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.
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-to-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 donor lymphocyte infusions (DLIs), with lymphocytes 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 used to selectively control graft-versus-host disease (GvHD). Seven patients given infusions late after HSCT developed an immune response against the transgene. Immunization involved appearance of thymidine kinase (TK)-specific CD8(+) effectors and required a level of immunocompetence at the time of TK-DLI that can be achieved only several months after transplantation. This did not prevent graft-versus-leukemia (GvL) effect of the TK-DLI, since 5 of 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-kinetics of GvL mediated by TK-transduced donor lymphocytes may allow the full exploitation of TK-DLI.
Traversari
Catia
C
MolMed, Milan,Italy.
Marktel
Sarah
S
Magnani
Zulma
Z
Mangia
Patrizia
P
Russo
Vincenzo
V
Ciceri
Fabio
F
Bonini
Chiara
C
Bordignon
Claudio
C
D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D015316:Genetic Therapy / Q000379:methods; D006086:Graft vs Host Disease / Q000517:prevention & control / Q000628:therapy; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism*; D012306:Risk; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics*; D019076:Transgenes
D017252:CD3 Complex; D007371:Interferon-gamma; D013937:Thymidine Kinase