Article

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: 10.43). 09/2005; 106(3):1123-9. DOI: 10.1182/blood-2005-01-0393
Source: PubMed

ABSTRACT 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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    • "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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    • "Most of the published methods rely on the stimulation of donor T cells with recipient-derived APCs to activate the alloreactive T cell component, followed by specific elimination of the activated cells using antimetabolite drugs, photodepletion, or using immunotoxins or magnetic beads to target differentiallyexpressed cell surface molecules. The majority of groups have depleted alloactivated cells based on their expression of activation markers, including CD69 (Hartwig et al, 2006), CD25 (Andre-Schmutz et al, 2002; Amrolia et al, 2003, 2006; Solomon et al, 2005), CD134 (O · 40) (Ge et al, 2008) and CD137 (41BB)(Wehler et al, 2007), which are upregulated on donor T cells in response to stimulation with recipient cells. Barrett and colleagues have pioneered an approach to selectively deplete alloreactive cells using a TH9402-based photodepletion technique. "
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