Selective depletion of alloreactive donor lymphocytes: A novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation

Stem Cell Allogeneic Transplantation Section, Hematology Branch, NHLBI, NIH Bldg 10, Hatfield CRC, Rm 3-5320, 10 Center Dr, MSC 1202, Bethesda, MD 20892-1202, USA.
Blood (Impact Factor: 10.45). 09/2005; 106(3):1123-9. DOI: 10.1182/blood-2005-01-0393
Source: PubMed


We have selectively depleted host-reactive donor T cells from peripheral blood stem cell (PBSC) transplant allografts ex vivo using an anti-CD25 immunotoxin. We report a clinical trial to decrease graft-versus-host disease (GVHD) in elderly patients receiving selectively depleted PBSC transplants from HLA-identical sibling donors. Sixteen patients (median age, 65 years [range, 51-73 years]), with advanced hematologic malignancies underwent transplantation following reduced-intensity conditioning with fludarabine and either cyclophosphamide (n = 5), melphalan (n = 5), or busulfan (n = 6). Cyclosporine was used as sole GVHD prophylaxis. The allograft contained a median of 4.5 x 10(6) CD34 cells/kg (range, 3.4-7.3 x 10(6) CD34 cells/kg) and 1.0 x 10(8)/kg (range, 0.2-1.5 x 10(8)/kg) selectively depleted T cells. Fifteen patients achieved sustained engraftment. The helper T-lymphocyte precursor (HTLp) frequency assay demonstrated successful (mean, 5-fold) depletion of host-reactive donor T cells, with conservation of third-party response in 9 of 11 cases tested. Actuarial rates of acute GVHD were 46% +/- 13% for grades II to IV and 12% +/- 8% for grades III to IV. These results suggest that allodepletion of donor cells ex vivo is clinically feasible in older patients and may reduce the rate of severe acute GVHD. Further studies with selectively depleted transplants to evaluate graft-versus-leukemia (GVL) and survival are warranted.

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Available from: Ellen S Vitetta, Jan 15, 2014
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    • "An alternative would be to develop strategies to selectively modulate alloresponses against GvHD target organs. For example, selective depletion of alloreactive T cells in vitro before infusion of stem cells has been explored in preclincical and clinical settings [100] [101] [102]. The ability to manipulate the post-transplant environment to enhance the graft-versus-malignancy reaction would result in less reliance on pretransplant conditioning for cure, potentially allowing the use of reduced-intensity conditioning regimens , which have been used successfully for pediatric nonmalignant diseases and adult malignancies. "
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    Hematology/oncology clinics of North America 02/2010; 24(1):109-27. DOI:10.1016/j.hoc.2009.11.010 · 2.30 Impact Factor
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    • "Efficient T-cell depletion of the graft can completely abolish GVHD, but is associated with an increased risk of leukaemic relapse compared to T-cell replete transplants (Goldman et al, 1988; Horowitz et al, 1990; Marmont et al, 1991; Aschan et al, 1993). Using mixed lymphocyte culture (MLC) it is possible to deplete alloreactive T-cells by treatment with anti-CD25 antibody in vitro (Cavazzana-Calvo et al, 1990; Mavroudis et al, 1996; Solomon et al, 2005). By add-back of donor T-cells with depleted alloreactivity and maintained GVL, the hope is to improve immune reconstitution and at the same time prevent GVHD. "
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    ABSTRACT: Allogeneic haematological stem cell transplantation (HSCT) has developed into immunotherapy. Donor CD4+, CD8+ and natural killer (NK) cells have been reported to mediate graft-versus-leukaemia (GVL) effects, using Fas-dependent killing and perforin degranulation to eradicate malignant cells. Cytokines, such as interleukin-2, interferon-gamma and tumour necrosis factor-alpha potentiate the GVL effect. Post-transplant adoptive therapy of cytotoxic T-cells (CTL) against leukaemia-specific antigens, minor histocompatibility antigens, or T-cell receptor genes may constitute successful approaches to induce anti-tumour effects. Clinically, a significant GVL effect is induced by chronic rather than acute graft-versus-host disease (GVHD). An anti-tumour effect has also been reported for myeloma, lymphoma and solid tumours. Reduced intensity conditioning enables HSCT in older and disabled patients and relies on the graft-versus-tumour effect. Donor lymphocyte infusions promote the GVL effect and can be given as escalating doses with response monitored by minimal residual disease. A high CD34+ cell dose of peripheral blood stem cells increases GVL. There is a balance between effective immunosuppression, low incidence of GVHD and relapse. For instance, T-cell depletion of the graft increases the risk of relapse. This paper reviews the current knowledge in graft-versus-cancer effects. Future directions, such as immunotherapy using leukaemia-specific CTLs, allo-depleted T-cells and suicide gene manipulated T-cells, are presented.
    British Journal of Haematology 10/2009; 147(5):614-33. DOI:10.1111/j.1365-2141.2009.07886.x · 4.71 Impact Factor
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    • "Simple T cell infusion may not be a good idea to overcome these barriers, one of the most promising approaches is to selectively remove GVHD-causing alloreactive T cells, while keeping cells mediating the graft versus leukemia (GVL) effect and antimicrobial immune responses in grafts[26]. Some pioneering clinical trials have demonstrated its availability and feasibility[27,28]. Amrolia's group used an anti-CD25 immunotoxin to deplete alloreactive lymphocytes in 16 haploidentical transplantation patients. "
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