TY - JOUR
T1 - A clinical-scale selective allodepletion approach for the treatment of HLA-mismatched and matched donor-recipient pairs using expanded T lymphocytes as antigen-presenting cells and a TH9402-based photodepletion technique
AU - Mielke, Stephan
AU - Nunes, Raquel
AU - Rezvani, Katayoun
AU - Fellowes, Vicki S.
AU - Venne, Annie
AU - Solomon, Scott R.
AU - Fan, Yong
AU - Gostick, Emma
AU - Price, David A.
AU - Scotto, Christian
AU - Read, Elizabeth J.
AU - Barrett, A. John
PY - 2008/4/15
Y1 - 2008/4/15
N2 - Selective allodepletion is a strategy to eliminate host-reactive donor T cells from hematopoietic stem cell allografts to prevent graft-versus-host disease while conserving useful donor immune functions. To overcome fluctuations in activation- based surface marker expression and achieve a more consistent and effective allodepletion, we investigated a pho-todepletion process targeting activation-based changes in p-glycoprotein that result in an altered efflux of the photosen-sitizer TH9402. Expanded lymphocytes, generated using anti-CD3 and IL-2, were cocultured with responder cells from HLA-matched or -mismatched donors. Optimal results were achieved when cocultured cells were incubated with 7.5 μM TH9402, followed by dye extrusion and exposure to 5 Joule/cm 2 light energy at 5 × 106 cells/mL. In mismatched stimulator-responder pairs, the median reduction of alloreactivity was 474-fold (range, 43-fold to 864-fold) compared with the unmanipulated responder. Third-party responses were maintained with a median 1.4-fold (range, 0.9-fold to 3.3-fold) reduction. In matched pairs, alloreac-tive helper T-lymphocyte precursors were reduced to lower than 1:100 000, while third-party responses remained higher than 1:10 000. This establishes a clinical-scale process capable of highly efficient, reproducible, selective removal of alloreactive lymphocytes from lymphocyte transplant products performed under current Good Manufacturing Practice. This procedure is currently being investigated in a clinical trial of allotransplantation.
AB - Selective allodepletion is a strategy to eliminate host-reactive donor T cells from hematopoietic stem cell allografts to prevent graft-versus-host disease while conserving useful donor immune functions. To overcome fluctuations in activation- based surface marker expression and achieve a more consistent and effective allodepletion, we investigated a pho-todepletion process targeting activation-based changes in p-glycoprotein that result in an altered efflux of the photosen-sitizer TH9402. Expanded lymphocytes, generated using anti-CD3 and IL-2, were cocultured with responder cells from HLA-matched or -mismatched donors. Optimal results were achieved when cocultured cells were incubated with 7.5 μM TH9402, followed by dye extrusion and exposure to 5 Joule/cm 2 light energy at 5 × 106 cells/mL. In mismatched stimulator-responder pairs, the median reduction of alloreactivity was 474-fold (range, 43-fold to 864-fold) compared with the unmanipulated responder. Third-party responses were maintained with a median 1.4-fold (range, 0.9-fold to 3.3-fold) reduction. In matched pairs, alloreac-tive helper T-lymphocyte precursors were reduced to lower than 1:100 000, while third-party responses remained higher than 1:10 000. This establishes a clinical-scale process capable of highly efficient, reproducible, selective removal of alloreactive lymphocytes from lymphocyte transplant products performed under current Good Manufacturing Practice. This procedure is currently being investigated in a clinical trial of allotransplantation.
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U2 - 10.1182/blood-2007-08-104471
DO - 10.1182/blood-2007-08-104471
M3 - Article
C2 - 17878399
AN - SCOPUS:43249122409
SN - 0006-4971
VL - 111
SP - 4392
EP - 4402
JO - Blood
JF - Blood
IS - 8
ER -