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

Academic Article

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.
  • Published In

  • Blood  Journal
  • Digital Object Identifier (doi)

    Author List

  • Zhou X; Dotti G; Krance RA; Martinez CA; Naik S; Kamble RT; Durett AG; Dakhova O; Savoldo B; Stasi AD
  • Start Page

  • 4103
  • End Page

  • 4113
  • Volume

  • 125
  • Issue

  • 26