The infusion of suicide gene-modified donor T cells after hematopoietic stem cell transplantation prompts thymic renewal in adult patients by an IL-7 dependent mechanism (169.4)

Abstract

Abstract The infusion of donor lymphocytes genetically modified to express the HSV-Thymidine kinase (Tk) suicide gene after T cell-depleted Hematopoietic Stem Cell Transplanation (HSCT) provides protection against pathogens and disease recurrence, while allowing complete GvHD control. In the TK007 phase I/II clinical trial 28 adults with hematologic malignancies received purified Tk-transduced cells after T cell-depleted haploidentical HSCT, and 22 experienced a rapid immune reconstitution. Ten patients had GvHD that was controlled by ganciclovir (Lancet Oncol. 2009). Since the newly reconstituting T cells were mostly Tkneg, we hypothesized that Tk cells, which are necessary to achieve this effect, might act by prompting T cell development from graft progenitors. Patients treated with Tk cells showed prompt recovery of Tkneg naïve T cells. In particular, the CD4+ naïve subset was highly enriched in CD31+ cells, bona fide recent thymic emigrants. Accordingly, after Tk cell add-backs we documented an increase in single joint T cell Receptor Excision Circles counts and in thymic volume, as evidenced by chest CT scans. Serum levels of IL-7 markedly rose after Tk cell add-backs, suggesting that gene-modified cells may act by inducing IL-7 release, in turn supporting thymopoiesis. Taken together, our data show that the infusion of Tk cells boosts the function of adult thymus, prompting the recovery of a polyclonal, fully competent, T cell repertoire by an IL-7 dependent mechanism.