title: IL-7 receptor expression identifies suicide gene-modified allospecific CD8+ T cells capable of self-renewal and differentiation into antileukemia effectors.
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.
authors.affiliation: Department of Immunohematology and Blood Bank, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Attilio
authors.initials: A
authors.lastname: Bondanza
authors.forename: Lothar
authors.initials: L
authors.lastname: Hambach
authors.forename: Zohara
authors.initials: Z
authors.lastname: Aghai
authors.forename: Bart
authors.initials: B
authors.lastname: Nijmeijer
authors.forename: Shin
authors.initials: S
authors.lastname: Kaneko
authors.forename: Sara
authors.initials: S
authors.lastname: Mastaglio
authors.forename: Marina
authors.initials: M
authors.lastname: Radrizzani
authors.forename: Katharina
authors.initials: K
authors.lastname: Fleischhauer
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.forename: Els
authors.initials: E
authors.lastname: Goulmy
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000502:physiology; D041722:Genes, Transgenic, Suicide / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007938:Leukemia / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011379:Prognosis; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D014184:Transplantation, Homologous
chemical_list: D015415:Biomarkers; D020395:Receptors, Interleukin-7