Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy

By A. Di Stasi, Siok-Keen Tey, G. Dotti, Y. Fujita, A. Kennedy-Nasser, C. Martinez, K. Straathof, E. Liu, A. Durett, B. Grilley and 10 more. New England Journal of Medicine, 2011

1,438 citations recorded by the source corpus.

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.)

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/2ea300c2f79bad2c16d49f3d9c7f9ad1673c6f0d

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Citations in the corpus

Emerging trends and new developments in regenerative medicine: a scientometric update (2000 – 2014) (2014, background): “2011 Inducible apoptosis as a safety switch for adoptive cell therapy NEW ENGL J MED [58]”
Remote control of therapeutic T cells through a small molecule-gated chimeric receptor (2015, background): “A small-molecule drug–inducible “suicide” switch that induces apoptosis in engineered T cells can be used to abort cellular therapeutics (18, 24).”
Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. (2016, methodology): “Suicide gene “safety switch” systems already in use in clinical trials, such as iCaspase-9 (57), EGFR mutation (58), and herpes simplex virus thymidine kinase (59), which mediate T cell elimination after administration of a prodrug or antibody, can be used in PD-1 DNR CAR T cells.”
Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent anti-tumor activity (2017, positive): “To counteract excessive toxicity mediated by the release of inflammatory cytokines by transduced CB-NK cells, we incorporated a suicide gene (iC9) into our construct.(21) The addition of as little as 10 nM of the small molecule dimerizer AP1903 to cultures of iC9/ CAR.”
Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses (2018, positive): “For instance, drug-inducible ON and kill switches have been developed to regulate CAR activity (Di Stasi et al., 2011; Wu et al., 2015).”
Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. (2013, background): “Another approach that may be useful would be the incorporation of a conditional suicide gene.(31) This approach effectively ablated alloreactive T cells in a clinical trial after human hematopoietic cell transplantation and may prove useful to abrogate on-target or offtarget toxicities of TCR-engine”
Global Manufacturing of CAR T Cell Therapy (2016, methodology): “For example, the iCasp9 safety switch has been effectively used to reduce graft-versus-host disease (GVHD) in patients receiving allogeneic stem cell transplant.(57) However, depletion of CAR T cells also may abrogate the potential benefit of long-term CAR T cell-mediated tumor surveillance.”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “One suicide switch, called iCasp9, has been clinically validated in limiting graft versus host disease in patients undergoing hematopoietic stem cell transplants (Di Stasi et al., 2011). iCasp9 has a split form of the apoptotic protein Caspase, which must be homodimerized to become active.”