Immunologic potential of donor lymphocytes expressing a suicide gene for early immune reconstitution after hematopoietic T-cell-depleted stem cell transplantation.
We have previously shown that the infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase (HSV-tk) gene is an efficient tool for controlling graft-versus-host disease (GVHD) while preserving the graft-versus-leukemia (GVL) effect. In addition to the GVL effect, the administration of donor HSV-tk(+) cells could have a clinical impact in promoting immune reconstitution after T-cell-depleted stem cell transplantation (SCT). To explore this hypothesis, we have investigated whether in vitro polyclonal activation, retroviral transduction, immunoselection, and expansion affect the immune competence of donor T cells. We have observed that, after appropriate in vitro manipulation, T cells specific for antigens relevant in the context of SCT are preserved in terms of frequency, expression of T-cell receptor, proliferation, cytokine secretion, and lytic activity. A reduction in the frequency of allospecific T-cell precursors is observed after prolonged T-cell culture, suggesting that cell manipulation protocols involving a short culture time and high transduction efficiency are needed. Finally, the long-term persistence of HSV-tk(+) cells was observed in a patient treated in the GVL clinical trial, and a reversion of the phenotype of HSV-tk(+) cells from CD45RO(+) to CD45RA(+) was documented more than 2 years after the infusion. Based on all this evidence, we propose a clinical study of preemptive infusions of donor HSV-tk(+) T cells after SCT from haploidentical donors to provide early immune reconstitution against infection and potential immune protection against disease recurrence.
Marktel
Sarah
S
Cancer Immunotherapy and Gene Therapy Program and Bone Marrow Transplantation Unit, Istituto Scientifico H. S. Raffaele, Milan, Italy.
Magnani
Zulma
Z
Ciceri
Fabio
F
Cazzaniga
Sabrina
S
Riddell
Stanley R
SR
Traversari
Catia
C
Bordignon
Claudio
C
Bonini
Chiara
C
D000956:Antigens, Viral / Q000276:immunology; D001782:Blood Donors; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology; D006086:Graft vs Host Disease / Q000517:prevention & control; D020544:Graft vs Leukemia Effect; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000032:analysis; D008212:Lymphocyte Depletion; D016131:Lymphocyte Subsets; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000201:enzymology* / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics*; D014162:Transfection
D000956:Antigens, Viral; D007376:Interleukin-2; D007519:Isoantigens; D007371:Interferon-gamma; D013937:Thymidine Kinase; D017493:Leukocyte Common Antigens