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Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

Researchers in the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston Methodist and Texas Children's Hospital have found that a single dose of an otherwise harmless drug can safely control the severe and often lethal side effects associated with haploidentical stem cell transplantation. Due to the immune-compromising nature of haploidentical stem cell transplantation, where the stem cells are only half matched, patients are at an increased risk of viral infection and of a lethal complication called graft versus host disease, when the graft cells, which have immune potential, attack the tissues of the person whose original immune system has been eliminated as part of treatment. Investigators have now shown how a molecular "switch" (inducible caspase 9 or iC9) that is activated by a single dose of a bio-inert chemical is able to clear all symptoms of graft versus host disease without jeopardizing the ability of the infused graft to fight infection.

To test the feasibility of a single T-cell manipulation to eliminate alloreactivity while sparing antiviral and antitumor T cells, we infused 12 haploidentical hematopoietic stem cell transplant (haplo-HSCT) patients with increasing numbers of alloreplete haploidentical T cells expressing the inducible caspase 9 suicide gene (iC9-T cells). We determined whether the iC9-T cells produced immune reconstitution and if any resultant GvHD could be controlled by administration of a chemical inducer of dimerization (CID) (AP1903/Rimiducid). All patients receiving >104 alloreplete iC9 T-lymphocytes/kg achieved rapid reconstitution of immune responses toward five major pathogenic viruses, and concomitant control of active infections. Four patients received a single AP1903 dose. CID infusion eliminated 85-95% of circulating CD3+CD19+ T cells within 30 minutes, with no recurrence of GvHD within 90 days. In one patient, symptoms and signs of GvHD-associated cytokine release syndrome (CRS-hyperpyrexia, high levels of pro-inflammatory cytokines and rash) resolved within 2 hours of AP1903 infusion. One patient with VZV meningitis and acute GvHD had iC9-T cells present in the CSF, which were reduced by >90% after CID. Notably, virus-specific T cells recovered even after AP1903 administration and continued to protect against infection. Hence, alloreplete iC9-T cells can reconstitute immunity post-transplant and administration of CID can eliminate them from both peripheral blood and CNS, leading to rapid resolution of GvHD and CRS. The approach may therefore be useful for the rapid and effective treatment of toxicities associated with infusion of engineered T lymphocytes.


Zhou and colleagues showed for the first time that the iC9-T cells can eliminate the uncontrolled cells in not only the peripheral blood but also in the central nervous system.


"This is an important advance for patients who develop a life threatening complication called graft versus host disease," said Zhou. "This could lead to rapid resolution for those patients without compromising their T cell therapy."

The chemical drug and the inducible caspase 9 suicide gene "switch" it activates are currently being developed by Bellicum Pharmaceuticals.

Journal Reference:

Xiaoou Zhou, et al. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation. Blood, May 2015 DOI: 10.1182/blood-2015-02-628354