Best Practice & Research Clinical Haematology最新文献

Patients undergoing allogeneic haematopoietic cell transplantation are prone to complications caused by viral infections. Cytomegalovirus (CMV) considerably impacts transplantation as it frequently requires antiviral intervention that evokes substantial side effects depending on the antiviral drug. Intermittent antiviral treatment may become necessary if CMV DNAemia cannot be permanently suppressed, and drug resistance may emerge that hampers and prolongs treatment. Despite sedulous endeavours, vaccination against CMV is not yet available. This review concisely summarises current approaches in managing CMV infection comprising risk factors, diagnostics including indications for resistance testing, and therapeutic options from antiviral drugs to virus-specific T cells.

Allogeneic hematologic stem cell transplantation is a cornerstone in modern hematological treatment, yet its efficacy is compromised by acute Graft-versus-Host Disease. In acute Graft-versus-Host Disease, conditioning regimen induced epithelial damage leads to release of damage and pathogen associated molecular patters which in turns triggers activation of alloreactive donor T cells, ultimately resulting in destruction of healthy tissue. Advances in major histocompatibility complex typing and preclinical studies using tissue specific major histocompatibility complex deletion have illuminated the contributions of both, hematopoietic and non-hematopoietic cells to acute Graft-versus-Host Disease pathophysiology. Concurrently, high-throughput sequencing techniques have enabled researchers to recognize the significant impact of the intestinal microbiome and newly discovered metabolites in the pathophysiology of acute Graft-versus-Host Disease. In this review, we discuss the implications of major histocompatibility complex expression on hematopoietic and non-hematopoietic cells, the effect on the intestinal microbiome and the metabolic alterations that contribute to acute Graft-versus-Host Disease. By combining these findings, we hope to untangle the complexity of acute Graft-versus-Host Disease, ultimately paving the way for the development of novel and more effective treatmen options in patients.

Chimeric antigen receptor (CAR) T cell therapy has shown impressive clinical efficacy in B cell malignancies and multiple myeloma, leading to the approval of six CAR T cell products by the U.S. Food and Drug Administration (FDA) to date. However, broad application of these autologous (patient-derived) CAR T cells is limited by several factors, including high production costs, inconsistent product quality, contamination of the cell product with malignant cells, manufacturing failure especially in heavily pre-treated patients, and lengthy manufacturing times resulting in subsequent treatment delay. A potential solution to these barriers lies in the use of allogeneic “off-the-shelf” CAR T cells produced from healthy donors. Many efforts are underway to make allogeneic CAR T cells a safe and efficacious therapeutic option. In this review, we will discuss the major challenges that have to be addressed to successfully develop allogeneic CAR T cell therapies, specifically graft-versus-host disease (GVHD) and host-mediated immune rejection of the donor cells. Furthermore, we will summarize approaches that have been utilized to overcome these limitations, focusing on the use of gene editing technologies and strategies employing alternative cell populations as the source for allogeneic CAR T cell production.

Hematopoietic cell transplantation (HCT) represents a potentially curative therapeutic approach for various hematologic and non-hematologic malignancies. Human leukocyte antigen (HLA) matching is still the central selection criterion for HCT donors. Nevertheless, post-transplant complications, in particular graft-versus-host disease (GvHD), relapse of disease and infectious complications, represent a major challenge and contribute significantly to morbidity and mortality. Recently, non-classical HLA class I molecules, especially HLA-E, have gained increasing attention in the context of allogeneic HCT. This review aims to summarize the latest findings on the immunomodulatory role of HLA-E, which serves as a ligand for receptors of the innate and adaptive immune system. In particular, we aim to elucidate how (i) polymorphisms within HLA-E, (ii) the NKG2A/C axis and (iii) the repertoire of peptides presented by HLA-E jointly influence the functionality of immune effector cells. Understanding this intricate network of interactions is crucial as it significantly affects NK and T cell responses and thus clinical outcomes after HCT.

The importance of the HLA gene system in haematopoietic cell transplant outcomes was established early on and advances in both fields have led to ever increasing success of this clinical therapy. In large part, improvements in the understanding of HLA have been driven by the advancement in typing technologies. Each iteration of typing technology has improved the resolution of HLA typing, and often enabled the identification of polymorphism within the HLA loci. The discovery of the enormous amount of variation in the HLA genes, and the need to be able to characterise this for clinical HLA typing, has often resulted in a move away from one typing method to another more suited to typing of this complexity. Today, the gold standard for HLA typing are methods that can produce definitive HLA typing results.

HLA class II antigen presentation is modulated by the activity of the peptide editor HLA-DM and its antagonist HLA-DO, with their interplay controlling the peptide repertoires presented by normal and malignant cells. The role of these molecules in allogeneic hematopoietic cell transplantation (alloHCT) is poorly investigated. Balanced expression of HLA-DM and HLA-DO can influence the presentation of leukemia-associated antigens and peptides targeted by alloreactive T cells, therefore affecting both anti-leukemia immunity and the potential onset of Graft versus Host Disease. We leveraged on a large collection of bulk and single cell RNA sequencing data, available at different repositories, to comprehensively review the level and distribution of HLA-DM and HLA-DO in different cell types and tissues of the human body. The resulting expression atlas will help future investigations aiming to dissect the dual role of HLA class II peptide editing in alloHCT, and their potential impact on its clinical outcome.

A comprehensive knowledge of human leukocyte antigen (HLA) molecular variation worldwide is essential in human population genetics research and disease association studies and is also indispensable for clinical applications such as allogeneic hematopoietic cell transplantation, where ensuring HLA compatibility between donors and recipients is paramount. Enormous progress has been made in this field thanks to several decades of HLA population studies allowing the development of helpful databases and bioinformatics tools. However, it is still difficult to appraise the global HLA population diversity in a synthetic way. We thus introduce here a novel approach, based on approximately 2000 data sets, to assess this complexity by providing a fundamental synopsis of the most frequent HLA alleles observed in different regions of the world. This new knowledge will be useful not only as a fundamental reference for basic research, but also as an efficient guide for clinicians working in the field of transplantation.

The European society for Blood and Marrow Transplantation (EBMT) has a long-standing interest in the evaluation of hematopoietic cell transplantation. More than three decades ago, its members established a continental registry. Today, more than 700,000 patients have been registered, and information has been gathered on more than 800,000 transplants. This huge amount of information has allowed conducting multiple retrospective studies, evaluating changes in practices over time and for different categories of diseases, benchmarking outcome across EBMT affiliated centers, and increasingly serves to build synthetic comparators to evaluate the introduction of therapeutic innovations in the field of hematology. CAR-T cells therapies draw on human and technical resources that are also used to deliver HCT; they elicit side effects that require the implementation of risk mitigation plans; they are living drugs that persist in the body of the recipient and thus deserve prolonged follow-up; the introduction of CAR-T cells in the pharmacopeia is likely to significantly impact on the practice of BMT; for all these reasons and even before the first approvals of CAR-T Cells in Europe, EBMT engaged in a project aiming at complementing the EBMT Registry with a Cellular Therapy Form, with the objective to register CAR-T cells treated patients and collect information on their short-, middle- and long-term outcome. The goal is to provide EBMT investigators with a tool for primary analyses of the collected information and to support secondary use of data transferred at the individual level to Marketing Authorization Holders and other interested parties, to fulfill their obligations to health authorities and further evaluate the actual medical values of CAR-T Cells in different contexts and indications. The EBMT Registry received a positive opinion from the European Medicines agency in 2019, and five years later contains information on more than 9.000 treated patients. This article describes the journey to start this new activity, lessons to be drawn in view of improving the collection of real-world data, and what existing information tells us in terms of patient access.

The human adaptive immune repertoire is characterized by specificity and diversity to provide immunity against past and future tasks. Such tasks are mainly infections but also malignant transformations of cells. With its multiple lines of defense, the human immune system contains both, rapid reaction forces and the potential to capture, disassemble and analyze strange structures in order to teach the adaptive immune system and mount a specific immune response. Prevention and mitigation of autoimmunity is of equal importance. In the context of allogeneic hematopoietic cell transplantation (HCT) specific challenges exist with the transfer of cells from the adapted donor immune system to the immunosuppressed recipient. Those challenges are immunogenetic disparity between donor and host, reconstitution of immunity early after HCT by expansion of mature immune effector cells, and impaired thymic function, if the recipient is an adult (as it is the case in most HCTs). The possibility to characterize the adaptive immune repertoire by massively parallel sequencing of T-cell receptor gene rearrangements allows for a much more detailed characterization of the T-cell repertoire. In addition, high-dimensional characterization of immune effector cells based on their immunophenotype and single cell RNA sequencing allow for much deeper insights in adaptive immune responses. We here review, existing – still incomplete – information on immune reconstitution after allogeneic HCT. Building on the technological advances much deeper insights into immune recovery after HCT and adaptive immune responses and can be expected in the coming years.