Active T cell depletion allows a focused depletion of unwanted cells, while several populations of potential therapeutic benefit are preserved within the graft. Different strategies can be applied, as described below.
In contrast to the strategy of CD34+ cell enrichment, active T and B cell depletion results in a graft that contains CD34+ stem cells, CD34– stem cells, other progenitor cells and natural killer (NK) cells, monocytes, and dendritic cells, which might have engraftment facilitating effects.32 This active T cell depletion strategy is currently being evaluated, especially in combination with reduced intensity conditioning.12, 23
Another possibility for active T cell depletion is provided by the CliniMACS® TCRα/β System.
Cells which are responsible for the development of graft-versus-host disease (GvHD) are thought to derive from the pool of TCRα/β+ T cells, whereas TCRγ/δ+ T cells and NK cells may bear graft-versus-leukemia (GvL) effects, engraftment facilitating functions, and may help to fight infections.25-28
Thus, depletion of TCRα/β+ T cells may be a helpful tool to prevent GvHD, while preserving different cell populations of potential therapeutic value within the cellular product.2 The CliniMACS TCRα/β product line can also be used in combination with the CliniMACS CD19 Reagent to additionally remove the CD19+ B cells from the graft.30
CD45RA is expressed on naive T cells, whereas memory T cells are CD45RA–. CD45RA depletion results in a cellular product passively enriched for memory T cells, while naive T cells, which have the potential to induce GvHD, are depleted.31 The potential benefit of memory T cell infusion probably results from the high anti-infection potential of this cell type. It should be noted that CD45RA is also present on part of other lymphocytes and hematopoietic stem cells. This should be considered if memory T cell infusion is planned to be combined with the initial transplant. In exceptional cases it may happen that donors have CD45+ memory T cells. This should be tested prior to any clinical application.
Please find below a list of product lines that can be used for active T cell depletion.
CliniMACS® CD3/CD19 Product Line – For simultaneous T and B cell depletion.
CliniMACS TCRα/β Product Line – For TCRα/β+ T cell depletion. Aim: Maintenance of γ/δ T cells, NK cells, and graft facilitating cells in the graft. For additional removal of B cells, this product line can also be used in combination with CliniMACS CD19 Product Line.TCRα/β depletion is currently available as RUO (research use only) in the USA.
CliniMACS CD45RA Product Line – For naive T cell depletion. Aim: Maintenance of memory T cells in the graft or DLI product. Part of CD34 hematopoietic stem cells are also CD45RA+. This should be considered if memory cell infusion is planned to be combined with the initial transplant. In exceptional cases it may happen that donors have CD45+ memory T cells. This should be tested prior to any clinical application.
Allogeneic stem cell transplantation is a therapeutic option for the treatment of patients with distinct malignant and non-malignant diseases.32, 41
Active T cell depletion strategies can be used for haploidentical transplantation when an human leukocyte antigen (HLA) Id Sib or other HLA-matched related or unrelated donor is not available. CliniMACS technology enables the active depletion of B cells, T cells, or T cell subsets from the graft (CD3/CD19 depletion, TCRα/β/CD19 depletion). These depleted grafts have been used in the context of reduced intensity conditioning (RIC) regimens.24, 33, 34
Clinical investigation during recent years has focused on treatment of hematological malignancies but, to a certain extent, solid tumor disease and non-malignant disease have also been the subject of clinical studies.35,36 Data have been acquired for patient populations, both children and adults, which demonstrate improved engraftment and immune reconstitution33, 37-39. The authors conclude that CD3/CD19 depletion for graft engineering under RIC is a promising approach for patients without a matched related donor.
Especially children and elderly patients potentially benefit from the strategy of RIC. Recent findings show that a CD3/CD19 depletion graft engineering strategy for non-HLA identical donor stem cell transplantation in children resulted in a remarkable cumulative TRM rate of only 10.7% - a result which was previously only found in HLA Id Sib transplantation.40
Results are accumulating on a most innovative active T cell depletion strategy, which is based on TCRα/β/CD19 depletion of HLA-mismatched stem cell grafts for treatment of children with advanced malignant and non-malignant disease under RIC.29, 34 Patients showed a rapid and sustained engraftment, a rapid immune reconstitution, and a low incidence of graft-versus-host disease (GvHD). More recent data show that promising data could be generated not only on the basis of RIC but also after myeloablative conditioning, even when no post-transplant GvHD prophylaxis was administered.30
2. Aversa et al. (2005): J. Clin. Oncol. 23: 3447–3454
12. Lang et al. (2006) Bone Marrow Transplant. 37 (Suppl. 1): 67.
23. Schumm et al. (2006) Cytotherapy 8: 465–472.
24. Gonzalez-Vicent et al. (2010) J. Pediatr. Hematol. Oncol. 32: 85–90.
25. D’Asaro et al. (2010) J. Immunol. 184: 3260–3268.
26. Kordelas et al. (2008) Blood 112: Abstract 2223.
27. Godder et al. (2007) Bone Marrow Transplant. 39: 751–757.
28. Knight et al. (2010) Blood 116: 2164–2172.
29. Schumm et al. (2011) Bone Marrow Transplant. 46 (Suppl. 1): 1093.
30. Handgretinger et al. (2011) Blood 118: Abstract 1005.
31. Anderson et al. (2003) J. Clin. Invest. 112: 101–108.
32. Handgretinger et al. (2007) Ann. N. Y. Acad. Sci. 1106: 279–289.
33. Lang et al. (2005) Klin. Padiatr. 217: 334–348.
34. Lang et al. (2011) Bone Marrow Transplant. 46 (Suppl. 1): 559.
35. Handgretinger et al. (2008) Cytotherapy 10: 443–451.
36. Lang et al. (2008) Bone Marrow Transplant. 42 (Suppl. 2): 54–59.
37. Bethge et al.(2008) Blood Cells Mol. Dis. 40: 13–19.
38. Federmann et al. (2009) Bone Marrow Transplant. 43 (Suppl. 1): S66.
39. Federmann et al.(2011) Leukemia 25: 121–129.
40. Bader et al.(2011) Best Pract. Res. Clin. Hematol. 24: 331–337.
41. The EBMT Handbook 6th Edition, Haematopoietic Stem Cell Transplantation, 2012