Submitted April 14, 2006
Accepted February 7, 2007
The potential immunogenicity of the TK suicide gene does not prevent full clinical benefit associated with the use of TK-transduced donor lymphocytes in HSCT for hematologic malignancies
Catia Traversari, Sarah Marktel, Zulma Magnani, Patrizia Mangia, Vincenzo Russo, Fabio Ciceri, Chiara Bonini, and Claudio Bordignon*
MolMed S.p.A., Milan, Italy
Hematology and Bone Marrow Transplantation Unit, Istituto Scientifico San Raffaele, Milan, Italy
Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico San Raffaele, Milan, Italy
Universita Vita-Salute San Raffaele, Milan, Italy
* Corresponding author; email: claudio.bordignon{at}hsr.it.
Gene therapy is a promising therapeutic strategy for genetic and acquired hematologic diseases. With the improvements in gene transfer and expression, factors affecting safety and efficacy of gene therapy can now be evaluated to establish the best clinical benefit-risk ratio. The induction of immune responses against gene therapy components is one of the potential limitations. We studied the occurrence of such event in 23 patients treated with the infusion of donor lymphocytes (DLI) transduced to express the HSV-TK suicide gene for relapse of hematologic malignancies occurring after allogeneic hematopoietic stem cell transplantation (HSCT). The suicide gene was utilized to selectively control graft-versus-host disease (GvHD). Seven patients infused late after HSCT developed an immune response against the transgene. Immunization involved appearance of TK-specific CD8+ effectors and required a level of immune competence at the time of TK-DLI that can be achieved only several months after transplantation. This did not prevent graft-vs-leukemia (GvL) effect of the TK-DLI, since 5/7 immunized patients maintained the complete remission achieved prior to immunization. We suggest that appropriate study designs taking into account the immune suppression of the patient and time-kinetic of GvL mediated by TK-transduced donor lymphocytes may allow the full exploitation of TK-DLI.
