title: Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation.
abstract: The extensive exploitation of the antitumor effect of donor lymphocytes infused after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is limited by the risk of graft-versus-host disease (GvHD). To overcome this limitation, we investigated the therapeutic potential of donor lymphocytes engineered with the suicide gene thymidine kinase of herpes simplex virus (TK) in 23 patients experiencing recurrence of hematologic malignancies after allo-HSCT. Long-term follow-up of infused patients included analysis of engraftment of genetically engineered lymphocytes, in vivo assessment of antitumor effect, and control of GvHD by ganciclovir. All 17 patients evaluable for engraftment and graft-versus-leukemia (GvL) had circulating TK(+) cells detectable beginning at a median time of 18 days. Eleven patients (65%) experienced a substantial clinical benefit resulting in 6 (35%) complete remissions and 5 (29%) partial responses. The antitumor effect tightly correlated with the in vivo expansion of TK(+) cells. Seven patients received ganciclovir, resulting in elimination of TK(+) cells and effective and selective treatment of GvHD. Immunization against HSV-TK was observed in 7 patients but did not preclude an effective GvL. These data validate the feasibility, safety, and efficacy of TK(+) cells in the context of allografting and represent the basis for a broader application of this technology.
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.forename: Sarah
authors.initials: S
authors.lastname: Marktel
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Zappone
authors.forename: Paolo
authors.initials: P
authors.lastname: Servida
authors.forename: Massimo
authors.initials: M
authors.lastname: Bernardi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pescarollo
authors.forename: Attilio
authors.initials: A
authors.lastname: Bondanza
authors.forename: Jacopo
authors.initials: J
authors.lastname: Peccatori
authors.forename: Silvano
authors.initials: S
authors.lastname: Rossini
authors.forename: Zulma
authors.initials: Z
authors.lastname: Magnani
authors.forename: Monica
authors.initials: M
authors.lastname: Salomoni
authors.forename: Claudia
authors.initials: C
authors.lastname: Benati
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Luciano
authors.initials: L
authors.lastname: Callegaro
authors.forename: Paolo
authors.initials: P
authors.lastname: Corradini
authors.forename: Marco
authors.initials: M
authors.lastname: Bregni
authors.forename: Catia
authors.initials: C
authors.lastname: Traversari
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D006086:Graft vs Host Disease / Q000517:prevention & control; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008214:Lymphocytes / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D018139:Simplexvirus / Q000201:enzymology*; D033581:Stem Cell Transplantation / Q000379:methods*; D013937:Thymidine Kinase / Q000378:metabolism*; D014184:Transplantation, Homologous / Q000379:methods*
chemical_list: D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir