Almanac 2012, cell therapy in cardiovascular disease: The national society journals present selected research that has driven recent advances in clinical cardiology

The rapid translation from bench to bedside that has been seen in the application of regenerative medicine to cardiology has led to exciting new advances in our understanding of some of the fundamental mechanisms related to human biology. The first generation of cells used in phase I–II trials (mainly bone marrow mononuclear cells) are now entering phase III clinical trials with the goal of producing a cell based therapeutics that can change the outcome of cardiac disease. First generation cell therapy appears to have addressed safety concerns as well as showing ‘activity’ in numerous published meta-analyses. With the knowledge gained to date, the field is moving towards the next generation of cells—the ‘engineered’ cell—that has been developed to display a phenotype that will further enhance the myocardial repair/salvage process. This almanac review covers the latest basic research that may soon have application to humans as well as the results of the latest clinical trials.     

Development of cell adhesion molecule antagonists as therapeutics for asthma and COPD

Airway inflammation is a hallmark of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Cell adhesion molecules play critical roles in the recruitment and migration of cells to sites of inflammation. Not surprisingly, these receptors have garnered the attention of the pharmaceutical industry as targets for the development of drugs to treat inflammatory and autoimmune diseases. Although several potential cell adhesion targets exist, development of compounds for pulmonary indications has centered around the selectins and the integrin VLA-4. In vitro and in vivo studies have implicated these receptors in the recruitment of inflammatory cells to the lung as well as to key cellular activation pathways. Several first generation compounds are currently in clinical development for asthma. Positive data from a phase II clinical trial using an inhaled formulation of a selectin antagonist has recently been reported. Initial results from clinical trials using first generation VLA-4 antagonists have been less promising but additional trials with more fully optimized compounds are underway. Results from these trials will provide insight into what the future holds for this exciting new class of drugs to treat pulmonary diseases.     

Advance in bone marrow derived cell therapy:CD31-expressing cells as next generation cardiovascular cell therapy

In the recent past,bone marrow(BM)-derived cells have been used to regenerate damaged cardiovascular tissues post myocardial infarction (MI).Recent clinical trials have shown controversial results in recovering damaged cardiac tissue. New progress has shown that the underlying mechanisms of cell-based therapy relies more heavily on humoral and paracrine effects rather than on new tissue generation.However,studies have also reported the potential of new endothelial cell generation from BM cells.Thus,efforts have been made to identify cells having higher humoral or therapeutic effects as well as their surface markers.Specifically, BM-derived CD31~+ cells were isolated by a surface marker and demonstrated high angio-vasculogenic effects. I will present recent advances in the therapeutic use of BM-derived cells and the usefulness of CD31~+ cells as a next generation cell therapy.     

Gene therapy for inborn and acquired immune deficiency disorders

Gene therapy has been under development as a way to correct inborn errors for over 20 years. Immune deficiencies are favorable candidates for gene therapy because of the potential selective advantage of genetically corrected cells in these conditions. Gene therapy for immune deficiencies has been the only application to show incontrovertible benefit in clinical trials to date. Despite the success in treating the underlying disease, there have been two cases of insertional oncogenesis reported in one of these early phase trials. Gene therapy approaches and clinical trials for several inborn as well as acquired immune deficiencies will be reviewed.     

The proteasome: a novel therapeutic target in haematopoietic malignancy

The proteasome plays a key role in regulating protein degradation in eukaryotic cells. A range of synthetic inhibitors of proteasome activity have been developed which have helped elucidate its role in the cell. These inhibitors have selectively induced apoptosis in malignant cells in vitro suggesting that the proteasome may be a novel therapeutic target. First generation proteasome inhibitors are currently showing promise in phase II/III clinical trials for patients with multiple myeloma.     

The Proteasome: A Novel Therapeutic Target in Haematopoietic Malignancy

The proteasome plays a key role in regulating protein degradation in eukaryotic cells. A range of synthetic inhibitors of proteasome activity have been developed which have helped elucidate its role in the cell. These inhibitors have selectively induced apoptosis in malignant cells in vitro suggesting that the proteasome may be a novel therapeutic target. First generation proteasome inhibitors are currently showing promise in phase II/III clinical trials for patients with multiple myeloma.     

Update on the use of stem cells for cardiac disease

Major advances have recently been made in our understanding of stem cell biology, and in the application of stem cells to treat cardiac disease. Resident cardiac stem cells have now been described and the long-accepted paradigm of the adult mammalian heart as an organ without regenerative capacity has been questioned. Various stem-cell-based approaches for ameliorating cardiac disease have been shown to be beneficial in animal models and are now being trialled in humans, with several phase I clinical studies already completed. Although these clinical studies lacked adequate placebo controls, they have consistently shown promising results. If confirmed by larger phase II/III trials, it is possible that within a few years a powerful new therapeutic option may be available for the burgeoning number of patients suffering from myocardial ischaemia and/or other cardiac disorders.     

CD34+ Stem Cells: Promising Roles in Cardiac Repair and Regeneration

Cell therapy has received significant attention as a novel therapeutic approach to restore cardiac function after injury. CD34-positive (CD34⁺) stem cells have been investigated for their ability to promote angiogenesis and contribute to the prevention of remodelling after infarct. However, there are significant differences between murine and human CD34⁺ cells; understanding these differences might benefit the therapeutic use of these cells. Herein we discuss the function of the CD34 cell and highlight the similarities and differences between murine and human CD34 cell function, which might explain some of the differences between the animal and human evolutions. We also summarize the studies that report the application of murine and human CD34⁺ cells in preclinical studies and clinical trials and current limitations with the application of cell therapy for cardiac repair. Finally, to overcome these limitations we discuss the application of novel humanized rodent models that can bridge the gap between preclinical and clinical studies as well as rejuvenation strategies for improving the quality of old CD34⁺ cells for future clinical trials of autologous cell transplantation.     

B‐cell receptor signalling and its crosstalk with other pathways in normal and malignant cells

The physiology of B cells is intimately connected with the function of their B‐cell receptor (BCR). B‐cell lymphomas frequently (dys)regulate BCR signalling and thus take advantage of this pre‐existing pathway for B‐cell proliferation and survival. This has recently been underscored by clinical trials demonstrating that small molecules (fosfamatinib, ibrutinib, idelalisib) inhibiting BCR‐associated kinases (SYK, BTK, PI3K) have an encouraging clinical effect. Here we describe the current knowledge of the specific aspects of BCR signalling in diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukaemia (CLL) and normal B cells. Multiple factors can contribute to BCR pathway (dys)regulation in these malignancies and the activation of ‘chronic’ or ‘tonic’ BCR signalling. In lymphoma B cells, the balance of initiation, amplitude and duration of BCR activation can be influenced by a specific immunoglobulin structure, the expression and mutations of adaptor molecules (like GAB1, BLNK, GRB2, CARD11), the activity of kinases (like LYN, SYK, PI3K) or phosphatases (like SHIP‐1, SHP‐1 and PTEN) and levels of microRNAs. We also discuss the crosstalk of BCR with other signalling pathways (NF‐κB, adhesion through integrins, migration and chemokine signalling) to emphasise that the ‘BCR inhibitors’ target multiple pathways interconnected with BCR, which might explain some of their clinical activity.     

Implications of recent neoadjuvant clinical trials on the future practice of radiotherapy in locally advanced rectal cancer

Over the last two decades, the standard treatment for locally advanced rectal cancer(LARC) has been neoadjuvant chemoradiotherapy plus total mesorectal excision followed by adjuvant chemotherapy. Total neoadjuvant treatment(TNT) and immunotherapy are two major issues in the treatment of LARC. In the two latest phase Ⅲ randomized controlled trials(RAPIDO and PRODIGE23), the TNT approach achieved higher rates of pathologic complete response and distant metastasis-free survival than conventional ch...     

Gene therapy with helper-dependent adenoviral vectors: current advances and future perspectives

Recombinant Adenoviral vectors represent one of the best gene transfer platforms due to their ability to efficiently transduce a wide range of quiescent and proliferating cell types from various tissues and species. The activation of an adaptive immune response against the transduced cells is one of the major drawbacks of first generation Adenovirus vectors and has been overcome by the latest generation of recombinant Adenovirus, the Helper-Dependent Adenoviral (HDAd) vectors. HDAds have innovative features including the complete absence of viral coding sequences and the ability to mediate high level transgene expression with negligible chronic toxicity. This review summarizes the many aspects of HDAd biology and structure with a major focus on in vivo gene therapy application and with an emphasis on the unsolved issues that these vectors still presents toward clinical application.     

Temperature gradient dissociation of red cell antigen-antibody complexes in the polybrene technique

Summary . The automated Polybrene technique for the detection of red cell antibodies has been adapted for the study of the thermal properties of various red cell antigen-antibody reactions. A continuous flow of antibody-induced red cell aggregates was subjected to gradually increasing temperature. The results produced ‘temperature gradient dissociation curves’ (TGDC) which represented not the influence of temperature on antibody uptake but the dissociation of already established immunological bonds. Temperature of dissociation was influenced by the thermal properties of the antibodies and by their concentration. Antibodies could be classified into ‘cold’, ‘intermediate’ and ‘warm’ reacting groups. The technique was also applicable to the study of antibodies that occur on sensitized red cells and, particularly, to patients with acquired haemolytic anaemia. Determination of TGDC has provided a new approach to the study of autoimmune diseases, and may have significant clinical implications.     

New cytokines and their role in supportive care

Several cytokines stimulating hematopoiesis, mainly lineage restricted, are already widely used in supportive care to correct myelosuppression or anaemia (GM-CSF, G-CSF, EPO). The new growth factor are tested in preclinical or clinical studies to abrogate other anti-cancer therapy side-effects (thrombocytopenia, mucositis etc.). IL-3 has been shown to have only limited effect on neutrophils and platelets production respectively. IL-6 and IL-11 have been tested to improve thrombocytopenia and mucositis (IL-11). Thrombopoetin (TPO, c-mpl) is tested in clinical trials and shows very strong effect on platelet counts. Stem cell factor (SCF) has shown to improve progenitor cell mobilisation, particularly in combination with other cytokines. The new promising factor, FLT-3 ligand, combines effect on hematopoiesis with effect on dendritic cells generation. The new group of synthetic cytokines (daniplestim, myelopoetin, promegapoetin and progenipoetin) is now tested in preclinical and clinical studies. Mucositis could be influenced by new keratinocyte growth factor (KGF), which is now in phase I trials.     

Multipotent Mesenchymal Stromal Cells for Pulmonary Fibrosis?

With the combination of ideologic beliefs and the will to survive, fraught patients and determined clinicians seek alternative therapies for treatment of terminal conditions, such as idiopathic pulmonary fibrosis. Unfortunately, the need for treatment has supported the growth of unapproved stem cell therapy over the years spanning across many countries. The reality, however, is that the science behind this therapy is lagging. While there have been promising results from phase I trials, there remain multiple reasons that “stem cells” are not ready for clinical application, starting from a gap in understanding at the bench research level, all the way to optimal clinical application in order to provide effective therapy.     

AIDS疫苗研究进展

AIDS疫苗研究过程充满了坎坷和挫折。第一代基于gp120蛋白抗原的AIDS疫苗在欧美和泰国的Ⅲ期临床试验先后失败;代表第二代疫苗设计的Merck公司的腺病毒载体T细胞疫苗不但未提供保护性免疫,反而在特定人群中增加了感染几率。但科学家们仍不断推出新的疫苗设计思路,如免疫原筛选策略和基于结构生物学的免疫原设计策略等。当AIDS疫苗研究走完第25个年头的时候,在泰国开展的AIDSVAXB／E初始-ALvAC-HIV加强免疫的Ⅲ期临床试验中终于观察到了部分的保护效果,这一结果重新点燃了人们对AIDS疫苗研制成功的信心。     

Prognostic discrimination for early chronic phase chronic myeloid leukemia in imatinib era: comparison of Sokal,Euro, and EUTOS scores in Korean population

Adoptive transfer of tumor-reactive T cells into cancer patients with the intent of inducing a cytotoxic anti-tumor effector response and durable immunity has long been proposed as a novel therapy for a broad range of malignancies; however, local and systemic tolerance mechanisms have hindered the generation of effective T cell therapies and limited the clinical efficacy of this approach in cancer patients. Chimeric antigen receptors (CARs) are recombinant receptors that comprise an extracellular antigen-targeting domain in conjunction with one or more intracellular T cell signaling domains that can be introduced into T cells by genetic modification to redirect their specificity to the CAR-targeted antigen. Administration of CD19-specific CAR-modified T cells that target B cell non-Hodgkin lymphomas and leukemia has been remarkably effective in recent clinical trials, energizing the field and stimulating new efforts to identify the critical parameters of CAR design and T cell engineering that are necessary for effective cancer therapy.     

Cell-based therapy for chronic ischemic heart disease--a clinical perspective

In patients with ischemic heart disease, the goal of cell therapy is to improve perfusion and function of the damaged heart muscle. For this review, we selected articles that reported the findings from the major clinical studies of cardiovascular stem cell therapy in patients with chronic ischemic heart disease. Because of the current status of development of clinical investigation in this field, all relevant studies were included. Initial clinical trials have shown that adult cell-based therapy is safe and may improve the quality of life and the functional status of patients with chronic myocardial ischemia. Adult bone marrow mononuclear cells have been most frequently used in cardiac cell therapy trials to date, but new cell types are now being assessed in both preclinical and clinical studies. Although not well defined, mechanisms underlying the benefits associated with cell therapy are most likely multiple and include a paracrine effect. Cell therapy in patients with chronic ischemic heart disease has been shown to be safe and feasible. Initial data have shown that cell therapy with autologous bone marrow cells is associated with modest functional improvements. This finding needs to be confirmed in subsequent phase 2 and 3 trials.     

Repairing damaged myocardium: Evaluating cells used for cardiac regeneration

Opinion statement Cellular cardiomyoplasty has raised hopes of regenerating mechanical function in the heart. Several cell sources have been investigated for their ability to repair the damaged heart, providing reason for optimism. Multiple mechanisms have been proposed for the beneficial effects of the delivered cells; however, true reversal of cardiac damage implies the generation of new contractile myocytes. The assessment of a cell’s ability to regenerate contractile cells requires a defined set of criteria that, if met, define success. Here we review data from the four primary players in cellular cardiomyoplasty (skeletal myoblasts, bone marrow cells, embryonic stem cells, and resident cardiac stem cells) and assess their potential to differentiate into contractile myocytes as indicated by their ability to meet such specified milestones. Both animal studies and clinical trials suggest that current experimental approaches to cellular cardiomyoplasty yield short-term improvement, although it may be independent of cell type used. However, the mechanisms underlying this salutary effect, as well as its persistence in the longer term, have remained elusive.     

Developments over the last 60 years in diffuse large B-cell lymphomas

At the time of the formation of the British Society of Haematology diffuse large B-cell lymphoma was not recognised as a specific entity and was included in the category of ‘large cell’ or ‘aggressive’ lymphomas. These were fatal in 95% of cases. Today the cure rate in adults entered into clinical trials is ~70% and a large number of British physicians have contributed to this progress.     

Rehabilitation for patients with myalgic encephalomyelitis/chronic fatigue syndrome: time to extent the boundaries of this field

The adult brain has a very limited capacity for generation of new neurons, and neurogenesis only takes place in restricted regions. Some evidence for neurogenesis after injury has been reported, but few, if any, neurons are replaced after brain injury or degeneration, and the permanent loss of neurons leads to long‐term disability and loss of brain function. For decades, researchers have been developing cell transplantation using exogenous cell sources for brain repair, and this method has now been shown to successfully restore lost function in experimental and clinical trials. Here, we review the development of cell‐replacement strategies for brain repair in Parkinson's disease using the example of human foetal brain cells being successfully translated from preclinical findings to clinical trials. These trials demonstrate that cell‐replacement therapy is a viable option for patients with Parkinson's disease, but more importantly also show how the limited availability of foetal cells calls for development of novel cell sources and methods for generating new neurons for brain repair. We focus on new stem cell sources that are on the threshold of clinical application for brain repair and discuss emerging cellular reprogramming technologies. Reviewing the current status of direct neural conversion, both in vitro and in vivo, where somatic cells are directly reprogrammed into functional neurons without passing through a stem cell intermediate, we conclude that both methods result in the successful replacement of new neurons that mature and integrate into the host brain. Thus, this new field shows great promise for future brain repair, although much work is still needed in preclinical animal models before it can be seriously considered for clinical applications.