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

Xiaoou Zhou, Gianpietro Dotti, Robert A. Krance, Caridad A. Martinez, Swati Naik, Rammurti T. Kamble, April G. Durett, Olga Dakhova, Barbara Savoldo, Antonio Di Stasi, David M. Spencer, Yu-Feng Lin, Hao Liu, Bambi J. Grilley, Adrian P. Gee, Cliona M. Rooney, Helen E. Heslop and Malcolm K. Brenner

Key points

  • Alloreplete iC9-T cells can promote immune recovery post-transplant and protect patients against viral infections.

  • iC9-T cells can be eliminated from both peripheral blood and CNS by administration of AP1903 leading to a rapid resolution of GvHD.

Abstract

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. This study is registered at www.clinicaltrials.gov as NCT01494103.

  • Submitted February 10, 2015.
  • Accepted April 4, 2015.