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Blood, 1 March 2006, Vol. 107, No. 5, pp. 1828-1836.
Prepublished online as a Blood First Edition Paper on November 17, 2005; DOI 10.1182/blood-2005-09-3716.
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Submitted September 23, 2005
Accepted October 24, 2005
Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes
Attilio Bondanza, Veronica Valtolina, Zulma Magnani, Maurilio Ponzoni, Katharina Fleischhauer, Mark Bonyhadi, Catia Traversari, Francesca Sanvito, Salvatore Toma, Marina Radrizzani, Simona La Seta-Catamancio, Fabio Ciceri, Claudio Bordignon, and Chiara Bonini*
Cancer Immunotherapy and Gene Therapy Program, Experimental Hematology Laboratory, Milano, Italy; Universita Vita-Salute S. Raffaele, S.Raffaele Scientific Institute, Milano, Italy
Cancer Immunotherapy and Gene Therapy Program, Experimental Hematology Laboratory, Milano, Italy
Pathology Unit, S.Raffaele Scientific Institute, Milano, Italy
Telethon Institute for Gene Therapy, S.Raffaele Scientific Institute, Milano, Italy
Xcyte Therapies Inc., Seattle, WA, USA
Molmed SpA, Milano, Italy
* Corresponding author; email: bonini.chiara{at}hsr.it.
In allogeneic hematopoietic cell transplantation (allo-HCT), the immune recognition of host antigens by donor T lymphocytes leads to a beneficial graft-versus-leukemia (GvL) effect as well as to life-threatening graft-versus-host disease (GvHD). Genetic modification of T lymphocytes with a retroviral vector (RV) expressing the Herpes Simplex Virus-thymidine kinase (TK) suicide gene confers selective sensitivity to the pro-drug ganciclovir (GCV). In patients, the infusion of TK+ lymphocytes and the subsequent administration of GCV resulted in a time-wise modulation of anti-host reactivity for a GvL effect, while controlling GvHD. Since activation required for genetic modification with RV may reduce anti-host reactivity, we investigated the requirements for maximizing the potency of human TK+ lymphocytes. Whereas T-cell receptor triggering alone led to effector memory (EM) TK+ lymphocytes, the addition of CD28 co-stimulation through cell-sized beads resulted in the generation of central memory (CM) TK+ lymphocytes. In a quantitative model for GvHD using non-obese diabetic/severely combined immuno-deficient mice, CM TK+ lymphocytes were more potent than EM TK+ lymphocytes. GCV administration efficiently controlled GvHD induced by CM TK+ lymphocytes. These results warrant the clinical investigation of CM suicide gene-modified human T lymphocytes for safe and effective allo-HCT.
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