Abstract

Hematopoietic stem cell transplantation from a haploidentical donor is increasingly used and has become a standard donor option for patients lacking an appropriately matched sibling or unrelated donor. Historically, prohibitive immunological barriers resulting from the high degree of HLA-mismatch included graft-vs.-host disease (GVHD) and graft failure. These were overcome with increasingly sophisticated strategies to manipulate the sensitive balance between donor and recipient immune cells. Three different approaches are currently in clinical use: (a) ex vivo T-cell depletion resulting in grafts with defined immune cell content (b) extensive immunosuppression with a T-cell replete graft consisting of G-CSF primed bone marrow and PBSC (GIAC) (c) T-cell replete grafts with post-transplant cyclophosphamide (PTCy). Intriguing studies have recently elucidated the immunologic mechanisms by which PTCy prevents GVHD. Each approach uniquely affects post-transplant immune reconstitution which is critical for the control of post-transplant infections and relapse. NK-cells play a key role in haplo-HCT since they do not mediate GVHD but can successfully mediate a graft-vs.-leukemia effect. This effect is in part regulated by KIR receptors that inhibit NK cell cytotoxic function when binding to the appropriate HLA-class I ligands. In the context of an HLA-class I mismatch in haplo-HCT, lack of inhibition can contribute to NK-cell alloreactivity leading to enhanced anti-leukemic effect. Emerging work reveals immune evasion phenomena such as copy-neutral loss of heterozygosity of the incompatible HLA alleles as one of the major mechanisms of relapse. Relapse and infectious complications remain the leading causes impacting overall survival and are central to scientific advances seeking to improve haplo-HCT. Given that haploidentical donors can typically be readily approached to collect additional stem- or immune cells for the recipient, haplo-HCT represents a unique platform for cell- and immune-based therapies aimed at further reducing relapse and infections. The rapid advancements in our understanding of the immunobiology of haplo-HCT are therefore poised to lead to iterative innovations resulting in further improvement of outcomes with this compelling transplant modality.

Highlights

  • Allogeneic hematopoietic cell transplantation (HCT) remains a curative approach for many patients with malignant and non-malignant hematologic indications [1]

  • These results were subsequently consolidated in a larger cohort of 112 AML patients, where transplantation from a natural killer (NK)-cell alloreactive donor was associated with a significantly lower relapse rate (3% compared to 47%) when transplanted in complete remission and better event-free survival (EFS) when transplanted in relapse (34% compared to 6%) or CR (67% compared to 18%) [144]

  • Bivariate correlation analysis showed that the proportion of myeloid DCs (mDCs), but not Dendritic cells (DCs) and plasmacytoid DCs (pDCs), in white blood cells (WBCs) was significantly correlated with the recovery of Vδ2+ T cells after haplo-HCT

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Summary

INTRODUCTION

Allogeneic hematopoietic cell transplantation (HCT) remains a curative approach for many patients with malignant and non-malignant hematologic indications [1]. Ruggeri et al first established that a NK-cell alloreactivity of the donor toward recipient (based on KIR receptor-ligand mismatch in the GVL direction and presence of alloreactive clones against recipient targets) lowered the AML relapse risk in the context of ex vivo depleted haplo-HCT [72] These results were subsequently consolidated in a larger cohort of 112 AML patients, where transplantation from a NK-cell alloreactive donor was associated with a significantly lower relapse rate (3% compared to 47%) when transplanted in complete remission and better EFS when transplanted in relapse (34% compared to 6%) or CR (67% compared to 18%) [144]. These data show that haplo-HCT provides a comparable or even expedited neutrophil recovery compared to standard matched donor-HCT

Dendritic Cells
Haploidentical Donor Lymphocyte Infusions
Findings
CONCLUSION
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