Advances in cell and gene therapy最新文献

Viral infections are common causes of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). In particular, allogeneic HSCT induces a profound immunocompromised state that may last up to 24 months post transplant, or longer in case of chronic graft vs host disease (GVHD). The common viruses affecting HSCT patients are HSV, VZV, CMV, EBV, adenovirus, HHV6, BK virus and upper respiratory viruses such as influenza, parainfluenza, and RSV. These infections typically occur in three distinct phases: pre-engraftment, early postengraftment, and late postengraftment. This review will have two major sections, the first will discuss the epidemiology and natural history of different viral infections and second part will discuss preventive and therapeutic strategies among HSCT patients.

Chronic graft-versus host disease (GvHD) affects approximately 30%-70% of patients undergoing hematopoietic stem cell transplantation. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that is often used as a second-line therapeutic option for steroid-resistant chronic GvHD. There is a several week delay between the onset of ECP and clinical improvement in symptoms. Thus, a biomarker that precedes improvement in disease activity or predicts response to therapy would be of clinical value. In this study, we sought to determine how previously studied GvHD biomarkers change over a course of ECP therapy. Seven chronic GvHD biomarkers (ST2, MMP-3, CXCL9, CXCL10, CXCL11, BAFF, and CD163) were measured by ELISA in 16 patients before and after 2 months of ECP. Initial ST2 levels were high compared to healthy donors and patient samples required more than the manufacturer-recommended dilution. The median ST2 level decreased over the first 2 months of treatment (193 v. 96 ng/mL, P = 0.03); the other biomarkers did not change significantly. Serial ST2 levels at 2, 4, and 6 months after ECP initiation showed that ST2 levels declined over the course of therapy. The results of this study show that ST2 is substantially elevated and declines during therapy in patients who receive ECP as a second-line therapy for chronic GvHD.

Graft-versus-host (GVHD) is an important cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). As donor T cells are recognized as key drivers of GVHD, some approaches to prevent GVHD have focused on T cell depletion of the allograft. In this review we summarize methods and outcomes of ex vivo T cell depleted (TCD) HCT with a focus on CD34+ selection. This platform is efficacious in preventing acute and chronic GVHD across a wide range of hematologic malignancies, and with the exception of chronic myeloid leukemia, is not associated with adverse relapse or survival outcomes compared to conventional GVHD prophylaxis platforms. In retrospective comparisons recipients of CD34+ selected HCT have higher rates of GVHD-free relapse-free survival (GRFS) than conventional HCT counterparts. Although CD34+ selected allografts require myeloablative and antithymocyte-globulin based conditioning to support engraftment, abrogation of calcineurin inhibitors and methotrexate in this approach reduces its toxicity such that it can be considered in select older and more comorbid patients who could benefit from ablative HCT. A trial comparing GVHD prophylaxis regimens (BMT CTN 1301, NCT 02345850) has completed accrual and will be the first to compare CD34+ selected HCT with conventional HCT in a randomized prospective setting. Its findings have a potential to establish CD34+ selected HCT as a new standard-of-care platform for GVHD prevention.

Haploidentical hematopoietic cell transplantation (haplo-HCT) using either T-cell depletion or T-cell repletion (Beijing protocol or post-transplantation cyclophosphamide) has shown great advancements in recent years. Haplo-HCT can achieve comparable outcomes for transplantation from matched sibling donors and unrelated donors and has been used increasingly worldwide. For almost every patient, multiple haploidentical donors are available. Therefore, it is necessary to choose the best donor. However, there is no universal consensus on donor selection. The aim of this review was to discuss the general principles of and controversial factors related to donor selection. Several principles have been widely accepted. For example, human leukocyte antigen disparity is no longer taken into account, donor-specific antibodies should be avoided, and younger donors and ABO matches are preferred. However, factors such as donor gender, family relationship, cytomegalovirus serological status, and natural killer cell alloreactivity are still controversial. Moreover, the factors may depend on the transplantation regimen. Finally, we summarize practical points for donor selection according to different haplo-HCT protocols.

Relapse is the main cause of treatment failure in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and limits the curative potential of allogeneic blood stem cell transplantation (allo-HCT). Many patients can either not tolerate or do not achieve durable remissions through commonly used treatment options such as salvage chemotherapy, donor lymphocyte infusions (DLI), and/or second transplants. Thus, patients who relapse after allo-HCT have a very poor prognosis with the currently available therapies implicating the great medical need for relapse prevention. After having demonstrated efficacy and tolerability as salvage therapy in patients with myeloid malignancies who relapse after allo-HCT the hypomethylating agents azacitidine (Aza) and decitabine (DAC) have also been tested as prophylactic and preemptive approaches in patients with AML and MDS after allo-SCT. Here, we summarize the current literature reporting on results from prospective trials and retrospective analyses regarding the prophylactic and preemptive use of Aza and DAC after allo-SCT and aim to give an answer if these hypomethylating agents (HMA) are able to prevent relapse of myeloid malignancies after allo-HCT.

Natural killer (NK) cells belong to innate lymphoid immune cells that contribute to antitumor responses without requiring prior sensitization. There is strong evidence that NK cells may induce graft-vs-leukemia (GvL) effect without causing graft-vs-host disease (GvHD), and significant efforts are currently undertaken to design and optimize NK cell-based immunotherapeutic strategies against human cancers, particularly against leukemias. However, the results of a number of adoptive NK cell transfer studies have been somewhat disappointing. This may be explained with difficulties in integrating the sequentially appearing activating signals into a directed NK cell response and may also be due to the lack of longevity of the transferred NK cells. The recent understanding that NK cells share developmental and homeostatic properties with T cells led to the hypothesis that NK cells should be able to elicit an (antigen-specific) recall response and should as such theoretically confer the potential for self-renewal and clonal expansion which may translate into longevity. Although immunological memory is per se a hallmark of the adaptive immune system, recent studies performed in mice and humans indicate that NK cells may indeed acquire (under certain conditions) features of adaptive immune cells. This review pursues the aim of providing a general understanding of the cellular and molecular aspects of various forms of memory NK cells with inherent antitumor properties and attempt to describe the translation of this knowledge into recent clinical adoptive transfer protocols with the aim of optimally harnessing the memory NK cell response to certain leukemias.

This report summarizes the 5th annual symposium on minimal residual disease (MRD) testing in multiple myeloma gathered experts from academia, industry and the FDA in New York City on 14 September 2018. Three recommendations were made: (a) MRD testing should be performed in patients who achieve a very good partial response (VGPR) in addition to complete response (CR); (b) MRD negativity at one tumor cell in 1 000 000 bone marrow cells (10⁻⁶) should be considered as a response category alongside the current definition of MRD negativity at 10⁻⁵; and (c) clinical trials reports should specify the sensitivity of MRD testing as well as the applied threshold for MRD negativity (ie, 10⁻⁵ or 10⁻⁶), and if possible report outcome data for both MRD thresholds. Overall, as discussed at the meeting, there is already solid evidence that bone marrow based MRD assessment is one of the strongest prognostic factors in multiple myeloma, and deeper responses correlate with increasingly favorable outcomes. Indeed, achieving MRD negativity appears to be more important than what treatment was used to get there. Going forward, there is a need for clinical trials focusing on MRD-directed therapy to determine the role of MRD testing in everyday clinical decision-making. Standardization of MRD testing and harmonization across centers will make it easier to learn from common experiences. Ongoing efforts are anticipated to establish MRD status as a regulatory endpoint for accelerated drug approval in multiple myeloma in the near future.

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).