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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2003-01-0297.
Submitted January 31, 2003
Accepted March 13, 2003
Human T lymphocytes transduced by lentiviral vectors in the absence of TCR-activation maintain an intact immune competence
Simona Cavalieri, Sabrina Cazzaniga, Massimo Geuna, Zulma Magnani, Claudio Bordignon, Luigi Naldini, and Chiara Bonini*
Institute for Cancer Research and Treatment, University of Torino Medical School, Turin, Italy
Cancer Immunotherapy and Gene Therapy Program, H.S. Raffaele, Milan, Italy
* Corresponding author; email: chiara.bonini{at}hsr.it.
Gene transfer into T lymphocytes is currently tested for the treatment of lympho-hematologic disorders. We previously showed that suicide gene transfer into donor lymphocytes infused to treat leukemic relapse after allogeneic hematopoietic stem cell transplantation allowed control of graft-versus-host disease. However, the T-cell receptor activation and sustained proliferation required for retroviral vector transduction may impair the half-life and immune competence of transduced cells and reduce graft-versus-leukemia activity. Thus, we tested lentiviral vectors (LV) and stimulation with cytokines involved in antigen-independent T-cell homeostasis, such as IL-7, IL-2 and IL-15. Late-generation LV transduced efficiently non-proliferating T cells which had progressed from G0 to the G1 phase of the cell cycle upon cytokine treatment. Importantly, IL-2 and IL-7, but not IL-15 stimulation preserved physiologic CD4/CD8 and naive/memory ratios in transduced cells with only minor induction of some activation markers. Functional analysis of immune response to cytomegalovirus (CMV) showed that, although CMV-specific T cells were preserved by all conditions of transduction, proliferation and specific killing of autologous cells presenting a CMV epitope were higher for IL-2 and IL-7 than IL-15. Thus, LV transduction of IL-2 or IL-7 pre-stimulated cells overcome the limitations of retroviral vectors and may significantly improve the efficacy of T cell-based gene therapy.
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