)