IL-7 receptor expression identifies suicide gene-modified allospecific CD8+ T cells capable of self-renewal and differentiation into antileukemia effectors

Attilio Bondanza, Lothar Hambach, Zohara Aghai, Bart Nijmeijer, Shin Kaneko, Sara Mastaglio, Marina Radrizzani, Katharina Fleischhauer, Fabio Ciceri, Claudio Bordignon, Chiara Bonini, Els Goulmy

Research output: Contribution to journalArticlepeer-review

Abstract

In allogeneic hematopoietic cell transplantation (HSCT), donor T lymphocytes mediate the graft-versus-leukemia (GVL) effect, but induce graft-versus-host disease (GVHD). Suicide gene therapy - that is, the genetic induction of a conditional suicide phenotype into donor T cells - allows dissociating the GVL effect from GVHD. Genetic modification with retroviral vectors after CD3 activation reduces T-cell alloreactivity. We recently found that alloreactivity is maintained when CD28 costimulation, IL-7, and IL-15 are added. Herein, we used the minor histocompatibility (mH) antigens HA-1 and H-Y as model alloantigens to directly explore the antileukemia efficacy of human T cells modified with the prototypic suicide gene herpes simplex virus thymidine kinase (tk) after activation with different stimuli. Only in the case of CD28 costimulation, IL-7, and IL-15, the repertoire of tk+ T cells contained HA-1- and H-Y-specific CD8+ cytotoxic T cells (CTL) precursors. Thymidine kinase-positive HA-1- and H-Y- specific CTLs were capable of self-renewal and differentiation into potent antileukemia effectors in vitro, and in vivo in a humanized mouse model. Self-renewal and differentiation coincided with IL-7 receptor expression. These results pave the way to the clinical investigation of T cells modified with a suicide gene after CD28 costimulation, IL-7, and IL-15 for a safe and effective GVL effect.

Original languageEnglish
Pages (from-to)6469-6478
Number of pages10
JournalBlood
Volume117
Issue number24
DOIs
Publication statusPublished - Jun 16 2011

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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