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Abstract: Background: T‐cell depletion (TCD) effectively reduces severe graft‐versus‐host disease in recipients of HLA‐mismatched allografts. However, TCD is associated with delayed immune recovery and increased infections. We hypothesized that specific depletion of CD45RA+ naive T cells, rather than broad depletion of CD3+ T cells, can preserve memory‐immunity in the allografts and confer protection against important viral infections in the early post‐transplant period. Methods: Sixty‐seven patients who received TCD haploidentical donor transplantation for hematologic malignancy on 3 consecutive trials were analyzed. Results: Patients receiving CD45RA‐depleted donor grafts had 2000‐fold more donor T cells infused, significantly higher T‐cell counts at Day +30 post transplant (550/μL vs 10/μL; P < .001), and higher T‐cell diversity by Vbeta spectratyping at Day +100 (P < .001). Importantly, these recipients experienced a significant reduction in both the incidence (P = .002) and duration (P = .02) of any viremia (cytomegalovirus, Epstein‐Barr virus, or adenovirus) in the first 6 months post transplant. Specifically, recipients of CD3‐depleted grafts were more likely to experience adenovirus viremia (27% vs 4%, P = .02). Conclusion: CD45RA‐depletion provided a large number of donor memory T cells to the recipients and was associated with enhanced early T‐cell recovery and protection against viremia. [ABSTRACT FROM AUTHOR]

Background: Excessive T-cell depletion (TCD) is a prerequisite for graft manufacturing in haploidentical stem cell (SC) transplantation by using either CD34 selection or direct TCD such as CD3/CD19 depletion.Study Design and Methods: To optimize graft composition we compared 1) direct or indirect TCD only, 2) a combination of CD3/CD19-depleted with CD34-selected grafts, or 3) TCD twice for depletion improvement based on our 10-year experience with 320 separations in graft manufacturing and quality control.Results: SC recovery was significantly higher (85%, n = 187 vs. 73%, n = 115; p < 0.0001), but TCD was inferior (median log depletion, -3.6 vs. -5.2) for CD3/CD19 depletion compared to CD34 selection, respectively. For end products with less than -2.5 log TCD, a second depletion step led to a successful improvement in TCD. Thawing of grafts showed a high viability and recovery of SCs, but low NK-cell yield. To optimize individualized graft engineering, a calculator was developed to estimate the results of the final graft based on the content of CD34+ and CD3+ cells in the leukapheresis product.Conclusion: Finally, calculated splitting of the starting product followed by CD3/19 depletion together with CD34+ graft manipulation may enable the composition of optimized grafts with high CD34+-cell and minimal T-cell content. [ABSTRACT FROM AUTHOR]

Alloreactivity triggered by interaction between killer cell immunoglobulin-like receptors ( KIRs) and natural killer ( NK) cells plays a role in the graft-versus-tumor effect after hematopoietic stem cell transplantation ( SCT). Our aim in this study was to evaluate this role in the setting of T-cell-repleted haploidentical SCT with postinfusion high-dose cyclophosphamide ( PT-Cy). We included 33 patients. Among patient-donor pairs with at least 1 inhibitory KIR ( iKIR) gene mismatch, event-free survival ( EFS) and cumulative incidence of relapse 1 year after transplant were significantly better (85% vs. 37% [ P = 0.008] and 18% vs. 46% [ P = 0.041], respectively). A subanalysis in 12 patients with Hodgkin's lymphoma ( HL) showed an improvement in EFS 1 year after transplant in those patients with KIR ligand mismatch (100% vs. 25%, P = 0.012), although overall survival ( OS) was not affected (85% vs. 80%, P = 0.2). Eight of 12 patient-donors pairs presented iKIR mismatches. Of note, this outcome was better in the small subgroup, both for EFS (100% vs. 25%, P = 0.012) and for OS (100% vs. 37%, P = 0.004). Our data suggest that in the setting of T-cell-repleted haploidentical SCT with PT-Cy, iKIR mismatch is associated with improved survival, with particularly good results for both iKIR and KIR ligand mismatches in patients with HL. [ABSTRACT FROM AUTHOR]

