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Thymic Renewal and Anti-Leukemic Effect In Adults After Haploidentical Transplantation and Donor T Cell Suicide Gene Therapy
- Source :
- Blood. 116:833-833
- Publication Year :
- 2010
- Publisher :
- American Society of Hematology, 2010.
-
Abstract
- Abstract 833 Introduction: Hematopoietic Stem Cell Transplantation (HSCT) from partially HLA-matched (haploidentical) family donors represents a promising therapy for high-risk leukemia, but requires appropriate strategies to control the adverse reactions mediated by the partially incompatible, transplanted immune system. In a recent phase II study (TK007 study), we demonstrated that the infusion of donor lymphocytes transduced with the Herpes Simplex Virus Thymidine kinase (HSV-Tk) suicide gene allows to control Graft-versus-Host Disease (GvHD) and to rapidly provide an effective and polyclonal anti-infective T cell repertoire (Ciceri and Bonini et al., Lancet Oncology, 2009). Even though their engraftment is necessary to achieve these effects, HSV-Tkpos cells represent the minority of lymphocytes circulating in treated patients. Therefore, in the present study, we investigated the putative role of HSV-Tkpos cells in promoting thymic activity and T cell development from graft progenitors. Methods: Twenty-eight adult patients underwent haploidentical HSCT and infusion of purified suicide gene-modified donor T cells for high-risk hematologic malignancies in the TK007 study. Thymic function was investigated in a selected cohort of this study (n=14) and in a control group who underwent unselected T cell-replete haploidentical transplantation with an ATG-rapamycin-mycophenolate-based GvHD prophylaxis (n=31), after validation in healthy pediatric and adult controls. T cell subsets and the proportion of CD31+ recent thymic emigrants (RTEs) amongst CD4+ naïve T cells were measured by immunophenotypic analysis. Single joint T cell Receptor Excision Circles (sjTREC) were quantified by qPCR. Thymic output was correlated with thymic volume, as assessed by CT scans. Post-transplantation pathogen-specific immune response was quantified by ELISpot. Alloreactivity against leukemic blasts was studied by mixed lymphocyte cultures. Results: Post-transplantation recovery of naïve CD45RA+CD62L+ T cells occurred in patients treated with gene modified T cells, reaching values of healthy controls in approximately one year. At the time of immune reconstitution (median 76 days after HSCT, defined as CD3+ cells > 100/ml peripheral blood), 76.5% of circulating T cells did not carry the HSV-Tk suicide gene, and the CD4+ naïve subset was largely comprised of cells recently originated from the thymus (90.5±3.2%). This observed frequency of CD31+ RTEs in these patients was significantly higher than that measured in the same patients before HSCT (60.7±6%, p=0,0087) or in patients analyzed 90 days after T cell-replete haploidentical HSCT (31.0±6.3%, p Conclusions: These data show that the infusion of suicide gene-modified T cells prompts the renewal of thymic activity, which contributes to the recovery of a polyclonal T cell repertoire protective against pathogens. Contextually, the infused transduced cells mediate also a direct antitumor effect through their recognition of allogeneic determinants on leukemic cells. A phase III clinical trial (TK008 study) to assess the efficacy of HSV-Tkpos cells in the context of haploidentical HSCT for leukemia started in 2010 in Italy, and is currently expanding to multiple centers throughout Europe. Disclosures: Bonini: MolMed S.p.A.: Consultancy.
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 116
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi...........4a3333c5d3f441c50e5e1294be49eb91