title: IL-7 and IL-15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T lymphocytes.
abstract: Long-term clinical remissions of leukemia, after allogeneic hematopoietic stem cell transplantation, depend on alloreactive memory T cells able to self-renew and differentiate into antileukemia effectors. This is counterbalanced by detrimental graft-versus-host disease (GVHD). Induction of a selective suicide in donor T cells is a current gene therapy approach to abrogate GVHD. Unfortunately, genetic modification reduces alloreactivity of lymphocytes. This associates with an effector memory (T(EM)) phenotype of gene-modified lymphocytes and may limit antileukemia effect. We hypothesized that alloreactivity of gene-modified lymphocytes segregates with the central memory (T(CM)) phenotype. To this, we generated suicide gene-modified T(CM) lymphocytes with a retroviral vector after CD28 costimulation and culture with IL-2, IL-7, or a combination of IL-7 and IL-15. In vitro, suicide gene-modified T(CM) cells self-renewed upon alloantigen stimulation and resisted activation-induced cell death. In a humanized mouse model, only suicide gene-modified T cells cultured with IL-7 and IL-15 persisted, differentiated in T(EM) cells, and were as potent as unmanipulated lymphocytes in causing GVHD. GVHD was halted through the activation of the suicide gene machinery. These results warrant the use of suicide gene-modified T(CM) cells cultured with IL-7 and IL-15 for the safe exploitation of the alloreactive response against cancer.
authors.affiliation: Experimental Hematology Unit, Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Shin
authors.initials: S
authors.lastname: Kaneko
authors.forename: Sara
authors.initials: S
authors.lastname: Mastaglio
authors.forename: Attilio
authors.initials: A
authors.lastname: Bondanza
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Luca
authors.initials: L
authors.lastname: Aldrighetti
authors.forename: Marina
authors.initials: M
authors.lastname: Radrizzani
authors.forename: Simona
authors.initials: S
authors.lastname: La Seta-Catamancio
authors.forename: Elena
authors.initials: E
authors.lastname: Provasi
authors.forename: Anna
authors.initials: A
authors.lastname: Mondino
authors.forename: Toshiro
authors.initials: T
authors.lastname: Nagasawa
authors.forename: Katharina
authors.initials: K
authors.lastname: Fleischhauer
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Russo
authors.forename: Catia
authors.initials: C
authors.lastname: Traversari
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
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D041722:Genes, Transgenic, Suicide / Q000235:genetics / Q000276:immunology*; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology*; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology / Q000494:pharmacology*; D007519:Isoantigens / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C508594:IL2 protein, human; C508605:IL7 protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D007519:Isoantigens