Advances in cell and gene therapy最新文献

Transfusion-dependent thalassemia occurs globally and represents a major growing health problem worldwide. In majority, the disorder involves deficient or absent synthesis of the β-globin chains that constitute hemoglobin molecules and results in chronic hemolytic anemia. Subjects with the disorder must adhere to continuous red blood cell replacement program to sustain life; unfortunately such approach comes with undesirable and life-threatening complications. Without regular transfusions, thalassemic patients are prone to develop skeleton deformities, hepatosplenomegaly, and iron overload. Allogeneic hematopoietic cell transplantation preferably from HLA-matched sibling donor is widely accepted curative therapy. Gene therapy, although at its infancy, is emerging as an alternate curative option, however, with its own unique challenges. This article aims to review advances, challenges, controversies, and future prospects of allogeneic hematopoietic cell transplantation and gene therapy in subjects with transfusion dependent β-thalassemia.

There is a need to create improved treatments for HIV infection. Growing evidence indicates that HIV treatment strategies must target and reduce viral replication in lymphoid follicles where HIV replication is most concentrated. In this mini-review, three cell therapy approaches are described: CAR-T and CAR-NK cells, adoptive transfer of autologous HIV-specific T cells, and HIV-resistant cells. The potential for these innovative strategies to reduce viral replication in follicles and the potential of combining cell therapies with other treatment strategies to achieve a complete eradication of HIV is discussed.

Multiple myeloma is an incurable hematologic malignancy characterized by recurrent relapses and remissions. Immunotherapeutic agents such as immunomodulatory drugs and monoclonal antibodies have improved outcomes for relapsed refractory disease, however, the majority of patients still succumb to complications of relapsed disease. CAR T cells provide a mechanism of direct antigen specific myeloma cytotoxicity without graft versus host disease. Different complications such as cytokine release syndrome (CRS) or CAR T cell related encephalopathy syndrome (CRES) may occur which require prompt interventions. Early phase clinical trials with CAR T cell therapies have demonstrated very promising outcomes for relapsed refractory myeloma patients, especially when specific for the B cell maturation antigen (BCMA).

Primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) are chronic disorders that may extend over years or decades. Therapy tends to be conservative, but once marrow fibrosis and peripheral cytopenias become the dominant characteristics, prognosis is poor. Hematopoietic cell transplantation (HCT) is the only treatment with curative potential, leading to survival in remission in 35%-70% of patients. However, HCT is associated with risks, and despite the development of numerous risk scoring systems, optimal timing of HCT remains controversial. The identification of “driver mutations” in JAK2, MPL1, and CALR, and prognostically relevant additional mutations, may assist in the decision-making process. While patients with type 1 CALR mutations generally have a superior prognosis, absence of all driver mutations is associated with inferior outcome. Mutations in ASXL1, SRSF2, IDH1/2, and EZH2 are linked to more rapid disease progression and, along with biallelic TP53 mutations, leukemic transformation. The strongest risk factor is the presence of multiple mutations. By MIPSS70 criteria, considering mutations, median survival was 27 years for the best risk group, but 2.3 years for the highest-risk group. The presence of nondriver mutations, particularly in the absence of CALR mutations, and association with adverse cytogenetics, should lead to consideration of HCT. But the role of mutations has to be assessed in the context of the overall presentation. Unfortunately, risk factors that affect the natural history of the disease also impact post-HCT outcome. Needed are innovative transplant strategies, also including pre-HCT and post-HCT adjuvant therapy.

Two Chimeric Antigen Receptor (CAR) T-cell therapies are now approved for the treatment of relapsed and refractory large cell lymphomas, with many others under development. The dawn of CAR T-cell therapy in non-Hodgkin Lymphoma (NHL) has been characterized by rapid progress and high response rates, with a subset of patients experiencing durable benefit. In this review, we describe commercially available and investigational CAR T-cell therapies, including product characteristics and clinical outcomes. We review patient selection, with an emphasis on sequencing cell therapies including autologous and allogeneic stem cell transplantation. Finally, we discuss durability of response, highlighting mechanisms of escape and investigational approaches to prevent and treat relapse after CAR T cell therapy.

Mechanism of action of GO in AML

Illustrator credit: Claudia Bentley

The Center for International Blood and Marrow Transplant Research (CIBMTR) is a research collaboration between the National Marrow Donor Program (NMDP)/Be The Match and the Medical College of Wisconsin (MCW). The CIBMTR collaborates with the global scientific community to advance hematopoietic cell transplantation (HCT) and cellular therapy worldwide to increase survival and enrich quality of life for patients. The observation research program within CIBMTR is organized into 15 working committees. This review is aiming to highlight the observational research studies published by the CIBMTR Lymphoma Working committee over the last 5 years (2013-18) and to summarize how these studies have impacted the field by helping inform clinical practice in scenarios where prospective data from high quality randomized trials were not available or where owing to the rarity of a particular transplant indication such data were unlikely to be generated, outside the setting of a large observational research database. The salient findings reviewed include; (a) studies supporting role of autologous HCT in diffuse large B-cell lymphoma (DLBCL) patients with sensitive relapse of disease within 1 year of diagnosis, (b) role of autologous HCT vs allogeneic HCT in follicular lymphoma patients with early therapy failure, (c) prognostic scoring system development for classical Hodgkin lymphoma and DLBCL patients with prior autograft failure, (d) defining the role of alternative donor transplantation in lymphomas, (e) evaluating appropriate conditioning regimens for HCT in lymphoma, and (f) outcomes of HCT in rare lymphoid malignancies.

Mesenchymal stem/stromal cells (MSCs) infusions are a promising investigational treatment strategy for steroid-refractory acute graft-versus-host disease (GVHD). Herein we describe the rationale for their use in acute GVHD, the clinical data reported from animal and human studies to date, and we highlight recent areas of research and investigation that provide the basis for improvements in the next generation of studies.

In the early years of hematopoietic cell transplantation (HCT), matching of patients and donors was poorly understood and complications related to genetic (especially HLA) mismatching were profound, resulting in a very high incidence of fatal graft-versus-host disease (GVHD). This essentially limited the choice of a donor to a sibling, and as the understanding of HLA improved, defined the donor as an HLA-identical sibling. As patient outcomes improved, the use of an unrelated donor (URD) became more common. Later, with the advent of URD registries and improved HLA typing techniques, the use of an URD overtook that of an HLA-identical sibling in frequency both in Europe and in the United States (US). Increasing confidence in our ability to manage and prevent the immune complications of HCT led to the use of HLA-mismatched donors being expanded, in the setting of umbilical cord blood (UCB) and haploidentical transplantation. In 2018, it is unusual for a patient not to go to transplant due to the lack of a suitable donor option. In this manuscript, we describe the impact of genetic factors, in particular HLA, and the technologies for typing these, on the outcomes of HCT. We highlight both well-accepted donor selection practices and newer or more controversial advances in donor selection.

CD34⁺ cell enumeration is a critical parameter used to determine the timing of apheresis collections of hematopoietic progenitor cell products (HPC(A)). Automated hematology analyzers equipped with flow cytometry capabilities may be a solution to the problem of limited access to standard flow cytometry testing. We compared CD34⁺ cell enumeration using a reference flow cytometry procedure employing modified International Society of Hematotherapy and Graft Engineering (ISHAGE) analysis with a hematology analyzer/flow cytometer hybrid (CELL DYN (CD)Sapphire) using a sequential gating analysis designed to emulate the ISHAGE gating strategy. CD34⁺ cell values obtained from the ISHAGE and CD Sapphire analysis was plotted and compared in a linear regression analysis which showed a high degree of correlation (R² = 0.96). No statistically significant (P = 0.53) differences in CD34⁺ cell enumeration values were observed between the flow cytometer and automated hematology analyzer using manual analysis schema. We have demonstrated that an automated hematology analyzer equipped with a flow module can provide CD34⁺ cell enumeration results in the peripheral blood for clinical decision algorithms without the need for a dedicated flow cytometry laboratory.