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, Malcolm K. Brenner

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

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 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 graft-versus-host disease (GVHD) could be controlled by administration of a chemical inducer of dimerization (CID; AP1903/ Rimiducid).Allpatients receiving ≥104 alloreplete iC9-T lymphocytes per kilogramachieved rapid reconstitution of immune responses toward 5 major pathogenic viruses and concomitant control of active infections. Four patients received a single AP1903 dose. CID infusion eliminated 85% to 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 GVHDassociated cytokine release syndrome (CRS-hyperpyrexia, high levels of proinflammatory cytokines, and rash) resolved within 2 hours of AP1903 infusion. One patient with varicella zoster virus meningitis and acute GVHD had iC9-T cells present in the cerebrospinal fluid,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 posttransplant andadministration of CID can eliminate them from both peripheralblood and the central nervous system (CNS), leading to rapid resolution of GVHD and CRS. The approachmay therefore be useful for the rapid and effective treatment of toxicities associated with infusion of engineered T lymphocytes.

Original languageEnglish (US)
Pages (from-to)4103-4113
Number of pages11
JournalBlood
Volume125
Issue number26
DOIs
StatePublished - Jun 25 2015

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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