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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4698-4707.
Prepublished online as a Blood First Edition Paper on February 27, 2007; DOI 10.1182/blood-2006-05-023416.
 Previous Article | Next Article 
Submitted May 17, 2006
Accepted February 8, 2007
Anti-tumor effects of HSV-TK engineered donor lymphocytes after allogeneic stem cell transplantation
Fabio Ciceri, Chiara Bonini, Sarah Marktel, Elisabetta Zappone, Paolo Servida, Massimo Bernardi, Alessandra Pescarollo, Attilio Bondanza, Jacopo Peccatori, Silvano Rossini, Zulma Magnani, Monica Salomoni, Claudia Benati, Maurilio Ponzoni, Luciano Callegaro, Paolo Corradini, Marco Bregni, Catia Traversari, and Claudio Bordignon*
Hematology & Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy
Cancer Immunotherapy & Gene Therapy Program, San Raffaele Scientific Institute, Milan, Italy
Universita Vita-Salute San Raffaele, Milan, Italy
MolMed SpA, Milan, Italy
Dept of Pathology, San Raffaele Scientific Institute, Milan, Italy
* Corresponding author; email: c.bordignon{at}hsr.it.
The extensive exploitation of the anti-tumor effect of donor lymphocytes infused after allogeneic hematopoietic 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 anti-tumor 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 complete remissions (35%) and 5 (29%) partial responses. The anti-tumor effect tightly correlated with the in vivo expansion of TK+ cells. Seven patients received ganciclovir that resulted 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.
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