T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation.
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.
Experimental Hematology Unit,San Raffaele Scientific Institute, Milano, Italy.
Luca
L
Vago
Giacomo
G
Oliveira
Attilio
A
Bondanza
Maddalena
M
Noviello
Corrado
C
Soldati
Domenico
D
Ghio
Immacolata
I
Brigida
Raffaella
R
Greco
Maria Teresa
MT
Lupo Stanghellini
Jacopo
J
Peccatori
Sergio
S
Fracchia
Matteo
M
Del Fiacco
Catia
C
Traversari
Alessandro
A
Aiuti
Alessandro
A
Del Maschio
Claudio
C
Bordignon
Fabio
F
Ciceri
Chiara
C
Bonini
D000328:Adult; D003131:Combined Modality Therapy; D015870:Gene Expression; D041722:Genes, Transgenic, Suicide / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D019337:Hematologic Neoplasms / Q000097:blood / Q000235:genetics / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D015851:Interleukin-7 / Q000097:blood; D018655:Lymphocyte Count; D011446:Prospective Studies; D013902:Radiography, Thoracic; D012038:Regeneration / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism* / Q000637:transplantation; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism / Q000503:physiopathology; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
D015851:Interleukin-7; D013937:Thymidine Kinase