Volociximab in cancer

Importance of the field: Despite the advances in the cardiovascular field, cardiovascular diseases remain an important health problem with a high mortality rate. Novel therapeutic attempts that target myocardial ischemia and heart failure offer attractive adjuncts and/or alternatives to commonly employed regimens. The development of novel laboratory technologies over the last decade has led to substantial progress in bringing new therapies to the bedside.

Areas covered in this review: Current experimental and clinical trials in the use of erythropoietin (EPO) in cardiovascular diseases are reviewed.

What the reader will gain: This review will widen knowledge of the therapeutic potential of EPO's non-erythropoietic beneficial effects in a clinical cardiovascular setting.

Take home message: Results from preclinical trials regarding the non-erythropoietic effects of erythropoietin are really encouraging. Further clinical studies are warranted to define the beneficial role of EPO in the clinical setting of coronary artery disease, heart failure and peripheral artery disease.     

Adipose tissue-derived mesenchymal stem cells as a strategy to improve recovery after stroke

Introduction: Based on the positive results observed in experimental animal models, adipose tissue-derived mesenchymal stem cells (AD-MSCs) constitute a promising therapy for stroke treatment. However, several aspects need to be clarified to identify the optimal conditions for successful clinical translation.

Areas covered: This review focuses on AD-MSC treatment for ischemic and hemorrhagic stroke in experimental animal models. In addition, we will explore the optimization of treatment conditions including AD-MSC production, administration routes and therapeutic windows for their appropriate use in patients. Finally we will provide an update on clinical trials on this therapy.

Expert opinion: Compared with other cell types, AD-MSCs have been less investigated in stroke studies. Currently, experimental animal models have shown safety and efficacy with this treatment after stroke. Due to several advantages of AD-MSCs, such as their abundance and accessibility, they can be considered a promising strategy for use in patients. However, many questions are still to be resolved regarding their mechanisms of action, immune system modulation and the effects of AD-MSCs on all components of the brain that may be affected after ischemic and hemorrhagic strokes.     

Oncolytic vaccinia virus for the treatment of cancer

Introduction: Gene therapy offers promising approaches for the development of anticancer agents with new modes of action. Among gene therapy vectors, vaccinia virus has emerged as an attractive agent especially when used as an oncolytic virus.

Areas covered: This review describes the use of vaccinia virus in cancer therapy as a gene therapy vector, as an oncolytic virus and in the generation of oncolysates. The main achievements of each field are summarized with a special emphasis on vaccinia as an oncolytic vector and its combination therapies. The virus that has advanced furthest in clinical trials, GM-CSF expressing JX-594, is described in detail and its preclinical and clinical data are reviewed.

Expert opinion: Vaccinia virus has great potential in cancer gene therapy, especially when used as an oncolytic virus. In particular, JX-594 has shown promising preclinical and clinical data, and a multi-continental randomized Phase III trial in hepatocellular carcinoma is expected to start soon.     

Evaluating the role of IL-12 based therapies in ovarian cancer: a review of the literature

Introduction: Immunotherapy, in its entirety, represents a promising field at the forefront of cancer. Treatment with potent cytokine IL-12 has provided science with many challenges, but has also demonstrated promise as therapeutic strategy in ovarian cancer.

Areas covered: This review examines the anti-tumor mechanism of action of IL-12 and the development of IL-12 as a potential therapeutic option in a variety of malignancies. It also reviews the immunogenicity of ovarian cancer and covers preclinical and clinical trials that have contributed to the advancement of IL-12 as a potential therapy for ovarian malignancy. The obstacles that researchers have overcome and currently face regarding the use of IL-12 in clinical ovarian cancer trials are also discussed.

Expert opinion: IL-12, as a therapeutic modality, is mechanistically logical and shows great promise in preclinical trials. Further clinical studies are warranted to optimize the potential of IL-12 as a treatment strategy for ovarian cancer.     

Cell-based therapy for ischemic stroke

Introduction: Stroke is a major cause of mortality and disability in adults worldwide. Unfortunately, current therapy which targets vessel recanalization has a narrow treatment window, and at this time neuroprotective approaches are not effective for stroke treatment. However, after stroke the parenchymal and endothelial cells in the central nervous system (CNS) respond in concert to ischemic stressors and create a microenvironment in which successful recovery may ensue. Neurogenesis, synaptogenesis, axonal sprouting, glial cell activation, angiogenesis and vascular remodeling within the brain and the spinal cord are stimulated post stroke. Cell based-therapy amplifies these endogenous restorative effects within the CNS to promote functional outcome.

Areas covered: This article reviews current knowledge of cell-based therapy in the adult brain after stroke, including transplanted cell type, benefits and risks, with an emphasis on mechanisms of action.

Expert opinion: Experimental studies and clinical trials with cell-based therapy in stroke appear promising. Cell-based therapy is not intended for the replacement of damaged cells, but for the remodeling of the CNS by promoting neuroplasticity, angiogenesis and immunomodulation. However, there are risks associated with the use of cell-based therapy, and adequate evaluation of these potential risks is a prerequisite before clinical application for stroke patients.     

Kinoid of human tumor necrosis factor-alpha for rheumatoid arthritis

Introduction: Anti-TNF-α drugs have dramatically changed treatment of rheumatoid arthritis (RA) in terms of both clinical control and articular damage prevention. Despite this, they hold some important drawbacks, such as frequent therapeutic failures and high costs. Anti-TNF-α active immunization, with a therapeutic vaccine against TNF-α, is a promising alternative anti-TNF-α targeting strategy, potentially devoid of treatment limitations of some of current anti-TNF blocking agents.

Areas covered: This review covers the preclinical proof-of-concept of anti-TNF-α vaccination with the kinoid of human TNF-α (TNFK) and analyzes the body of evidence forming the rationale for the application of this strategy in RA and other TNF-α-dependent diseases. We describe the theoretical bases of anti-TNF-α active immunization and of experimental data supporting the applicability of TNFK to human disease in terms of both safety and efficacy.

Expert opinion: Based on preclinical efficacy and safety data supporting its feasibility in a Phase I – II trial in Crohn's disease, anti-TNF-α vaccination with TNFK has entered the phase of clinical development and promises to be a valuable anti-TNF-α targeting strategy in human disease. The focus is made in the first clinical trial in RA (Phase II) on the efficacy in active RA patients having developed antibodies against anti-TNF mAbs.     

Recent advances in the use of therapeutic cancer vaccines in genitourinary malignancies

Introduction: Despite a recent increase in US FDA-approved treatments, genitourinary malignancies remain a source of significant morbidity and mortality. One focus of research is the use of therapeutic cancer vaccines in these diseases, and a significant body of clinical trial experience now exists for refining vaccine strategies to enhance antitumor efficacy and develop immune-based combination regimens.

Areas covered: In recent years, clinical data from multiple trials in genitourinary malignancies have enhanced our understanding of the potential for immunotherapy in these cancers. There are also emerging clinical strategies that combine cancer vaccines with chemotherapy, radiation, androgen-deprivation therapy and immune checkpoint inhibitors. This review is based on a search of relevant literature for data presented over the past 5 years from clinical trials of cancer vaccines in prostate, bladder and renal carcinomas.

Expert opinion: In the coming years, clinical trials informed by decades of preclinical data and emerging clinical data will help to define the role of immunotherapy in genitourinary malignancies. Combination strategies that capitalize on the immune properties of standard treatments will bring greater clinical benefits, and immune-based combinations will likely be moved to the neoadjuvant setting, where they may have optimal clinical impact.     

Tremelimumab for the treatment of malignant mesothelioma

Introduction: Tremelimumab demonstrated therapeutic activity in different malignancies, including malignant pleural mesothelioma (MPM); however, continued research could improve the therapeutic index of this agent.

Areas covered: This review describes tremelimumab’s clinical efficacy, administration and safety in patients affected with MPM and reports the state of the art clinical trials of tremelimumab. A literature search using the PubMed database was conducted using the search terms tremelimumab, MPM, current therapy, immune checkpoint blockage and cytotoxic T lymphocyte-associated antigen-4. Data was also obtained from meeting abstracts and clinical trial registries.

Expert opinion: The use of immunotherapy has been extended from melanoma to thoracic malignancies or lung cancer and MPM. The first clinical trials for MPM with drugs modulating immune checkpoints have been tested or are currently being tested with the first results now under critical consideration. Among these drugs, tremelimumab has been attracting attention as a potential new treatment for MPM. Nevertheless, even though clinical efficacy has been preliminarily demonstrated, the cost/benefit ratio of this drug for this neoplasm is yet to be ascertained.     

Intra-arterial administration of cell-based biological agents for ischemic stroke therapy

Introduction: Ischemic stroke is becoming a primary cause of disability and death worldwide. To date, therapeutic options remain limited focusing on mechanical thrombolysis or administration of thrombolytic agents. However, these therapies do not promote neuroprotection and neuro-restoration of the ischemic area of the brain.

Areas covered: This review highlights the option of minimal invasive, intra-arterial, administration of biological agents for stroke therapy. The authors provide an update of all available studies, discuss issues that influence outcomes and describe future perspectives which aim to improve clinical outcomes. New therapeutic options based on cellular and molecular interactions following an ischemic brain event, will be highlighted.

Expert opinion: Intra-arterial administration of biological agents during trans-catheter thrombolysis or thrombectomy could limit neuronal cell death and facilitate regeneration or neurogenesis following ischemic brain injury. Despite the initial progress, further meticulous studies are needed in order to establish the clinical use of stem cell-induced neuroprotection and neuroregeneration.     

Sclerostin monoclonal antibody therapy with AMG 785: a potential treatment for osteoporosis

Importance of the field: Osteoporosis is a common skeletal disease characterized by loss of bone strength that leads to increased risk of fractures. Fractures of the hip and spine are associated with disability, increased risk of death and high healthcare costs. Recent improvement in the understanding of the molecular regulators of bone metabolism has led to the investigation and development of new therapeutic agents with novel mechanisms of action that may offer advantages over currently available treatments for osteoporosis.

Areas covered in this review: Sclerostin is a small protein secreted by osteocytes that downregulates osteoblast-mediated bone formation. This is a review of the rationale, mechanism of action, preclinical and clinical development of AMG 785 (CDP7851), an investigational humanized mAb that inhibits the activity of sclerostin, resulting in increased bone formation.

What the reader will gain: The reader will gain an insight into the potential use of sclerostin mAb therapy for the treatment of osteoporosis.

Take home message: Preclinical studies and an early report of a clinical study suggest that inhibition of sclerostin with AMG 785 may provide skeletal benefit for patients with osteoporosis.     

Edoxaban for the prevention of stroke in patients with atrial fibrillation

Introduction: Edoxaban is the last direct oral anticoagulant marketed for the prevention of stroke among patients with nonvalvular atrial fibrillation (AF).

Areas covered: ENGAGE AF–TIMI 48 was the pivotal clinical trial that led to the approval of edoxaban 60 mg once daily. After the publication of this study, a great number of substudies and post hoc analyses have been published, together with some observational studies. The aim of this review was to update the current evidence about the use of edoxaban in AF patients.

Expert opinion: In the ENGAGE AF–TIMI 48 trial, edoxaban 60 mg was noninferior to warfarin for the prevention of stroke or systemic embolism, but significantly reduced the risk of bleeding, major adverse cardiac events and death from cardiovascular causes. The relative efficacy and safety of edoxaban 60 mg compared with warfarin were independent of different clinical conditions, such as prior stroke, age, risk of falls, renal function, hepatic disease, ischemic heart disease, heart failure, valvular heart disease, or cancer. Data about the effectiveness and safety of edoxaban in real-life patients are scarce, but consistent with those of the pivotal clinical trial. Edoxaban seems a cost-effective alternative to warfarin among AF patients with moderate to high thromboembolic risk.     

Naptumomab estafenatox: a new immunoconjugate

Importance of the field: New agents that specifically engage the immune system are being tested in a variety of malignancies. This review provides an overview of naptumomab, an immunotoxin, with encouraging clinical activity in Phase I trials.

Areas covered in this review: This review examines the preclinical and the published clinical data with regards to naptumomab.

What the reader will gain: This review provides the reader with an understanding of the mechanism of action, immunology, pharmacokinetics and clinical activity of this agent.

Take home message: Naptumomab has a unique mechanism of action and appears to be an active agent in the treatment of refractory solid tumors such as renal cell carcinoma.     

Erythropoietin for stroke treatment: dead or alive?

Endothelial progenitor cell (EPC) mobilization from the bone marrow was considered to improve outcome after ischemic stroke. Erythropoietin (EPO) might be a potential candidate stroke drug that increases the number of circulating EPCs. In the previous issue of Critical Care, Yip and colleagues investigated the effect of EPO in stroke patients on both clinical outcome and EPC stimulation. Although beneficial effects of EPO were observed, several issues regarding EPO's suitability as a stroke drug remain.     

RNAi-mediated gene silencing in cancer therapy

Introduction: This review presents the intriguing success of RNA interference (RNAi)-mediated gene silencing and its advantages and obstacles in cancer therapy.

Areas covered: RNAi has implications in metabolic disease, viral hepatitis, cardiovascular and cerebrovascular diseases, HIV, neurodegenerative disorders and cancer. RNAi can enhance the specificity and efficacy of therapeutic intervention for human diseases while at the same time reducing toxicity. The existing research related to gene therapy suggests encouraging prospects of a new high-efficiency and low-toxicity anti-tumor therapy. Although gene therapy is still in the experimental research phase, in the near future, this method will become an important means for the treatment of cancer therapies and it will be widely used in clinical practice.

Expert opinion: RNAi-based drug development is still in preclinical trial and several challenges limit the use of RNAi in the clinic. It is believed that further investigation of the mechanisms of RNAi-based therapies will help overcome these limitations and provide powerful weapons in the oncology clinic.     

Stem cells for brain repair and recovery after stroke

Introduction: Stroke is a major worldwide cause of death and disability. Currently, intravenous thrombolysis and reperfusion therapies, but not the so-called neuroprotectant drugs, have been shown to be effective for acute ischemic stroke. Thus, new strategies to promote brain plasticity are necessary. Stem cell administration is an attractive future therapeutic approach.

Areas covered: Brain protection and repair mechanisms are activated after stroke. This article is focused on the capacity of stem cell-based therapy to enhance this postinfarct brain plasticity and recovery. Future therapeutic considerations and prospects for stroke are discussed.

Expert opinion: Although cell therapy is promising in stroke treatment, mechanisms of action need to be characterized in detail. Further, the different mechanisms of axonal plasticity and remodeling involucrated in brain repair, not only in the gray but also in white matter, must be investigated through noninvasive techniques, and a multidisciplinary approach is fundamental in this.     

Rehabilitation professionals’ perceptions of the use of new visualisation software tools with people with stroke

Purpose: The envisage programme of research was funded to explore and evaluate the use of visualisation software tools using biomechanical data within rehabilitation. Three work packages were developed to evaluate the impact of the tools within stroke rehabilitation. The research presented here aimed at exploring the perceptions of rehabilitation therapists about the use of the visualisation software tools in the context of future randomised controlled trials and stroke rehabilitation practice. Methods: Sixteen therapists working in a range of stroke rehabilitation contexts participated in semi-structured interviews. Interview questions explored their current practice, and the perceived impact of the new visualisation technologies on their workplace environment and practice. Framework analysis was used to analyse the textual data. Results: In general, the stroke therapists were enthusiastic about the potential application of the visualisation software tools. Three themes were identified through qualitative framework analysis: potential uses of the visualisation tools; integration within current service provision; and trial involvement. Conclusions: The study highlights important contextual considerations which may impact significantly on the success of novel technologies in stroke rehabilitation. Normalisation process theory was proposed as a useful process evaluation methodology to optimise both trial evaluation and future service implementation.

• Implications for Rehabilitation

• There is limited research exploring the use of visual software technologies featuring biomechanical data within stroke rehabilitation.

• The perspectives of stroke rehabilitation therapists about the potential of such tools are useful both in terms of planning trial evaluations, and implementation.

• Therapists were generally positive about the contribution of visual software tools in stroke rehabilitation, but highlighted a number of practical constraints which required addressing.

• Normalisation process theory provides a useful process evaluation methodology which can support both trial evaluation and implementation of such novel technologies within stroke rehabilitation.

     

Toward the use of endometrial and menstrual blood mesenchymal stem cells for cell-based therapies

Introduction: Bone marrow is a widely used source of mesenchymal stem cells (MSCs) for cell-based therapies. Recently, endometrium – the highly regenerative lining of the uterus – and menstrual blood have been identified as more accessible sources of MSCs. These uterine MSCs include two related cell types: endometrial MSCs (eMSCs) and endometrial regenerative cells (ERCs).

Areas covered: The properties of eMSCs and ERCs and their application in preclinical in vitro and in vivo studies for pelvic organ prolapse, heart disorders and ischemic conditions are reviewed. Details of the first clinical Phase I and Phase II studies will be provided.

Expert opinion: The authors report that eMSCs and ERCs are a readily available source of adult stem cells. Both eMSCs and ERCs fulfill the key MSC criteria and have been successfully used in preclinical models to treat various diseases. Data on clinical trials are sparse. More research is needed to determine the mechanism of action of eMSCs and ERCs in these regenerative medicine models and to determine the long-term benefits and any adverse effects after their administration.     

Camelid single-domain antibody-fragment engineering for (pre)clinical in vivo molecular imaging applications: adjusting the bullet to its target

Introduction: Molecular imaging is a fast developing field and there is a growing need for specific imaging tracers in the clinic. Camelid single-domain antibody-fragments (sdAbs) recently emerged as a new class of molecular imaging tracers.

Areas covered: We review the importance of molecular imaging in the clinic and the use of camelid sdAbs as in vivo molecular imaging tracers. Interest in imaging tracers based on antibody fragments or man-made protein scaffolds expanded over the last years. Camelid sdAbs are small, monomeric binding fragments that are derived from unique heavy-chain-only antibodies. In vivo imaging studies with sdAbs targeting various cell membrane receptors in different disease models have been reported and more sdAb imaging tracers are under development. The first clinical trial with a camelid sdAb as a molecular imaging tracer targeting the breast cancer marker Human Epidermal growth factor Receptor 2 is currently ongoing.

Expert opinion: We expect that the development and use of sdAbs as tracers for both preclinical and clinical molecular imaging applications will become widespread.     

IDegAsp: a novel soluble insulin analogs combination

Introduction: Basic fibroblast growth factor (bFGF) has been shown to reduce volume in acute ischemic stroke models, and to promote functional recovery as well as new synapse formation when given to animals with completed cerebral infarction. A recombinant native form of human bFGF, trafermin, has been tested in Phase III clinical trials in patients with stroke.

Areas covered: The role of trafermin in stroke. Data were identified by searching PubMed for single or combined terms including: trafermin, basic fibroblast growth factors, neuroprotection, neuroprotective drugs, stroke therapy, stroke rehabilitation and acute stroke. Original research papers, clinical series and reviews are included. Our research covered all relevant data up until 1 April 2011.

Expert opinion: To date, all Phase III trials have failed to demonstrate the superiority of trafermin over placebo when given within 6 h from stroke onset because trafermin causes a dose-dependent hypotension and an increased mortality rate in treated patients. However, a 24-h intravenous infusion seems to be safe for stroke patients and may result in an improved outcome when given 5 – 6 h after infarct. This finding may open renewed interest in restorative treatment for stroke, which could enhance recovery mechanisms rather than immediate neuroprotection. Studies suggest that growth factors can produce improvement in animal models of stroke, even when administered at postischemic intervals from many hours to days, when conventional neuroprotective approaches are typically ineffective. Because of the number of side effects and increased mortality reported in the first clinical studies with high dose of FGF, further experimental studies are necessary to asses whether it is possible to achieve a pharmacologically significant therapeutic level in the brain, by minimizing peripheral side effects. Another randomized clinical trial is needed to test trafermin in stroke patients but to enhance functional recovery.