T Cell Immunotherapy for Immune Reconstitution and GVHD Prevention After Allogeneic Hematopoietic Stem Cell Transplantation

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Clinical Outcome and Immune Recovery after Adoptive Infusion of BPX-501 Cells (donor iC9-transduced T cells) in Children with Wiskott-Aldrich Syndrome (WAS) Given Alfa/Beta T-Cell Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation (HSCT)

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Clinical Outcome after Adoptive Infusion of BPX-501 Cells (donor T cells transduced with iC9 suicide gene) in Children with Thalassemia Major (TM) Given Alfa/Beta T-Cell Depleted HLA-Haploidentical Stem Cell Transplantation (HSCT)

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Preservation of Antigen-Specific Functions of αβ T Cells and B Cells Removed from Hematopoietic Stem Cell Transplants Suggests Their Use As an Alternative Cell Source for Advanced Manipulation and Adoptive Immunotherapy

Hematopoietic stem cell transplantation is standard therapy for numerous hematological diseases. The use of haploidentical donors, sharing half of the HLA alleles with the recipient, has facilitated the use of this procedure as patients can rely on availability of a haploidentical donor within their family. Since HLA disparity increases the risk of graft-versus-host disease, T-cell depletion has been used to remove alloreactive lymphocytes from the graft. Selective removal of αβ T cells, which encompass the alloreactive repertoire, combined with removal of B cells to prevent EBV-related lymphoproliferative disease, proved safe and effective in clinical studies. Depleted αβ T cells and B cells are generally discarded as by-products. Considering the possible use of donor T cells for donor lymphocyte infusions or for generation of pathogen-specific T cells as mediators of graft-versus-infection effect, we tested whether cells in the discarded fractions were functionally intact. Response to alloantigens and to viral antigens comparable to that of unmanipulated cells indicated a functional integrity of αβ T cells, in spite of the manipulation used for their depletion. Furthermore, B cells proved to be efficient antigen-presenting cells, indicating that antigen uptake, processing, and presentation were fully preserved. Therefore, we propose that separated αβ T lymphocytes could be employed for obtaining pathogen-specific T cells, applying available methods for positive selection, which eventually leads to indirect allodepletion. In addition, these functional T cells could undergo additional manipulation, such as direct allodepletion or genetic modification

Outcome of children with acute leukemia given HLA-haploidentical HSCT after \u3b1\u3b2 T-cell and B-cell depletion

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of \u3b1\u3b2 T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach (ClinicalTrial.gov identifier: NCT01810120). Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GvHD); no patient received any post-transplantation GvHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence (CI) of skin-only, grade I-II acute GvHD was 30%; no patient developed extensive chronic GvHD. Four patients died, the CI of non-relapse mortality being 5%, while 19 relapsed, resulting into a 24% CI of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GvHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after \u3b1\u3b2 T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft