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High-dose, high-frequency IFN beta-1a in multiple sclerosis (MS) can prevent lesion formation, decrease the frequency/severity of relapses and delay progression of disability, with a proven safety profile. Rates of non-adherence are high. There are drugs under investigation that may have greater efficacy and different safety profiles from existing therapies.Evidence supporting the efficacy of IFN beta-1a, factors contributing to non-adherence, and strategies to combat non-adherence. It is hoped that these strategies, coupled with future advances in pharmacogenetics, might lead to better outcomes. The PubMed database was searched using the terms "multiple sclerosis" and "interferon beta-1a", for papers published between 1998 and 2010. Relevant manuscripts and pivotal papers from clinical trials were cited. Searches of abstracts from congresses were also performed to obtain recent findings.An overview of early pivotal trials, comparative studies with other treatments, and recent studies assessing the development of this therapy.Long-term treatment with IFN beta-1a has benefits in MS and a good safety profile. Although adherence outside of clinical trials can be poor, injection devices, better tolerated drug formulations and education regarding treatment expectations are some of the strategies employed to help patients to adhere to treatment in the hope of improving outcomes.

For many years the annual meeting of the American Society of Clinical Oncology (ASCO) has been the premier meeting in clinical oncology, and one that is closely scrutinised by Wall Street and international investors because of the economic significance of cancer therapies to the pharmaceutical and biotechnology industries. The area of biologicals and targeted therapies exploded in the late 1990s after the blockbuster results with the monoclonal antibody rituximab in the treatment of lymphoma. Although historically a somewhat conservative organisation that is still closely tied to classical cytotoxic chemotherapy, ASCO has been able to integrate various areas of biological therapy into its scope of clinical activity. Although ASCO still has 'American' in its title, it is really the 'International' Society of Clinical Oncology, as reflected by the attendance at this year's meeting by approximately 30,000, with approximately two-thirds attending from outside the US. There were 9708 abstracts published in conjunction with the meeting, 86 of which are referenced in this review. There were 10 papers chosen for plenary presentations and many other key papers were presented at other oral abstract sessions and poster discussion session that were organised by tumour type. In addition to key papers submitted by specific tumour type, for this year's meeting there were 103 abstracts published in the session entitled 'Developmental Therapeutics: Immunotherapy', and 218 in the session entitled Developmental Therapeutics: Molecular Targets', for a total of 321 biological therapy abstracts compared with only 125 abstracts for the session entitled 'Developmental Therapeutics: Cytotoxic Therapy'. This meeting review is organised by biotherapy modality rather than tumour type.

Metastatic melanoma continues to present a significant therapeutic challenge, with an incidence rate rising faster than that of any other cancer. The last 5 years have seen a revolution in the development of new treatments for advanced melanoma, with oncogene targeted agents and checkpoint inhibitor immunotherapies providing the first convincing evidence of a positive shift in overall survival. The role of oncolytic virotherapy in this rapidly evolving field has long been the subject of debate. However, it is with the development of Talimogene Laheparepvec (T-Vec), an intratumourally administered, genetically modified clinical herpes simplex virus-1 strain that has shown positive results in Phase III testing, that the potential for the use of OV may be realised.This review will outline some of the recent advances in the treatment of advanced melanoma, with a detailed overview of evidence surrounding the development of T-Vec. A literature search was conducted using the databases ‘Medline’ and ‘Pubmed’, including a subsequent manual search of references to identify papers of further relevance.As the pivotal OPTiM trial concludes, we outline some of the potential new directions for T-Vec and OV therapy and evaluate the ever-increasing role these novel agents are likely to play in the future landscape of cancer immunotherapy.

Placental malaria (PM) is a major public health problem that constitutes a significant health concern for the mother, and especially for the developing fetus and offspring. Current means of prevention have limitations, including a restricted window of intervention that excludes the first trimester of pregnancy, and the fact that very few drugs can be used for this purpose. The identification of the VAR2CSA antigen, specific to PM parasites, offers an excellent opportunity to develop a vaccine against this disease. Proof of concept of a first-generation vaccine is nearing completion, and two clinical trials are underway.This review focuses on PM, which is mainly caused by Plasmodium falciparum. The review highlights recent advances and the key milestones that led to the identification of the optimal vaccine target within the large VAR2CSA protein. The paper also points out how future improvements can strengthen this process to achieve an effective vaccine in the field.The approach taken to develop a P. falciparum erythrocyte membrane protein 1-based vaccine to protect pregnant women is very promising in view of the current difficulties of achieving a sterilizing vaccine against malaria parasite. This approach could help us to control the deleterious effect of malaria infections that characterize severe clinical forms.

Stroke is a leading cause of mortality in the US. More so, its infliction often leaves patients with lasting morbidity and deficits. Ischemic stroke comprises nearly 90% of incidents and the majority of medical treatment aims at reestablishing perfusion and preventing recurrence.Long-term options for neurorestoration are limited by the infancy of their innovative approach. Accumulating evidence suggests the therapeutic potential of stem cells in neurorestoration, however, proper stem cell migration remains a challenge in translating stem cell therapy from the laboratory to the clinic. In this paper, we propose the role that exogenous stem cell transplantation may serve in facilitating the migration of endogenous stem cells to the site of injury, an idea termed 'biobridge'.Recent research in the field of traumatic brain injury has provided a foundational understanding that, through the use of exogenous stem cells, native tissue architecture may be manipulated by proteinases to allow better communication between the endogenous sites of neural stem cells and the regions of injury. There is still much to be learned about these mechanisms, though it is the devastating nature of stroke that necessitates continued research into the prospective therapeutic potential of this novel approach.

Plerixafor, a hematopoietic stem cell mobilizer, is indicated in combination with G-CSF to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. Current evidence suggests that the addition of plerixafor with chemotherapy plus G-CSF is safe and effective in the large majority of the patients with low blood CD34(+) cell count after mobilization and/or poor yield after the first collection. Nevertheless, there are several questions strongly debated, and in this paper, we would like to identify areas of possible future use and development of the drug.

Biologics drugs have succeeded in achieving a commercial dominance in the global market for new therapies and large pharmaceutical companies' interest remains strong through a continued commitment to pipeline development. It is not surprising, therefore, that next-generation biologics, particularly antibody-like scaffolds that offer many of the advantages of the original biologic drugs but in simplified formats, have entered the clinic as competing substitute therapeutic products, to capture market share.Specifically, this paper will position shark-derived variable new antigen receptors (VNARs) within an overview of the existing biologics landscape including the growth, diversity and success to date of alternative scaffolds. The intention is not to provide a comprehensive review of biologics as a whole but to discuss the main competing single-domain technologies and the exciting therapeutic potential of VNAR domains as clinical candidates within this context.The inherent ability to specifically bind target and intervene in disease-related biological processes, while reducing off-site toxicity, makes mAbs an effective, potent and now proven class of therapeutics. There are, however, limitations to these 'magic bullets'. Their size and complexity can restrict their utility in certain diseases types and disease locations. In contrast, a number of so-called alternative scaffolds, derived from both immunoglobulin- and non-immunoglobulin-based sources have been developed with real potential to overcome many of the shortcomings documented for mAb treatments. Unlike competing approaches such as Darpins and Affibodies, we now know that shark VNAR domains (like camel VHH nanobody domains), are an integral part of the adaptive immune system of these animals and have evolved naturally (but from very different starting molecules) to exhibit high affinity and selectivity for target. In addition, and again influenced by the environment in which they have evolved naturally, their small size, simple architecture, high solubility and stability, deliver additional flexibility compared to classical antibodies (and many non-natural alternative scaffolds), thereby providing an attractive basis for particular clinical indications where these attributes may offer advantages.

Numerous therapeutic strategies are used to treat leishmaniasis. The treatment of cutaneous leishmaniasis (CL) is solely depends on antimonate derivatives with safety issues and questionable efficacy and there is no fully effective modality to treat CL caused by Leishmania tropica and Leishmania braziliensis.There is no prophylactic vaccine available against any form of leishmaniasis. Immunotherapy for CL has a long history; immunotherapy trials of first and second generation vaccines showed promising results. The current article briefly covers the prophylactic vaccines and explains different immunotherapy strategies that have been used to treat leishmaniasis. This paper does not include experimental vaccines and only lays emphasis on human trials and those vaccines which reached human trials.Immunotherapy is currently used to successfully treat several disorders; Low cost, limited side effects and no possibility to develop resistance make immunotherapy a valuable choice especially for infectious disease with chemotherapy problems. Efforts are needed to explore the immunological surrogate marker(s) of cure and protection in leishmaniasis and overcome the difficulties in standardization of crude Leishmania vaccines. One of the reasons for anti-leishmaniasis vaccine failure is lack of an appropriate adjuvant. So far, not enough attention has been paid to develop vaccines for immunotherapy of leishmaniasis.

Addiction to cocaine is a major problem around the world, but especially in developed countries where the combination of wealth and user demand has created terrible social problems. Although only some users become truly addicted, those who are often succumb to a downward spiral in their lives from which it is very difficult to escape. From the medical perspective, the lack of effective and safe, non-addictive therapeutics has instigated efforts to develop alternative approaches for treatment, including anticocaine vaccines designed to block cocaine's pharmacodynamic effects.This paper discusses the implications of cocaine pharmacokinetics for robust vaccine antibody responses, the results of human vaccine clinical trials, new developments in animal models for vaccine evaluation, alternative vaccine formulations and complementary therapy to enhance anticocaine effectiveness.Robust anti-cocaine antibody responses are required for benefit to cocaine abusers, but since any reasonably achievable antibody level can be overcome with higher drug doses, sufficient motivation to discontinue use is also essential so that the relative barrier to cocaine effects will be appropriate for each individual. Combining a vaccine with achievable levels of an enzyme to hydrolyze cocaine to inactive metabolites, however, may substantially increase the blockade and improve treatment outcomes.

Systemic lupus erythematosus (SLE) is a diverse autoimmune disease affecting many different organ systems. Although disease manifestations are varied across the lupus population, the widespread presence of autoantibodies indicates that SLE immunopathology involves B-cell dysregulation. Belimumab, a human anti-B-cell activating factor (BLyS) monoclonal antibody, was invented by Human Genome Sciences and co-developed with GlaxoSmithKline and became, in 2011, the first new therapy approved for SLE patients in over 50 years.Belimumab approval represents a milestone as a new treatment for a subset of SLE patients and also a window onto the continued unmet need for many patients suffering from this diverse disease. This paper analyses the drugs and clinical trials of industry-sponsored development programs to profile the current SLE landscape and to consider how belimumab is shaping the future of SLE drug development.Our analysis demonstrates that the belimumab clinical program created a model for improvements in study designs that is reflected in ongoing clinical trials sponsored by a broad range of companies. Additional BLyS inhibitors, with distinctive targeting characteristics, are now in late stage development. A broad range of drugs with other mechanisms of action are also under investigation in Phase II - III trials, some of which are focused on the underserved lupus nephritis population.

Type I interferons (IFNs) comprise a group of at least 13 structurally related subtypes of IFN-α with similar, but not identical, biological activities. Each subtype displays a unique activity profile; only IFN-α2a and IFN-α2b subtypes together with natural IFN-α preparations are currently used in the clinical practice, so that the remaining IFN-α subtypes are a still unexploited reservoir of opportunity also in the new era of direct-acting antiviral agents for the treatment of hepatitis C virus (HCV).This paper reviews recent progress in the study of the biology of IFN family, the antiviral action mechanism and the strategies employed by HCV to evade IFN action. Currently available IFN preparations for the treatment of chronic hepatitis C infection are described and what is currently known on the pharmacokinetics, pharmacodynamics and immunogenicity of IFN-α preparations used in clinical practice are summarized.The characterization of multifunctional nature of IFN system together with recent advances in the identification of HCV IFN evasion strategies and the variety of host factors influencing IFN treatment response should be considered to improve HCV and other infectious diseases treatment in the future.

Immunotherapy of breast cancer has been shown to prevent recurrence, improve survival and eliminate breast cancer in humans.The reason for this review is to present the current information and the prospects for the future of immunotherapy of breast cancer in humans to include tumor antigens for vaccines and targets for monoclonal antibodies and adoptive T-cell therapy, and immune modulatory agents, such as adjuvants to stimulate the immune response and inhibitors of checkpoint blockade to prevent downmodulation of activated lymphocytes, to enhance these modalities. The research discussed and the literature search undertaken is of the clinical immunotherapy of breast cancer in humans, from 2000 to September, 2011.The key message of the paper is that one reason for the failure of the immune system to control macroscopic disease is that the immune escape mechanisms involving both tumor and the tumor stroma prevent the immune system from destroying the tumor. Changing the tumor microenvironment is necessary to eliminate macroscopic tumors. Prospects for improvement are proposals for combining current modalities of therapy with type 1 cellular immunity-inducing agents, all targeting multiple tumor antigens and in the context of minimal disease.

At the beginning of the new millennium, there was a breakthrough in platelet-rich plasma (PRP) therapy for tissue repair. The mechanisms governing the effects of this therapy in joint pathology remain largely unexplored.This review is primarily based on PubMed and Web of Knowledge searches with the terms osteoarthritis in combination with PRP, treatment, cartilage, synovium, platelets, inflammation and/or angiogenesis. This search was completed by a manual search for relevant studies. We mainly include papers from the last 5 years. The concept of dynamic reciprocity is used to shape understanding of the spatial relationship between cells and their microenvironments as well as between tissues within the joint. We describe the processes of joint injury and pathology relevant to the mechanism of action of PRP, and elaborate insights into how PRP components may influence inflammation, angiogenesis, cell death and cartilage chondroprotection.PRP therapies are more complicated than previously acknowledged, and an understanding of the fundamental processes and pivotal molecules involved will hopefully be elucidated soon. This challenge is to provide a comprehensive description of the relationship between PRP components, healing mechanisms and clinical outcomes. Although PRP therapies in clinical trials await assessment, they have shed light on new avenues of management because of their effects on repair functions.

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.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.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.

This paper evaluates a recent study whereby a four-drug combination regimen adding bevacizumab to triplet fluorouracil, oxaliplatin and irinotecan chemotherapy is described for the first-line treatment of metastatic colorectal cancer. It extends the use of intensive medical treatments combining chemotherapy and the VEGF inhibitor bevacizumab, opening new perspectives for the design of four-drug intensive regimen-associating chemotherapy and targeted agents. In the future, these four-drug intensive regimens should be further improved for efficacy:toxicity ratio and verification in randomized trials.

Chronic hepatitis C affects 2.2 - 3% of the world population (130 million - 170 million). Pegylated IFN-α in combination with ribavirin, the currently approved therapy, leads to viral eradication in about 50% of treated patients, nevertheless it is associated with not negligible adverse events. Continuous efforts are being applied to improve the efficacy by means of new interferon molecules. Consensus IFN-α is currently available for use, while albumin-interferon, IFN-λ and IFN-ω are under investigation. Research is focussed on the directly acting antivirals, such as telaprevir and boceprevir, which are anticipated to enter the drug market during the next few years.This paper reviews the classification of interferons, mechanism of action, pegylated IFN-α molecules and their differences, current chronic hepatitis C treatment regimen and new drugs for HCV treatment.Pegylated IFN-α will remain the basis of anti-HCV therapy during the next decade, since new IFN formulation are not proven to be superior or are in early stages of development and directly acting antivirals show limited antiviral activity as monotherapy.

Biomimetic scaffolds and substrates of extracellular matrices (ECMs) play an important role in the regulation of cell function and in the guidance of new tissue regeneration, as an ECM has the intrinsic cues necessary to communicate with and dictate to cells.This paper reviews the latest developments in ECM scaffolds and substrates obtained from decellularized tissues, organs or cultured cells and their application in tissue engineering. The ECM composition, structure, interaction with surrounding cells, preparation method and usage in the regeneration of various tissues and organs are summarised.The advantages and challenges of decellularized matrices are highlighted.Similarity in the composition, microstructure and biomechanical properties of the decellularized scaffolds and substrates to those of the native tissues and organs maximizes the promotion effect in the regeneration of both structural and functional tissues and organs. Simple tissues as well as complicated organs have been decellularized and decellularization methods have been optimized to completely remove the cellular components while keeping the ECM intact.

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.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.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.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.

Defibrotide is a polydisperse oligonucleotide with antiatherosclerotic, anti-inflammatory, anti-ischaemic, pro-fibrinolytic and antithrombotic actions without significant systemic anticoagulant effects. It has been used in the treatment of various cardiovascular disorders, and especially in endothelial complications of allogeneic stem-cell transplantation. We reviewed the published work for the mechanism of action and clinical use of defibrotide to consolidate data and to describe new applications of this drug. We reviewed the most relevant papers on defibrotide published from November 1982 to January 2008. (selected through PubMed), and used recent meeting abstracts as sources for this review. Reports have suggested that defibrotide has clinical efficacy for treatment and prophylaxis of hepatic sinusoidal obstruction syndrome occurring after stem-cell transplantation. Animal models have clearly shown the potential antineoplastic effect of this drug. Further clinical investigations are needed to clarify this new application.

Background: Epaxal®, a virosomal vaccine against hepatitis A virus (HAV) infection, has been in use for nearly 15 years, especially among at-risk adults. Recent studies have shown that it is also a potent vaccine for children. Objective: To summarise recent advances of Epaxal® Junior (0.25 ml, paediatric formulation). Methods: Published papers reporting results on the virosomal HAV vaccine were abstracted and reviewed. Results/conclusion: In a comparative randomised trial, the paediatric dose was found to be highly immunogenic and non-inferior to the standard dose with respect to seroprotection rates. The concomitant administration of virosomal HAV vaccine with routine childhood vaccines was investigated in another trial. The virosomal HAV vaccine did not interact with the antibody response of routine childhood vaccines which in turn did not reduce the antibody response to HAV. In countries that recommend immunisation against hepatitis A, this virosomal vaccine is an excellent candidate with few side effe...

T4 endonuclease V was originally isolated from Escherichia coli infected with T4 bacteriophage. It has been shown to repair ultraviolet (UV)-induced cyclobutane pyrimidine dimers in DNA, which, when unrepaired, contribute to mutations that result in actinic keratoses and non-melanoma skin cancers (NMSC). This is a particular concern in patients with genetic defects in their DNA repair systems, especially those with xeroderma pigmentosum (XP). When packaged in liposomes and applied topically, T4 endonuclease V can traverse the stratum corneum and become incorporated within the cytoplasm and nucleus of epidermal keratinocytes and Langerhans cells.To review all major studies evaluating the efficacy of T4 endonuclease V in animals and humans, the toxicity and safety profile of the topical medication and its potential clinical uses.A literature search was performed through PubMed/Medline, using the keywords 'T4N5', 'T4 endonuclease V' and 'dimericine'. Papers found in the bibliographies of those identified in the initial search and deemed relevant were also included.This enzyme increases the repair of UV-damaged DNA and produces other beneficial effects on UV-damaged cells. In clinical trials in XP patients, topical application of liposome-encapsulated T4 endonuclease V reduced the incidence of basal cell carcinomas by 30% and of actinic keratoses by68%. Adverse effects were minimal, and there was no evidence of allergic or irritant contact dermatitis. Although the photoprotective effect of T4N5 has been investigated only in XP patients, the possibility exists that it may benefit others likely to develop premalignant keratoses and NMSC, such as organ transplant recipients receiving immunosuppressive therapy and individuals who have had numerous psoralen plus UVA photochemotherapy treatments. It may be also be effective for normal individuals.

BACKGROUND: A recent incident, the halting of a Phase I/II trial utilising an adeno-associated vector, highlights the fact that there are more hurdles to overcome prior to a full realisation of gene therapy in the clinical arena. METHODS: The sources of information used to prepare the paper were obtained through published work on Pubmed/Medline and materials published on the US/UK governmental agency websites. RESULTS/CONCLUSION: Over the years, two fatal incidents associated with viral vector usage have been reported. Viral vectors used as carriers for gene therapy have failed in safety trials on two occasions. Also, the human immune response and the oncogenic property of the vectors have restricted the advancement of gene therapy as a therapeutic tool. Nonetheless, gene therapy has now progressed from its infancy 'proof of concept' stage, to the next stage in which we try to overcome the problems associated with therapeutic application. However, this progression has been slow as more and more setbacks have occurred. This calls for a new perspective and radical thinking about future vector development.

There is still considerable controversy concerning the issue of testosterone replacement therapy. This is because testosterone replacement therapy is not a 'risk-free' treatment and a randomized controlled trial to evaluate safety of prolonged testosterone replacement therapy is not available, nor is it likely to be in the near future. However, recent testosterone delivery systems, such as the 1% gel (Testogel, Androgel and Testim), have proven to have a good physiologic profile, allowing constant monitoring of the possible complications and prompt discontinuation in the event of adverse effects. The aim of this paper is to provide a comprehensive review of the available testosterone preparations to treat male hypogonadism, with special interest in the treatment of ageing men and late-onset hypogonadism. In addition, the experimental and clinical data on the effect of testosterone on sexual function domains is reviewed along with the indication for the combination therapy of androgens with pro-erectile drugs, for example, type 5 phosphodiesterase inhibitors.

This paper covers highlights from the International Society for Biological Therapy of Cancer (iSBTc) 21st Annual Meeting, including the associated iSBTc Primer on Tumor Immunology and Biological Therapy, and the iSBTc Mini-Symposium on the Biologic Effects of Targeted Therapies. The programs ran from 26 – 29 October 2006 and were held at the Hyatt Regency Century Plaza in Los Angeles, CA, USA. Focussed on the varying aspects of biological cancer therapies and tumor immunology, the iSBTc 21st Annual Meeting featured 131 scientific posters, 29 oral abstract presentations, 20 invited speaker lectures and 2 keynote addresses. The 21st Annual Meeting, Primer and Mini-Symposium were attended by > 400 clinicians and basic scientists from academia, industry and government. The iSBTc was founded in 1984 as the Society for Biological Therapy with 40 charter members. At present, the Society has > 500 members consisting primarily of MDs, PhDs, RNs and corporate representatives. Scientific and business meetings have b...

Cancer immunotherapy looks back over one century of clinical applications. In spite of major advances in the comprehension of oncogenesis and treatment of cancer, malignant tumours remain a leading cause of disability and death worldwide. Since 1991, a breakthrough in immunology allowed the identification of tumour-associated antigens, opening the era of specific immunotherapy. On the other hand, recombinant virus are powerful vectors that are able to express various gene products in vivo, including cytokines and tumour antigens. Therefore, many groups have implemented clinical trials of active specific tumour immunotherapy. Phase I trials have demonstrated favourable safety profiles. However, major tumour responses remain anecdotal in heavily metastatic patients. This review will critically present and discuss the clinical achievements of recombinant virus-based cancer immunotherapy. This paper will attempt to shed some light on the perspectives opened by advanced cancer immunotherapy protocols, review the drawbacks of this approach and the reasons why it is believed that recombinant virus-based cancer immunotherapy may be of relevance in the treatment of human malignancies.

Organ damage or loss can occur from congenital disorders, cancer, trauma, infection, inflammation, iatrogenic injuries or other conditions and often necessitates reconstruction or replacement. Replacement may take the form of organ transplant. At present, there is a severe shortage of donor organs that is worsening with the aging of the population. Tissue engineering follows the principles of cell transplantation, materials science and engineering towards the development of biological substitutes that can restore and maintain normal tissue function. Therapeutic cloning involves the introduction of a nucleus from a donor cell into an enucleated oocyte to generate embryonic stem cell lines whose genetic material is identical to that of its source. These autologous stem cells have the potential to become almost any type of cell in the adult body, and thus would be useful in tissue and organ replacement applications. This paper reviews recent advances in stem cell research and regenerative medicine, and describes the clinical applications of these technologies as novel therapies for tissue or organ loss.

As our understanding of the immunological and genetic basis of inflammatory bowel disease (IBD) grows, potential therapeutic options are being developed at a rapid pace. Nevertheless, new drugs for IBD are needed because about half of all patients with severe ulcerative colitis (UC) eventually undergo colectomy, and a significant part of Crohn's disease (CD) patients do not respond to standard medical therapies, including immunosuppressants and TNF-alpha neutralising antibodies, or suffer from significant side effects. Finally, recurrence of disease activity following remission is frequent in both UC and CD, and there is an unmet need for effective maintenance strategies. It is well-known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only does active suppression by regulatory T (TR) cells play an important role in the normal intestinal homeostasis, but also its dysregulation might lead to the development of IBD. TR cells are functional subsets of T cells that downregulate adaptive immune responses by interfering with the activation of dendritic cells and proliferation of T cells. From experimental work it is now clear that TR cells play a critical role in maintaining immune homeostasis, and several therapeutic approaches have been targeted at the induction of TR cells in order to control mucosal inflammation. Before using TR cells clinically as living immunosuppressants for the treatment of IBD, however, we have to pass many critical checkpoints, such as the in vitro expansion of TR cells and the confirmation of their safety. This paper will discuss recently gained knowledge of human TR cells and the possibility of their clinical usages as a new strategy for the treatment of IBD.

The selection of high-producing cell lines is usually time-consuming and labour-intensive. Following transfection, high-producing cells are selected using limiting dilution cloning to prevent non- and low-producing cells from outgrowing high-producing cells, a process that normally takes > 3 months. During this time, the cells have to be screened occasionally to ensure stability of the selected clone. Several new methods for selecting and screening cells using flow cytometry and cell sorting have recently been developed; these include gel microdrop technology, which encapsulates the cells in gelatine beads, and matrix-based secretion assays. This paper reviews these techniques for selecting high-producing cell lines and isolating rare cells.

Asthma is a disorder of increasing severity and prevalence. Present understanding of the pathogenesis of asthma emphasises its inflammatory nature. Unbridled inflammation appears to induce irreversible changes, collectively known as airway remodelling. CpG oligonucleotides are a class of compounds that have been developed from studies of prokaryotic DNA. Bacterial DNA, for example, contains sequence motifs based on the dinucleotides cytosine-guanine (CpG); these motifs are suppressed in mammalian DNA and induce (as part of the innate immune system) inflammation, characterised by the induction of T helper type 1 and regulatory responses. The pattern of inflammation promoted by CpG DNA tends to suppress the cytokine and cellular responses characteristic of asthma and atopic disorders. This has led to the investigation and development of CpG DNA as a novel therapeutic approach for the treatment and prevention of these disorders. In addition to suppressing acute and persistent airway inflammation, CpG DNA also reduces the development of subepithelial collagen deposition, goblet cell hyperplasia/metaplasia, and other aspects of airway remodelling. In this paper, the effects of CpG DNA on asthma inflammation and remodelling are reviewed.

Cellular loss is a common pathological observation in many disease conditions. Recent evidence that these cells can be replaced has generated huge excitement over possible clinical applications. The use of stem or progenitor cells, which can differentiate into site-appropriate phenotypes required to "repair" the damaged tissue, has already demonstrated potential in animal models, but many aspects of this novel treatment strategy require further elucidation. Most importantly, the monitoring of the safety of cellular transplants in patients remains a challenge. Traditional histological methods do not address the dynamic nature of transplant-induced recovery and highlight the necessity of in vivo imaging to probe the survival, migration and functional consequences of transplanted cells. This paper reviews how non-invasive imaging technology can be used to serially assess intact living organisms in order to visualise and monitor cellular transplants.

The incidence of adenocarcinoma of the pancreas has risen steadily over the past four decades. Since pancreatic cancer is usually diagnosed at an advanced stage and because of the lack of effective therapies, the prognosis of such patients is extremely poor. Despite advances in our understanding of the molecular biology of pancreatic cancer, the systemic treatment of this disease remains unsatisfactory. Conventional chemotherapy has not produced dramatic improvements in response rates or patient survival. New treatment strategies are clearly needed. This paper will review emerging therapies for pancreatic carcinoma. A deeper understanding of the molecular biology of cell growth and proliferation, as well as of neoplastic cell transformation, has led to advances in several areas, including the use of hormones and antihormones as adjuvant therapy; inhibition of tumour growth and metastasis by inhibitors of matrix metalloproteases and angiogenesis, and by small molecules, such as retinoids, which interfere with progression through the cell cycle; immunotherapy with monoclonal antibodies; disruption of intracellular signal transduction with farnesyltransferase inhibitors; and, finally, gene therapy with specifically designed vaccines.

This paper aims to review the current progress in bioadhesion for drug delivery applications as well as new techniques related to this field. Research started with mucoadhesive polymers that had already been in use as excipients and were rapidly used in new formulations. Their major drawback was found in their unspecific binding, as they adhere to almost any mucosal surface. As some of the polymers showed additional properties such as enzyme inhibition and permeation enhancement, however, they remain interesting as multifunctional excipients. In contrast to mucoadhesion, the concept of specific bioadhesion by use of lectins and other adhesion molecules is now gaining increasing attention as these substances bind directly to receptors on the cell surface rather than to the mucus gel layer. Since specific binding to the cell surface is often followed by uptake and intracellular transport, new chances for drug delivery evolved. Bioadhesion may, thus, enable researchers to deliver macromolecular drugs directly to specific target cells and has implications also relevant to other fields of science, such as tissue engineering, gene delivery and nanotechnology.

The lack of any meaningful regeneration in the adult central nervous system (CNS) subsequent to damage or degeneration stimulated the concept of replacement of the deficient cells by transplantation. Thus, much time and effort has been spent on investigating the potential of cell replacement therapy for repair in a range of conditions of the CNS over the last 25 years. As promising proof of principle basic science results were slowly converted to success in clinical transplantation trials in Parkinson's disease (PD), the future seemed very encouraging for cell therapy. However, the recent randomised, double-blind, placebo-controlled studies of fetal neural transplantation in PD have produced more equivocal results, which has dampened enthusiasm for this approach. However, whilst the translation of cell therapies to the clinic is in limbo, the emergence of stem cells as a source of the replacement tissue has revitalised the laboratory-based studies. This paper attempts to reconcile these disparate views and put forward the authors' view on the future of this form of biological therapy and its implications for related therapies.

The June issue of Expert Opinion on Biological Therapy (EOBT) contains a review article entitled ‘Ipilimumab in the Treatment of Melanoma’ [1]. I highly recommend this excellent paper to all colleagues interested in the treatment of patients with metastatic melanoma, because it provides detailed information without neglecting open questions in a field where rapid change is just taking place and where new orientation is urgently needed. Among the white population, malignant melanoma is one of the malignancies with the currently highest increase in incidence worldwide, and even adolescents and young adults are more and more involved. Despite enormous efforts over many decades, the prognosis of stage IV melanoma remained very poor until 2010, characterized by median survival periods of about half a year and 2-year survival rates around 10%. Now, the struggle against melanoma has entered a new era. This was highlighted by two presentations about new therapies of advanced melanoma during the plenary session of the ASCO annual meeting 2011 in Chicago. Vemurafenib, a selective BRAF inhibitor, has become an option for about 50% of advanced melanoma patients, namely for those with V600 mutations of the BRAF gene in their metastatic melanoma cells [2]. Ipilimumab, a monoclonal antibody binding to the cytotoxic T-lymphocyte antigen 4, successfully pioneers the immunotargeted therapy for advanced melanoma [3,4]. The same strategy, namely blocking negative regulators of immune activity, appears to be as well successful in early trials with programmed death 1 antibodies not only in the fight against metastatic melanoma, but also against other advanced malignancies [5]. Interestingly, the breakdown of immune tolerance appears to result in more efficient anti-tumor therapies than previous attempts to stimulate the immune system with vaccinations or with cytokines [6-8]. Regarding ipilimumab, two successful phase-III trials brought both the approval of the FDA in the U.S.A. and that of the EMA in Europe for the treatment of stage-4 and of unresectable stage-3 melanoma. In Europe, however, this approval is reserved for the second-line therapy following the failure of another first-line treatment. At the first glance, this restriction seems to be hardly tolerable for patients, who urgently need an efficient therapy and who may not have good alternatives to ipilimumab. On the other hand, ipilimumab is efficient only for a minority of melanoma patients. These patients, who indeed tend to have long-term benefits, can unfortunately not yet be identified a priori. On the contrary, it may take 4 months, until such benefits----or the failure----of this highly expensive therapy become apparent, and even the detection of an increased T-cell infiltrate in a melanoma metastasis during the treatment is not a reliable predictor of clinical success [9]. Furthermore, severe adverse events resulting from the activation of auto-immunity, cannot be disregarded in the competition of ipilimumab with other therapeutic options for the priorities how to treat patients with advanced melanoma [10]. But is not a

Erythrocytes have been suggested to be smart carriers for drugs, biologics and other therapeutic agents, and a paper in the present issue of the journal confirms the wide interest and the expectations the technology has generated. In this Editorial, I briefly summarize the advances in the field and try to figure out the process that will take this technology to the clinic. The conclusion is that, after several years of basic research, the time is fast approaching since two companies in Europe are actively engaged in industrializing the process and searching approval for treatments with structured clinical trials.