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KEY CONCEPTS
The efficacy of allogeneic hematopoietic cell transplantation (HCT) is based on the graft-versus-tumor effect, by which the donor immune system achieves immunologic control of the tumor via the human leukocyte antigen (HLA) system.
Three key barriers to successful HCT are relapse caused by failure of immunologic control of the underlying disease, graft-versus-host disease (GVHD), and infectious complications, and studies are underway to improve on these complications.
Strategies to mitigate relapse include using prophylactic donor lymphocyte infusions, chimeric antigen receptor modified T-cells derived typically from the patient, and natural killer (NK) T-cells.
In contrast to B and T lymphocytes, NK T-cells do not express rearranged, antigen-specific receptors and as a consequence have a low risk for GVHD, allowing the use of allogeneic NK cells. An allogeneic product is advantageous because it is readily available and furthermore uses healthy immune cells for product production.
The pathogenesis of GVHD is complex and includes the differentiation of naïve donor T-cells into effector cells that attack host tissues. Increasing numbers of HLA misma tches are associated with higher incidence of GVHD and transplant-related mortality. Grades II to IV acute GVHD occur in 25% to 60% of cases with matched related donors and 45% to 70% of cases with matched unrelated donors. Recent improvements in GVHD include the approval of ruxolitinib for steroid-refractory acute GVHD and the use of posttransplant cyclophosphamide to decrease the incidence of GVHD.
Viral infection is a major cause of death after HCT, resulting from cellular and humoral immune deficiency. Viral infections of particular relevance after HCT are cytomegalovirus, Epstein-Barr virus, the polyoma viruses BK and JC, adenovirus, and human herpesvirus 6. Pharmacotherapy for these infections has limited efficacy. Viral-specific T-cells directed against these infections is feasible to generate and effective.
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The efficacy of allogeneic hematopoietic cell transplantation (HCT) in hematologic malignancies can in large part be attributed to a graft-versus-tumor (GVT) effect, by which the donor immune system achieves immunologic control of the tumor. As such, it is the prototype of cellular therapy. The human leukocyte antigen (HLA) system is fundamental to transplant biology. The HLAs are highly polymorphic proteins that have a key role in antigen presentation and immune regulation. Class I HLAs are expressed on the surfaces of all nucleated cells; class II are expressed on specialized antigen-presenting cells (APCs), such as macrophages, dendritic cells, and B cells.
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Peptides derived from microbes are presented on class I HLAs to CD8+ T-cells and result in immunologic destruction of infected cells; class II HLAs are recognized by CD4+ T-cells. T-cell activation requires costimulatory signals from the APC, specifically CD80/86 binding to CD28 or LFA-3 binding to CD2.1 Absence of a costimulatory signal results in T-cell anergy, which is a key mechanism of peripheral immune tolerance to self-antigen in normal immune regulation. Early after transplantation, there is a “cytokine storm”; release of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), ...