1. IL-7 receptor expression identifies suicide gene–modified allospecific CD8+ T cells capable of self-renewal and differentiation into antileukemia effectors
- Author
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Fabio Ciceri, Bart A. Nijmeijer, Zohara Aghai, Claudio Bordignon, Lothar Hambach, Marina Radrizzani, Attilio Bondanza, Katharina Fleischhauer, Shin Kaneko, Sara Mastaglio, Els Goulmy, Chiara Bonini, Bondanza, Attilio, Hambach, L, Aghai, Z, Nijmeijer, B, Kaneko, S, Mastaglio, S, Radrizzani, M, Fleischhauer, K, Ciceri, Fabio, Bordignon, Claudio, Bonini, MARIA CHIARA, and Goulmy, E.
- Subjects
Receptor expression ,CD3 ,Genetic Vectors ,Immunology ,Gene Expression ,T-Cell Antigen Receptor Specificity ,Mice, SCID ,CD8-Positive T-Lymphocytes ,Biology ,Immunotherapy, Adoptive ,Biochemistry ,Mice ,Antigen ,Mice, Inbred NOD ,Animals ,Humans ,Transplantation, Homologous ,Cytotoxic T cell ,Interleukin-7 receptor ,Cells, Cultured ,Cell Proliferation ,Leukemia ,Receptors, Interleukin-7 ,Genes, Transgenic, Suicide ,CD28 ,Cell Differentiation ,Genetic Therapy ,Cell Biology ,Hematology ,Suicide gene ,Prognosis ,surgical procedures, operative ,Cancer research ,biology.protein ,Female ,Biomarkers ,CD8 ,T-Lymphocytes, Cytotoxic - 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.
- Published
- 2011