Table 1.
Pros and cons of commonly used TCD vs. TCR approaches used in haplo-HSCT.
| T-Cell Deplete Method | Mechanism | Pros | Cons |
|---|---|---|---|
| General | Multiple (listed below) | Conceptually most effective means to prevent acute and chronic GvHD Low acute and chronic GvHD Reduced need for post-transplant immune-suppressive medications Lower pulmonary and hepatic toxicity peri-transplant Prevents EBV-PTLD (high potential morbidity and mortality) by removing CD19+ cells ex vivo |
More effective in children than adults (due to better thymus function in children with associated greater T-cell receptor diversity versus adults, who rely more on peripheral cytokine-mediated T-cell expansion post-transplant) Expensive Labor-intensive Specialized expertise required Not available at most stem cell transplant centers Higher graft rejection/lower engraftment related to depletion of T-cells (especially gamma/delta), natural killer cells, and hematopoietic progenitors that facilitate engraftment Delayed IR with increased risk of opportunistic infections |
| CD34-positive selection | Positive selection of CD34+ stem cells via immunoadsorption columns (immunomagnetic beads) Combined physical and immunological separation of cells |
Beneficial for engraftment (barrier overcome by “megadose” CD34+ stem cell infusion) | Loss of cells that facilitate engraftment, such as gamma/delta T-cells and natural killer cells, with a subsequent increased risk of graft rejection Potential for severely delayed IR with increased infectious risk profile for many months to years and conceptual risk of relapse of disease (return of sickle cell disease phenotype) Myeloablative conditioning is used more often (accentuates existing end-organ damage, higher risk of acute and chronic GvHD, higher transplant-related mortality) |
| CD3+ and CD19+ | Ex vivo negative selection of CD3 (T-cells) and CD19 (B-cells) | Lower risk of EBV-PTLD (from removing potential EBV-infected CD19 cells in the graft) | Risks as described in “General” and “CD34 positive selection” Loss of cells that promote engraftment (gamma/delta T-cells and natural killer cells) |
| T-cell receptor alpha/beta+ and CD19+ |
Ex vivo depletion of more specific T-cell subsets that drive acute GvHD and B-cells that increase the risk of EBV-PTLD | Retain gamma/delta+ T-cells (promote IR and provide pathogen-specific immunity) and natural killer cells while depleting alloreactive T-cells that cause acute GvHD Less delayed T-cell specific IR |
Requires even more specialized expertise than CD34-positive selection methods of CD3+ and CD19+ negative selection Available at fewer centers Data only reported in children |
| T-Cell Replete Method | Mechanism | Pros | Cons |
| General | In vivo rather than ex vivo depletion of recipient and donor alloreactive T-cells (with anti-thymocyte globulin or alemtuzumab, with or without total body or lymphoid irradiation) | Available at almost all transplant centers in Europe and the United States Methods are more easily replicable Conceptually lower cost compared with T-cell depletion methods (due to the lack of a need for expensive graft-manipulation technology) |
Need for in vivo T-cell depletion with anti-thymocyte globulin or alemtuzumab, with potential for delayed IR and increased risk of opportunistic pathogens Higher GvHD risk with peripheral blood stem cell grafts Potential for severe cytokine release syndrome (especially with peripheral blood stem cell grafts) due to rapid activation of T-cells |
| GIAC protocol | Modulation of alloreactive T-cells with (1) Granulocyte colony-stimulating factor donor priming, (2) Intensive immunosuppression post-transplant, (3) Anti-thymocyte globulin, (4) Combined peripheral blood and bone marrow allografts | Reduce alloreactivity of donor T-cells with granulocyte colony-stimulating factor (shift from T-helper 1 to T-helper 2 phenotype) and of both donor and recipient T-cells with anti-thymocyte globulin Improved engraftment due to the use of peripheral blood stem cells No need for graft manipulation Protocols are easily replicable at different institutions |
Morbidity from multiple drugs needed for post-transplant immune Increased risk of viral reactivation and opportunistic pathogens in the early post-transplant period due to anti-thymocyte globulin Unanswered question regarding non-inherited maternal and paternal antigens (for donor selection) Not as extensively studied in the setting of SCD |
| Post-transplant cyclophosphamide | Preferential deletion of proliferative alloreactive donor and recipient T-cells due to lack of expression of the enzyme aldehyde dehydrogenase 1 Reduce host T-cells responding to donor antigens peripherally post-transplant Intrathymic deletion of donor-reactive host T-cells (central tolerance) |
Reduced acute and chronic GvHD Expansion of regulatory T-cells that promote immune tolerance Replicable at any transplant center Used with either bone marrow or peripheral blood stem cell grafts (compared with GIAC protocol) Low likelihood of developing EBV-PTLD Low documented incidence of donor-derived malignancies |
Graft rejection chance is high (Bolanos-Meade et al. [31]) with the Johns Hopkins protocol alone, but is improved with the addition of thiotepa Potential acute toxicity from high doses of cyclophosphamide, including cardiac (type I agent, with hemorrhagic necrosis and heart failure), lung (pneumonitis and pulmonary fibrosis), bladder (associated with BK virus cystitis), secondary malignancy (chromosome 5 and 7 deletion signature, from alkylating agent exposure) Increased viral reactivation Increased risk of infertility secondary to additional alkylator therapy |
Legend: haplo-HSCT, haploidentical hematopoietic stem cell transplant; TCD, T-cell deplete; EBV, Epstein–Barr virus; PTLD, post-transplant lymphoproliferative disorder; IR, immune reconstitution; TCR, T-cell replete; GvHD, graft-versus-host disease.