Pharmacotherapy and interventional treatments for secondary hyperparathyroidism: current therapy and future challenges

Importance of the field: Chronic kidney disease is frequently complicated by secondary hyperparathyroidism, which causes bone disease and vascular calcification, leading to increased risk of morbidity and mortality.

Areas covered in this review: This review covers treatment options for secondary hyperparathyroidism in patients receiving dialysis, particularly focusing on active vitamin D derivatives, calcimimetics and direct injection therapy into parathyroid glands. In addition, the potential of gene therapy is also described.

What the reader will gain: The reader will gain a comprehensive review of the effectiveness and role of available therapies for patients with secondary hyperparathyroidism, as well as the results of observational studies that address the effect of these treatments on clinical outcomes.

Take home message: Treatment with active vitamin D derivatives and calcimimetics allows adequate control of secondary hyperparathyroidism, which it is hoped will translate into improved clinical outcomes. These treatments appear to be effective even in patients with advanced disease, but patients who develop resistance to therapy should undergo parathyroid intervention, such as surgical parathyroidectomy and direct injection therapy. Gene therapy is not applicable to humans at present, but they will help clarify the molecular pathogenesis of secondary hyperparathyroidism.     

Inotuzumab ozogamicin as novel therapy in lymphomas

Importance of the field: More than 65,000 cases of non-Hodgkin's lymphoma are estimated to have been diagnosed in 2009; the majority are of B-cell lineage, and diffuse large cell lymphoma and follicular together account for nearly half of cases. Despite advances in treatment, most patients are not cured.

Areas covered in this review: The antigen CD22 is a transmembrane glycoprotein found on mature B-cells, and on up to 90% of B-cell malignancies. Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 monoclonal antibody conjugated with calicheamicin. Preclinical data indicate activity against B-cell tumors, and early results from clinical trials indicate activity against B-cell lymphomas including follicular lymphoma and diffuse large cell lymphoma. This paper reviews the design, pharmacokinetic and pharmacodynamic characteristics, and preclinical and clinical experience of this promising novel targeted therapy, with data derived from abstracts and published reports from 2002 to the present.

What the reader will gain: This review will serve as an introduction to and overview of inotuzumab ozogamicin, and describe the rationale guiding advances in development.

Take home message: The data thus far confirm the tolerability and clinical activity of inotuzumab ozogamicin in B-cell malignancies, and further investigation as a single agent as well as in combination therapy is warranted.     

Monoclonal antibody treatments for rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is a systemic disease and the most prevalent of all autoimmune disorders. Here we review recent advances in the development and availability of biologic agents with a focus on monoclonal antibody or smaller formats of targeted engineered therapeutics including novel, non-antibody-based therapeutics.

Areas covered: Today an array of biologics blocking either proinflammatory cytokines or lymphocyte activation/survival are available that enable a substantial improvement over conventional disease-modifying antirheumatic drugs (DMARDs). We review the engineering process of antibody-based biologics, their preclinical and clinical application, and current efforts to treat RA by interfering with B-cell function (notable targets covered are CD20, CD38, B-cell activating factor, transmembrane activator and calcium-modulating and cyclophilin interactor), with T-cell function (CD3, CD4, CD28), with bone erosion (RANKL), and with cytokines or growth factors (tumor necrosis factor, interleukin-1 [IL-1], IL-6, IL-17, VEGF). Future treatment choices might encompass the blockade or modulation of danger-associated molecular patterns such as HMGB1, pattern recognition receptors, messenger RNAs or noncoding RNAs, histone acetylation, and inflammasome components.

Expert opinion: Although current therapies can reduce the signs and symptoms of RA for many patients, the quest for a cure (or a more complete blockade of the structural damage) in RA is still ongoing and will need treatment approaches, which are not exclusively confined to blocking a particular cytokine, receptor, or autoreactive B or T cell involved in disease progression. To this end exciting treatment alternatives and drug targets are on the horizon that may become available to patients in the future.     

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.     

I-131 tositumomab

Importance of the field: Follicular lymphoma (FL) is a subgroup of B-cell Non-Hodgkin's lymphomas (NHL) that account for 15 – 30% of all lymphomas. I-131 tositumomab is a radiommunoconjugate of ¹³¹I and the anti-CD20 monoclonal antibody tositumomab. It is one of two available radioimmunoconjugates for the treatment of recurrent, refractory, or transformed FL.

Areas covered in this review: This review describes the clinical pharmacology of I-131 tositumomab, dosing and administration guidelines, and the key clinical trials providing evidence of its efficacy and safety in patients with FL, transformed, or other aggressive B-NHL, in combination with chemotherapy, or its incorporation in transplant conditioning regimens. This review also covers safety and regulatory concerns regarding the use of I-131 tositumomab.

What the reader will gain: This review critically appraises the clinical trials behind approval of I-131 tositumomab as a second-line agent for FL and also outlines the data supporting its use in the upfront setting.

Take home message: I-131 tositumomab is a safe and effective option for patients with recurrent, refractory, or transformed FL and carries promise in the upfront treatment of FL, aggressive B-NHL, and as a transplant conditioning regimen.     

Gene therapy in rodent amygdala against fear disorders

Importance of the field: Successful treatment of fear and anxiety disorders is presently a difficult task. A major limitation is the fact that underlying physiological mechanisms of fear and anxiety are only now beginning to be understood. As we obtain more information about mechanisms and brain circuits involved, treatment of these conditions will become increasingly realistic.

Areas covered in this review: Gene therapy is a promising treatment strategy that has several advantages over the more widely used pharmacological approaches. In this review we discuss the potential and limitation of gene therapy in the amygdala. This review concerns itself with papers published within the last 20 years in the field of gene therapy for fear and anxiety, and has been primarily conducted in rodent models.

What the reader will gain: We present the current state of research into gene therapy for anxiety disorders, using a few case studies. The review will delineate challenges, limitations and opportunities for successful gene therapy.

Take home message: There are sizeable gains in knowledge about functioning of the fear system. This will inform future improvements in gene therapy approaches. An ideal gene therapy strategy will involve improvements in both delivery vectors and in design of therapeutic cargo.     

RNA interference therapy for glioblastoma

Importance of the field: Despite numerous advances made during the last decade in brain tumor therapy, the prognosis of glioblastoma has not improved and these tumors inevitably recur with no effective treatment. Thus, any new therapeutic strategy to target this most malignant tumor will be of significant benefit. RNAi is a powful gene silencing method that might be used in combination with other agents to improve the efficacy of glioblastoma treatment.

Areas covered in this review: Recent progress and challenges of pre-clinical and clinical research of RNAi therapy for glioblastoma. The review covers literature from 2003 to 2009.

What the reader will gain: The principle of RNA interference therapy, three categories of RNAi triggers, different RNAi delivery system and pre-clinical and clinical studies that are currently underway to evaluate the validity of RNAi as a potential therapeutic strategy against glioblastoma are discussed.

Take home message: RNA inference therapy combined with other therapeutics may offer therapeutic potential for glioblastoma multiforme. Further studies are required to develop more efficient and specific delivery systems, select suitable gene targets, optimize treatment dose and administration schedule, evaluate the efficacy of combination treatment strategies, establish a validated clinical response measure system etc.     

Alemtuzumab and multiple sclerosis: therapeutic application

Importance of the field: The cause and cure for multiple sclerosis (MS) remain unknown. Immunomodulatory agents are only partially effective and many patients do not tolerate the side effects or fail them. Immunosuppressive agents act non-specifically and are associated with serious complications. An emerging group of biologic agents with great potential for treatment of immune-mediated disorders such as MS are monoclonal antibodies. A review of alemtuzumab in MS is presented.

Areas covered in this review: Mechanisms of action of alemtuzumab and the results of Phase II clinical trials in MS.

What the reader will gain: Alemtuzumab is a humanized mAb, which targets the surface molecule CD52 on all T cell populations and other cellular components of the immune system such as thymocytes, B cells, and monocytes. Alemtuzumab, which is administered intravenously, depletes T as well as B lymphocyte populations for extended periods. Adverse effects in MS patients such as thyroid disorders and idiopathic thrombocytopenic purpura are discussed.

Take home message: Alemtuzumab may hold great promise for treatment of MS patients and serve as an option for patients refractory to immunomodulatory therapies. Due to its unique mechanism of action and profound effect on MS disease activity it enhances our knowledge about pathogenic mechanisms of MS.     

Interferons as potential adjuvants in prophylactic vaccines

Importance of the field: Vaccines are still one of the best approaches to manage infectious diseases. Despite the advances in drug therapies, prophylactic medicine is still more cost efficient and minimizes the burden in the heath system. Despite all the research in vaccine development, many infectious diseases are still without an effective vaccine. The use of adjuvants in vaccines has been one successful strategy to increase efficacy. IFNs are widely expressed cytokines that have potent antiviral effects. These cytokines are the first line of defense against viral infections and have important roles in immuno surveillance for malignant cells. One of the most promising uses of IFNs is as adjuvants that are co-applied with antigen in vaccines.

Areas covered in this review: In this review, a cumulative analysis of many of the studies that have used IFN-α, -β, -γ and -λ as adjuvants between 1987 and the present suggests that many do possess the capacity to serve as potent immunoadjuvants for vaccination.

What the reader will gain: This review provides a very large collection of studies involving all types of IFNs used as adjuvants in vaccines using different vaccination strategies and various animal models.

Take home message: It is clear that the use of IFNs not only improved the efficacy and safety of most vaccines, but also had important immunomodulatory effect directing T_H1 immune responses.     

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.     

The immune microenvironment in vulvar (pre)cancer: review of literature and implications for immunotherapy

ABSTRACT

Introduction: Vulvar squamous cell carcinoma (VSCC) develops via two different pathways: TP53 mutations in a background of lichen sclerosus or a persistent infection with high-risk human papilloma virus (HPV). The latter group of tumor responds better to treatment than the non-virally induced VSCC. This may be explained by a difference in the tumor immune microenvironment (TME).

Areas covered: This review summarizes literature on TME of VSCC and its precursors, and extrapolates this to foster the development of new therapeutic strategies.

Expert opinion: Both types of VSCC and their precursors are infiltrated with variable numbers of M2 macrophages, regulatory T cells and CD8+ T cells, indicating that they express targetable tumor antigens. Type 1 T cell immunity in precursor lesions is associated with fewer recurrences and better clinical responses to immunotherapy. Escape of these lesions and progression toward VSCC is associated with the downregulation of HLA Class I, increased expression of co-inhibitory molecules, infiltration with immunosuppressive cells and the local production of immunosuppressive enzymes and cytokines. More in-depth studies of the VSCC TME are required to fully comprehend the impact of the immune system on VSCC, and subsequently to identify patients who will benefit from immunotherapeutic strategies.     

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.     

Mesenchymal stem cells: biological properties and clinical applications

Importance of the field: In the last decade, knowledge of mesenchymal stem cells (MSCs) has evolved rapidly; their immunomodulatory properties and paracrine interactions with specific cell types in damaged tissues and promising results in some clinical applications have made these cells an attractive option for the treatment of certain diseases.

Areas covered in this review: We present some relevant methodological issues and biological properties of MSCs, as well as clinical applications of MSC therapies with particular emphasis in the treatment of graft versus host disease (GVHD), complex perianal fistula and refractory metastatic neuroblastoma. Other topical aspects relevant to the application of cellular therapies such as biosafety studies and cellular production of MSCs are also discussed in this review.

What the reader will gain: The growing optimism regarding MSCs research is based on the promising results obtained in in vitro and in vivo studies. The rapid translational research with MSCs necessitated standardization of methodology and terminology and greater focus on other aspects such as biosafety and cellular production, especially for clinical use of MSCs.

Take home message: Much has been learned about the biology and applications of MSCs and much remains to be learned.     

Stem cell transplantation as a biological therapy for peripheral T-cell lymphomas

Importance of the field: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin's lymphomas in which conventional chemotherapy has been characterized by poor outcomes when compared with most aggressive B-cell lymphomas. Autologous, and to a lesser extent allogeneic, hematopoietic stem-cell transplant (HSCT) have been advocated as potential means to improve and consolidate remissions in PTCL.

Areas covered in this review: Given the absence of large-scale randomized clinical controlled trials of transplantation for PTCL, we review existing data addressing the role and timing of HSCT in PTCL.

What the reader will gain: A detailed overview of the available data of overall and progression-free survival associated with HSCT in PTCL with discussion of existing studies, data on determinants of HSCT outcome in PTCL, and future directions for research.

Take home message: The optimal roles and timing of HSCT in PTCL remain unclear. Accordingly, clinicians are encouraged to register their patients in PTCL registry studies and enroll them in clinical trials investigating the role of HSCT. Risk-adapted treatment strategies utilizing identified prognostic parameters may provide future means for identifying the optimal use of HSCT for patients with PTCL, but additional studies are needed before such approaches can be routinely applied.     

GAD-alum (Diamyd) – a new concept for preservation of residual insulin secretion

Importance of the field: Type 1 diabetes is a common and very serious disease. There has been very active research going on for a long time aiming at preservation of the residual insulin secretion by some kind of intervention to stop the destructive autoimmune process. This review covers a new type of immune intervention using auto-antigen treatment.

Areas covered in this review: Immune interventions in type 1 diabetes have been tried during the last 30 years, this review mentions some of them, but the main topic is the use of the auto-antigen glutamic acid decarboxylase (GAD) to create tolerance to stop the autoimmune process. The clinical trials have been performed during the last 15 years and are all covered.

What the reader will gain: This review will give the reader a picture of the research behind treatment with GAD as an immune intervention in type 1 diabetes.

Take home message: The key finding so far is that treatment with Diamyd^® has not only been shown to preserve residual beta cell function in type 1 diabetes, but this treatment may be the proof in humans of a new concept of treating and perhaps even preventing autoimmune diseases.     

Erythropoietin in stroke: quo vadis

Importance of the field: Recombinant erythropoietin (rEPO) failed in a recent clinical study to protect from damages induced by ischemic stroke. The lack of acute treatments in ischemic stroke and the promising outcome in numerous preclinical studies in vivo demands a more critical evaluation of the future use of EPO as an acute treatment.

Areas covered in this review: The current use and administration of rhEPO and its analogs in animal models and the future use of this cytokine in the treatment of ischemic stroke.

What the reader will gain: In this review the potential reasons for the failure of EPO in the clinical trial are analysed and whether the preclinical trials sufficiently evaluated the true potential of recombinant EPO and its analogs is assessed. Alternative methods for administration of EPO to enhance its potential as a neuroprotective drug in ischemic stroke are discussed.

Take home message: Failure in clinical trial does not necessarily indicate the lack of therapeutic potential of EPO. This review encourages further investigation of the true potential of EPO as a candidate drug for the treatment of ischemic stroke by improved preclinical experimental design and utilization of alternative administration methods.     

Natural killer–dendritic cell cross-talk in cancer immunotherapy

ABSTRACT

Introduction: Rheumatoid arthritis (RA) treatment has been revolutionized by the development of highly efficacious biotherapeutics. However, a significant subset of RA patients has persistently active disease and ongoing erosive joint damage despite the available therapies. Sarilumab targets interleukin-6, one of the main cytokines mediating inflammation in RA. Positive results with sarilumab in RA clinical trials support the licensing application currently under review with the US Food and Drug Administration.

Areas covered: The rationale for IL-6 targeting in RA, the pharmacologic properties of sarilumab, and the clinical trial results are reviewed focusing on the pending application for the RA indication. Comparisons with other IL-6 targeting biologics as well as additional potential therapeutic directions are discussed.

Expert opinion: Sarilumab is a highly active therapeutic in patients with RA. While pharmacologic data demonstrate that sarilumab has a higher affinity than tocilizumab for the target receptor, available clinical results suggest that efficacy and adverse event profiles are similar to this other IL-6 blocker, which is currently approved for the treatment of RA. Whether there are other distinct differences or advantages of sarilumab that will support the approval and successful marketing of this drug, over existing therapies, remains to be determined.     

Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma,metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma

Importance to the field: In advanced renal cell cancer and malignant melanoma, the current FDA approved immune modulators, such as IL-2, are the only agents which provide a durable complete remission. These responses, however, occur in < 10% of treated patients and their applicability is limited to selected patients because of their toxicity. The identification of new immunotherapeutic agents with an improved response rate and toxicity profile would represent a significant advancement in the treatment of these malignancies.

Areas covered in this review: This is a comprehensive review of IL-21 including its pharmacology and current developmental status. A literature review was performed using all PubMed listed publications involving IL-21, including original research articles, reviews and abstracts. It also includes a review of current ongoing trials and information from the official product website.

What the reader will gain: Recombinant IL-21 (rIL-21) is a new immune modulator currently undergoing Phase I and II testing. It is a cytokine with a four helix structure that has structural and sequence homology to IL-2 and -15, but also possesses many unique biological properties. In this review, we evaluate the development, pharmacologic properties, safety profile and current clinical efficacy of rIL-21.

Take home message: rIL-21 has an acceptable safety profile and encouraging single agent activity in early phase renal cell carcinoma and melanoma clinical trials.     

Immunotherapy for metastatic prostate cancer: where are we at with sipuleucel-T?

Importance of the field: Prostate cancer is the leading malignancy in North American men and despite improvements in treatments 20 – 30% of patients will relapse. Immunotherapy using activated mononuclear cells is a way to harness the body's adaptive immune response to fight metastatic prostate cancer.

Areas covered in this review: In 2005, at least 10 therapeutic cancer vaccines, designed to confer active, specific immunotherapy against tumor-associated antigens, were in clinical trials. These covered potential fields of immunological strategy to overcome castration-resistant prostate cancer.

What the reader will gain: A literature review was performed using the search terms sipuleucel-T, Provenge and APC8015 or APC-8015, and restricted to English language articles from 2000 to 2010. The immunological design and development of sipuleucel-T are summarized. The efficacy and safety of sipuleucel-T are discussed based on current data from clinical trials. Ongoing clinical trials involving sipuleucel-T are summarized.

Take home message: Efficacy and safety with sipuleucel-T has been demonstrated in Phase I/II trials. The latest data from a Phase III trial shows that sipuleucel-T has met the primary endpoint of survival benefit. Further work is needed to understand the mechanisms behind cancer vaccine failure and elucidate the population for whom this vaccine will be suitable.     

Enhancing adoptive immunotherapy of cancer

Importance of the field: Conventional therapies, including surgery, chemotherapy and radiotherapy have contributed much to cancer treatment. However, these treatment modalities fail in a large proportion of patients, and there is a great need for effective alternate therapies. Adoptive immunotherapy can be effective against some cancers that have failed all other treatment options, even when disease burdens are massive.

Areas covered in this review: This review gives a brief introduction of the historical origins of adoptive immunotherapy and then provides details of strategies for increasing the potency of cell transfer. Approaches for enhancing adoptive immunotherapy include: selecting the right type of cell; providing cytokine support; preconditioning patients and tuning the tumor microenvironment. The review also provides insights into the safety, feasibility and costs of this form of therapy.

What the reader will gain: This article will give the reader an appreciation of the potential of adoptive immunotherapy, as well as an understanding of some limitations and current approaches for optimizing the effectiveness of this approach.

Take home message: With recent developments in knowledge of the interactions between the immune system and tumors, the field of adoptive immunotherapy is now poised to make dramatic contributions to cancer therapy.