Immune reconstitution after T-cell replete HLA haploidentical hematopoietic stem cell transplantation using high-dose post-transplant cyclophosphamide

Abstract

As HLA haploidentical related donors are quickly available, HLA haploidentical hematopoietic stem cell transplantation (haploHSCT) using high-dose post-transplant cyclophosphamide (PTCy) is now widely used. Recent basic and clinical studies revealed the details of immune reconstitution after T-cell replete haploHSCT using PTCy. T cells and NK cells in the graft proliferate abundantly at day 3 post-haploHSCT, and the PTCy eliminates these proliferating cells. After ablation of proliferating mature cells, donor-derived NK cell reconstitution occurs after the second week; however, recovering NK cells remain functionally impaired for at least several months after haploHSCT. PTCy depletes proliferating cells, resulting in the preferential accumulation of Treg and CD4+ T cells, especially the memory stem T cell (T SCM ) phenotype. T SCM capable of both self-renewal and differentiation into effector T cells may play an important role in the first month of immune reconstitution. Subsequently, de novo T cells progressively recover but their levels remain well below those of donor CD4+ T cells at the first year after haploHSCT. The phenotype of recovering T cells after HSCT is predominantly effector memory, whereas B cells are predominantly phenotypically naive throughout the first year after haploHSCT. B cell recovery depends on de novo generation and they are not detected until week 4 after haploHSCT. At week 5, recovering B cells mostly exhibit an unconventional transitional cell phenotype and the cell subset undergoes maturation. Recent advances in immune reconstitution have improved our understanding of the relationship between haploHSCT with PTCy and the clinical outcome.

Case report: HLA-haploidentical hematopoietic cell transplant with posttransplant cyclophosphamide in a patient with leukocyte adhesion deficiency type I

“…T-cell-memory phenotype skewing and inverted CD4/ CD8 ratio persisted until 5 months post-HCT. These posttransplant lymphocyte reconstitutions were similar to previous reports (24)(25)(26)(27)(28). Particularly, the rapid expansion of NK cells may be partly caused by comorbid CMV infections, and delayed T-cell reconstitution may have been affected by the relatively high dose of alemtuzumab in our case.…”

Epstein–Barr Virus Monitoring after an Allogeneic Hematopoietic Stem Cell Transplant: Review of the Recent Data and Current Practices in Canada

“…A recent meta-analysis showed that PTCy regimen versus ATG in allo-HSCT from unrelated donors was associated with a lower chance of developing EBV-related PTLD disease [36]. In the PTCy conditioning regimen, cyclophosphamide targets proliferating cells as NK and CD8+ T cells, but maintains CD4+ T cells in significant numbers compared to ATG, which could confer a clinical advantage to PTCy in maintaining control of EBV reactivation [37][38][39].…”

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment

“…In pediatric patients, adenovirus and cytomegalovirus remain frequent causes of transplant-related mortality [1][2][3][4][5][6][7][8] . While new approaches of HSCT such as αβT cell receptor (TCR) depletion or the use of post-transplant cyclophosphamide have expanded potential donor pools [9][10][11] , these approaches cause delayed T cell reconstitution 12,13 , impairing critical antiviral defenses 14 .…”