Thymic renewal and antileukemic effect in adults after haploidentical transplantation and suicide gene therapy.

Abstract

6534 Background: Hematopoietic Cell Transplantation from partially-HLA matched family donors (haplo-HCT) represents a promising therapy for high-risk leukemia. The infusion of donor lymphocytes transduced with the HSV-Tk suicide gene provides a rapid immune reconstitution while controlling GVHD (Ciceri and Bonini et al., Lancet Oncology, 2009). Here we investigated the contribution of gene-modified cells to post-transplantation thymic renewal and Graft-versus-Leukemia effect. Methods: In a phase II trial of haplo-HSCT for high-risk leukemia, 28 patients received Tk+ donor T-cells. In a selected subset of patients, thymic function was assessed quantitation of CD31+ recent thymic emigrants (RTEs) in CD4+ naïve T cells and was correlated with thymic volume, assessed by CT scans. Alloreactivity against leukemic blasts was studied by MLC. Results: Posttransplant recovery of Tk- Naïve T cells occurred, reaching values comparable to controls in approximately one year. After Tk+ cells infusion, CD4+ naïve T cells became almost entirely CD31+ RTEs, suggesting a direct role of the infused Tk+ cells in promoting thymopoiesis. Accordingly, CT scans documented an increase in thymic volume following Tk+ cell infusion. Tk+ cells displayed also a direct antileukemic effect, as demonstrated by their selective enrichment and functional activity against leukemic blasts. Consistent with their ex vivo alloreactivity, in two of the treated patients Tk+ cells drove in vivo selection of immunoresistant leukemic variants with genomic loss of the mismatched HLA haplotype. Conclusions: The infusion of gene-modified T cells prompts renewal of thymic activity which contributes to recovery of a polyclonal T cell repertoire. Contextually, transduced cells also mediate a direct antitumor effect. TK+ cell activity in the context of haplo-HSCT for leukemia is assessed in a phase III trial. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MolMed