T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation

Luca Vago, Giacomo Oliveira, Attilio Bondanza, Maddalena Noviello, Corrado Soldati, Domenico Ghio, Immacolata Brigida, Raffaella Greco, Maria Teresa Lupo Stanghellini, Jacopo Peccatori, Sergio Fracchia, Matteo Del Fiacco, Catia Traversari, Alessandro Aiuti, Alessandro Del Maschio, Claudio Bordignon, Fabio Ciceri, Chiara Bonini

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1820-1830
Number of pages11
JournalBlood
Volume120
Issue number9
DOIs
Publication statusPublished - Aug 30 2012

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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