Active T cell depletion in graft engineering

Background

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.
 

CD3/CD19 depletion
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}

TCRα/β depletion
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 depletion
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}

CD3/CD19 depletion
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 reconstitution^{33, 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

TCRα/β/CD19 depletion
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 6^th Edition, Haematopoietic Stem Cell Transplantation, 2012