Haematopoeitic stem cell transplantation ( HSCT) is a curative procedure for children with malignant and non-malignant haematological disease as well as an expanding number of inherited disorders. Most patients lack a human leucocyte antigen-matched related donor, making alternative donors, such as closely matched unrelated donors, unrelated umbilical cord blood donations and haploidentical donors, necessary choices. T cell depletion ( TCD) has been employed for over 30 years to reduce the risk of graft-versus-host disease ( Gv HD) associated with non-genoidentical HSCT. However, until recently overall survival had not improved with TCD due to increased rates of graft failure, disease relapse and delayed immune reconstitution. Recent advances in graft manipulation and reduced toxicity conditioning regimens have offered renewed hope, particularly for children undergoing haploidentical HSCT, where encouraging results have been achieved using negative depletion techniques to retain beneficial accessory cells, which speed immune reconstitution and reduce disease relapse. Translational work building on megadose CD34+ selected grafts, including pathogen-specific immunotherapy, suicide gene therapy and other adoptive cellular immunotherapies, has also offered improved outcomes for such patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Effective T-cell depletion is a prerequisite for haploidentical peripheral blood progenitor cell (PBPC) transplantation. This study was performed to investigate the performance of magnetic cell sorting–based direct large-scale T-cell depletion, which is an attractive alternative to standard PBPC enrichment procedures. STUDY DESIGN AND METHODS: PBPCs were harvested from 11 human leukocyte antigen (HLA)-haploidentical donors. T cells labeled with anti-CD3–coated beads were depleted with a commercially available magnetic separation unit (CliniMACS, Miltenyi Biotec) with either the Depletion 2.1 (D2.1, n = 11) or the novel Depletion 3.1 (D3.1, n = 12) program. If indicated, additional CD34+ selections were performed (n = 6). Eleven patients received T-cell-depleted grafts after reduced-intensity conditioning. RESULTS: The median log T-cell depletion was better with the D2.1 compared to the D3.1 (log 3.6 vs. log 2.3, p < 0.05) and was further improved by introducing an immunoglobulin G (IgG)-blocking step (log 4.5 and log 3.4, respectively). The D3.1 was superior to the D2.1 (p < 0.05) in median recovery of CD34+ cells (90% vs. 78%) and in median recovery of CD3– cells (87% vs. 76%). The median processing times per 1010 total cells were 0.90 hours (D2.1) and 0.35 hours (D3.1). The transplanted grafts (directly T-cell–depleted products with or without positively selected CD34+ cells) contained a median of 10.5 × 106 per kg CD34+, 0.93 × 105 per kg CD3+, and 11.6 × 106 per kg CD56+. Rapid engraftment was achieved in 10 patients. The incidences of acute graft-versus-host disease were less than 10 percent (Grade I/II) and 0 percent (Grade III/IV). CONCLUSION: The novel D3.1 program with IgG blocking enables highly effective, time-saving large-scale T-cell depletion. Combining direct depletion techniques with standard CD34+ selection enables the composition of grafts optimized to the specific requirements of the patients. [ABSTRACT FROM AUTHOR]

Investigates the clinical feasibility and safety of CD133-based selection and transplantation in a small number of pediatric patients. Marker of more primitive hematopoietic progenitors; Proportion of CD133 selected cells; Evidence of a rapid platelet recovery; T-cell regeneration.

Abstract: The transplantation of megadoses of haploidentical hematopoietic stem cells is for a number of children with malignant or nonmalignant diseases the only curative approach. In order to prevent severe GvHD, the removal of T lymphocytes from the stem cell graft either by positive selection of CD34+ stem cells or by negative depletion of CD3+ T lymphocytes is necessary. We present the results obtained so far by CD34+ positive selection and discuss new techniques of graft engineering which might hopefully further improve the outcome of haploidentical stem cell transplantation. [ABSTRACT FROM AUTHOR]