Editors' ChoiceStem Cell Transplantation

Suicide Genes Breathe New Life into Cell Therapies

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Science Translational Medicine  16 Nov 2011:
Vol. 3, Issue 109, pp. 109ec184
DOI: 10.1126/scitranslmed.3003414

Imagine designing cells that could kill a tumor, remyelinate damaged nerves, or stop an autoimmune response. Such cellular therapies have great promise; however, the potential of engineered cells or stem cells to expand excessively, damage normal tissues, or undergo malignant transformation has limited their clinical application. Now, Di Stasi et al. demonstrate the effective implementation of a “suicide gene” that can kill harmful alloreactive donor T cells in patients undergoing stem cell transplantation for relapsed acute leukemia.

Haploidentical stem cell transplantation (SCT) is used when fully human lymphocyte antigen (HLA)–matched donors for bone marrow transplantation are not available. T cells are a double-edged sword in this setting, providing beneficial antitumor (graft-versus-leukemia) and antiviral immunity but also promoting graft-versus-host disease (GvHD), which is caused by partial HLA mismatch. Di Stasi and colleagues introduced a safety switch in the donor T cells—an inducible caspase 9 expression system—that rapidly kills the cells after administration of the activating drug. Specifically, the bioinert small-molecule AP1903 activates caspase 9 in the engineered donor cells but not host cells, resulting in specific apoptosis of the transplanted cells.

Five patients undergoing haploidentical SCT received infusions of allodepleted T cells engineered with this suicide construct. Mild GvHD developed in four of the patients but was resolved after administration of a single dose of AP1903, which ablated more than 90% of the transplanted cells within 30 minutes. Despite a small re-expansion of donor T cells over a 1-year follow-up, these cells remained responsive to AP1903-induced killing in vitro. Notably, treatment with AP1903 did not affect the polyclonality of the surviving T cells, and antiviral T cell responses were preserved. Most importantly, the four patients treated with the drug exhibited no further GvHD over >12 months despite successful engraftment and complete leukemic remission.

The work of Di Stasi et al. represents a milestone in directed cell therapy, with potential applications in a wide array of diseases and disciplines. Further follow-up and studies in other cell types will be needed to assess the long-term safety and efficacy of their suicide gene system. With improved safety mechanisms, cellular therapies may soon be a reality in clinical medicine.

A. Di Stasi et al., Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011). [Abstract]

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