TY - JOUR
T1 - T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation
AU - Vago, Luca
AU - Oliveira, Giacomo
AU - Bondanza, Attilio
AU - Noviello, Maddalena
AU - Soldati, Corrado
AU - Ghio, Domenico
AU - Brigida, Immacolata
AU - Greco, Raffaella
AU - Lupo Stanghellini, Maria Teresa
AU - Peccatori, Jacopo
AU - Fracchia, Sergio
AU - Del Fiacco, Matteo
AU - Traversari, Catia
AU - Aiuti, Alessandro
AU - Del Maschio, Alessandro
AU - Bordignon, Claudio
AU - Ciceri, Fabio
AU - Bonini, Chiara
PY - 2012/8/30
Y1 - 2012/8/30
N2 - The genetic modification of T cells with a suicide gene grants a mechanism of control of adverse reactions, allowing safe infusion after partially incompatible hematopoietic stem cell transplantation (HSCT). In the TK007 clinical trial, 22 adults with hematologic malignancies experienced a rapid and sustained immune recovery after T cell-depleted HSCT and serial infusions of purified donor T cells expressing the HSV thymidine kinase suicide gene (TK + cells). After a first wave of circulating TK+ cells, the majority of T cells supporting long-term immune reconstitution did not carry the suicide gene and displayed high numbers of naive lymphocytes, suggesting the thymus-dependent development of T cells, occurring only upon TK +-cell engraftment. Accordingly, after the infusions, we documented an increase in circulating TCR excision circles and CD31+ recent thymic emigrants and a substantial expansion of the active thymic tissue as shown by chest tomography scans. Interestingly, a peak in the serum level of IL-7 was observed after each infusion of TK+ cells, anticipating the appearance of newly generated T cells. The results of the present study show that the infusion of genetically modified donor T cells after HSCT can drive the recovery of thymic activity in adults, leading to immune reconstitution.
AB - The genetic modification of T cells with a suicide gene grants a mechanism of control of adverse reactions, allowing safe infusion after partially incompatible hematopoietic stem cell transplantation (HSCT). In the TK007 clinical trial, 22 adults with hematologic malignancies experienced a rapid and sustained immune recovery after T cell-depleted HSCT and serial infusions of purified donor T cells expressing the HSV thymidine kinase suicide gene (TK + cells). After a first wave of circulating TK+ cells, the majority of T cells supporting long-term immune reconstitution did not carry the suicide gene and displayed high numbers of naive lymphocytes, suggesting the thymus-dependent development of T cells, occurring only upon TK +-cell engraftment. Accordingly, after the infusions, we documented an increase in circulating TCR excision circles and CD31+ recent thymic emigrants and a substantial expansion of the active thymic tissue as shown by chest tomography scans. Interestingly, a peak in the serum level of IL-7 was observed after each infusion of TK+ cells, anticipating the appearance of newly generated T cells. The results of the present study show that the infusion of genetically modified donor T cells after HSCT can drive the recovery of thymic activity in adults, leading to immune reconstitution.
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U2 - 10.1182/blood-2012-01-405670
DO - 10.1182/blood-2012-01-405670
M3 - Article
C2 - 22709689
AN - SCOPUS:84865708450
VL - 120
SP - 1820
EP - 1830
JO - Blood
JF - Blood
SN - 0006-4971
IS - 9
ER -