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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.
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GENE THERAPY
Antitumor effects of HSV-TK–engineered donor lymphocytes after allogeneic stem-cell transplantation
Fabio Ciceri1,3,
Chiara Bonini1,3,
Sarah Marktel1,2,
Elisabetta Zappone1,
Paolo Servida1,
Massimo Bernardi1,
Alessandra Pescarollo1,
Attilio Bondanza2,3,
Jacopo Peccatori1,
Silvano Rossini1,3,
Zulma Magnani2,
Monica Salomoni4,
Claudia Benati4,
Maurilio Ponzoni5,
Luciano Callegaro1,
Paolo Corradini1,
Marco Bregni1,
Catia Traversari4, and
Claudio Bordignon3,4
1 Hematology and Bone Marrow Transplantation Unit and
2 Cancer Immunotherapy and Gene Therapy Program, San Raffaele Scientific Institute, Milan, Italy;
3 Università Vita-Salute San Raffaele, Milan, Italy;
4 MolMed, Milan, Italy;
5 Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
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.
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