Table 1.

The rationale and potential shortcomings of the current approaches in haploidentical stem cell transplantation.

General approach/Modifications	Mechanism and rationale	Potential shortcomings
Complete/partial ex vivo T cell depletion	Most efficacious GVHD preventive method	↑ graft rejection ↑ NRM and possible ↑ RI due to delayed immune reconstitution
“Mega-dose” stem cells, ATG,  conditioning intensification	To prevent graft rejection by increasing inoculum and eliminating residual recipient immune cells with ATG and intensified conditioning	Immune reconstitution still delayed
Treg and Tcon co-infusion	Addition of Tcons to promote immune reconstitution while preventing GVHD with Tregs	Treg may decrease GvL effect Treg / Tcon ratio needs to be optimized
Allodepletion using anti-CD25  antibodies	ex vivo depletion of alloreactive T cells by targeting activation marker CD25 after incubation with recipients APCs	Treg also express CD25 Clinical efficacy not proven Possible effect on GvL response
Allodepletion with phototoxic dye	ex vivo depletion of alloreactive T cells with TH9402 that accumulates in activated T cells	Clinical efficacy not proven Possible effect on GvL response
Selective αβ T cell depletion	Preservation of γδ T cells (unlikely to induce GVHD while effective against infections with an innate-like response) while eliminating αβ T cells most responsive for aGVHD Potential to avoid post- transplant immunosuppression	Clinical efficacy not proven; however promising early data Possible effect on GvL response
Selective CD45RA+ T cell  depletion	Elimination of CD45RA+ naïve T cells (capable of precipitating GVHD) while preserving memory T cells (active against infections) Potential to avoid post- transplant immunosuppression	Clinical efficacy not proven Possible effect on GvL response
Alloanergization	Alloreactive T cells are anergized by blocking co- stimulatory CD80/86 signal	T cells are not depleted ↑ GVHD rate
High-dose post-transplantation cyclophosphamide  RIC/NMA conditioning	Eliminating the allo-activated T cells early after transplant without affecting stem cells. T cell preservation allows lower intensity conditioning extending transplantation to elderly patients Low incidence of cGVHD	Low cost GvHD incidence higher than after ex vivo T cell depletion; however similar with matched transplantation Higher leukemia relapse incidence after NMA conditioning
Myeloablative conditioning	To decrease relapse incidence in leukemia patients	↑ in NRM and possibly in GvHD
Peripheral blood as stem cell  source	To decrease relapse incidence and possible improve immune reconstitution through higher T cell content in PB	↑ in acute GvHD potential
Intensified immune suppression	To demeliorate immune reaction both ways G-CSF priming of BM and PB graft to induce T cell hyporesponsiveness	Higher aGVHD and cGVHD incidence
Post-transplant lymphocyte infusion after ex vivo T cell depleted transplantation	To treat disease relapse through GvL effect	Limited efficacy GVHD precipitation
Engineered donor lymphocytes  with a safety suicide switch	To prevent/treat disease relapse and improve immune reconstitution post-transplant. Safety switch allowing T cell suicide in case of GVHD precipitation => Higher T cell doses are possible	T cells are not targeted => While immune reconstitutive effect is demonstrated, GvL effect not yet clear
T cells with chimeric antigen  receptors	T cells engineered to recognize specific antigens (CD19) provides GvL effect without GVHD	Clinical efficacy after HaploSCT not shown yet

Legend: GVHD – graft-versus-host disease, NRM – non-relapse mortality, RI – relapse incidence, ATG – anti-thymocyte globulin, T_reg – regulatory T cells, T_con- conventional T cells, APCs – antigen presenting cells, GvL – graft versus leukemia effect, RIC – reduced-intensity conditioning, NMA – non-myeloablative conditioning, HaploSCT – haploidentical transplantation.