Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation.
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.
Ciceri
Fabio
F
Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
Bonini
Chiara
C
Marktel
Sarah
S
Zappone
Elisabetta
E
Servida
Paolo
P
Bernardi
Massimo
M
Pescarollo
Alessandra
A
Bondanza
Attilio
A
Peccatori
Jacopo
J
Rossini
Silvano
S
Magnani
Zulma
Z
Salomoni
Monica
M
Benati
Claudia
C
Ponzoni
Maurilio
M
Callegaro
Luciano
L
Corradini
Paolo
P
Bregni
Marco
M
Traversari
Catia
C
Bordignon
Claudio
C
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*
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir