Tuberculosis vaccines: beyond bacille Calmette-Guerin

Tuberculosis (TB) disease caused by Mycobacterium tuberculosis (M. tb) remains one of the leading infectious causes of death and disease throughout the world. The only licensed vaccine, Mycobacterium bovis bacille Calmette-Guérin (BCG) confers highly variable protection against pulmonary disease. An effective vaccination regimen would be the most efficient way to control the epidemic. However, BCG does confer consistent and reliable protection against disseminated disease in childhood, and most TB vaccine strategies being developed incorporate BCG to retain this protection. Cellular immunity is necessary for protection against TB and all the new vaccines in development are focused on inducing a strong and durable cellular immune response. There are two main strategies being pursued in TB vaccine development. The first is to replace BCG with an improved whole organism mycobacterial priming vaccine, which is either a recombinant BCG or an attenuated strain of M. tb. The second is to develop a subunit boosting vaccine, which is designed to be administered after BCG vaccination, and to enhance the protective efficacy of BCG. This article reviews the leading candidate vaccines in development and considers the current challenges in the field with regard to efficacy testing.     

Schizophrenia: moving beyond monoamine antagonists

Schizophrenia is a disabling psychiatric disorder characterized by positive, negative, and cognitive symptoms. The first pharmacological treatments for schizophrenia were discovered by serendipitous, albeit carefully documented, clinical observations. The discovery of chlorpromazine and other dopamine D2 receptor antagonists as antipsychotic agents set the early course of drug discovery in the context of schizophrenia and other psychiatric disorders, and various monoamine receptors became the prime focus of neuropharmacological studies. Success in treating the positive symptoms nevertheless remained limited by the general lack of efficacy in addressing negative symptoms and cognitive impairment. In recent years, several new experimental approaches have emerged for the identification and treatment of different symptom clusters that do not rely on blockade of monoamine receptors. Muscarinic, nicotinic, and glutamatergic signaling mechanisms have become essential to neuropharmacological and behavioral models of discrete aspects of schizophrenia. And as a consequence of these insights, novel drug entities have become available to study and potentially treat the disabling cognitive and negative symptoms of psychiatric disease. Current attempts to target a new range of receptors entail unprecedented fine-tuning in the pharmacological manipulation of specific receptor subtypes.     

Tumor vaccines and beyond

For the last two decades the immunotherapy of patients with solid and hematopoietic tumors has met with variable success. We have reviewed the field of tumor vaccines to examine what has worked and what has not, why this has been the case, how the anti-tumor responses were examined, and how we can make tumor immunity successful for the majority of individuals rather than for the exceptional patients who currently show successful immune responses against their tumors.     

Cancer immunotherapy: exploiting neoepitopes

The efficacy of cancer vaccines has long been hampered by insufficient definition of tumor-specific antigens. A recent study by Kreiter et al. published in Nature has provided a blueprint for a patient-tailored approach to develop individualized RNA vaccines.For the past two decades, the concept of vaccination against cancer has suffered from insufficient definition of relevant target antigens. Consequently, clinical vaccination trials, typically targeting tumor-associated self-antigens, have generally failed to elicit therapeutic immunity in spite of detection of vaccine-induced T-cell responses in blood. In hindsight, these failures can be readily explained by the finding that many of these self-antigens are expressed in the thymus, resulting in deletion of the highly reactive T-cell repertoire and development of suppressive T-regulatory cells¹. Moreover, circumvention of thymic tolerance by infusion of genetically engineered T cells targeting such antigens was found to be associated with severe toxicity in vital somatic tissues, vividly illustrating the physiological importance of immunological tolerance to many tumor-associated antigens².In an almost ironic twist of science, clinical trials employing the two main ''competing'' approaches for cancer immunotherapy, have shown us how to move forward with cancer vaccines. First, in-depth evaluation of the T-cell response in melanoma patients who responded to TIL-therapy, and infusion of ex vivo expanded tumor-infiltrating T cells, revealed that the T-cell clones driving therapeutic efficacy were not directed against lineage-specific and cancer testis antigens, but instead against neo-epitopes encoded by the tumor mutanome³. Essentially the same observation was subsequently made in patients responding to so-called checkpoint inhibitors, antibodies against cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) or the programmed cell death (PD)-1/PD-L1 axis, that can activate T cells by neutralizing inhibitory pathways in T cells⁴.Since checkpoint inhibitors are not uniformly effective in every patient and every cancer type, while durable clinical responses frequently occur in the absence of overt manifestations of autoimmunity, it was fair to postulate that T cells unleashed by checkpoint inhibitors recognize patient- and cancer-specific neoantigens derived from non-synonymous mutations rather than conserved self-antigens. Indeed, whole-exome sequencing of pre- and post-treatment tumor tissue has since revealed a strong association of the clinical response to checkpoint inhibition with the frequency of pre-treatment non-synonymous mutations in mouse models⁵ and in human melanoma⁴ and non-small cell lung cancer⁶, two types of cancer with a particularly high mutational load.These findings have set the stage for coordinated programs to identify patient-specific mutated antigens and target these through specific vaccines or transfer of antigen-specific T cells. Set aside the economic and regulatory challenges resulting from this highly individualized approach, several important questions have to be clarified: How can we predict which of the 50-500 mutations in a given tumor are immunogenic? How can we identify not only HLA class I-restricted epitopes, but also HLA class II-restricted CD4+ T-helper epitopes that are of critical importance to support the immune attack by CD8+ T cells and innate effector cells? How do we implement this information towards the design of patient-tailored vaccines?The recent study by Kreiter and coworkers provided a blueprint for such an approach in the context of syngeneic mouse tumor models⁷. After identification of non-synonymous mutations through RNA and DNA sequencing and prioritization of the mutations based on expression level and prediction of presentation on MHC, animals were vaccinated using synthetic RNA vaccines encoding long peptides. Interestingly, the majority of immunogenic epitopes where found to be MHC class II-restricted⁷. The fact that non-synonymous cancer mutations are preferentially recognized by CD4+ T cells may not be so surprising as the requirements for peptide processing and binding to MHC II are less restrictive than that for MHC I⁸. A downside of this flexibility is that prediction algorithms for MHC class II presentation suffers from inaccuracy compared to class I algorithms. Hence testing in pre-clinical models such as MHC-transgenic mice may be necessary to experimentally identify such epitopes, as exemplified by a recent study characterizing a class II neo-epitope of the glioma driver mutation IDH1R132H⁹. Complementary assays such as in situ proximity ligation assay¹⁰ may aid the selection of neo-epitopes presented on class II molecules by MHC class II+ tumor cells or tumor-infiltrating antigen-presenting cells.The efficacy of neoantigen-specific CD4+ T cells in controlling established tumors raises the question as to what their mechanism of action is. While direct cytotoxicity by CD4+ T cells¹¹ may play a role in tumors expressing MHC class II, more prominent effector mechanism probably include the orchestration of CD8+ T cells and innate effector cells, as well as the anti-tumor impact of cytokines such as interferon-γ or tumor necrosis factor¹². The study by Kreiter et al. suggests that a multimer vaccine targeting CD4 neoepitopes may act by unmasking CD8 epitopes previously not visible or not sufficiently visible to the immune system. The delineation of this complex process of antigen spreading to CD8 epitopes will be important in the future to help further tailor individualized (neo)antigen-specific cancer vaccines.     

Cancer immunotherapy

Cancer is the second leading cause of death in the industrialized world. Most cancer patients are treated by a combination of surgery, radiation and/or chemotherapy. Whereas the primary tumor can, in most cases, be efficiently treated by a combination of these standard therapies, preventing the metastatic spread of the disease through disseminated tumor cells is often not effective. The eradication of disseminated tumor cells present in the blood circulation and micro-metastases in distant organs therefore represents another promising approach in cancer immunotherapy. Main strategies of cancer immunotherapy aim at exploiting the therapeutic potential of tumor-specific antibodies and cellular immune effector mechanisms. Whereas passive antibody therapy relies on the repeated application of large quantities of tumor antigen-specific antibodies, active immunotherapy aims at the generation of a tumor-specific immune response combining both humoral and cytotoxic T cell effector mechanisms by the host's immune system following vaccination. In the first part of this review, concurrent developments in active and passive cancer immunotherapy are discussed. In the second part, the various approaches for the production of optimized monoclonal antibodies used for anti-cancer vaccination are summarized.     

Conceptualizing evolutionary novelty: moving beyond definitional debates

According to many biologists, explaining the evolution of morphological novelty and behavioral innovation are central endeavors in contemporary evolutionary biology. These endeavors are inherently multidisciplinary but also have involved a high degree of controversy. One key source of controversy is the definitional diversity associated with the concept of evolutionary novelty, which can lead to contradictory claims (a novel trait according to one definition is not a novel trait according to another). We argue that this diversity should be interpreted in light of a different epistemic role played by the concept of evolutionary novelty-the structuring of a problem space or setting of an explanatory agenda-rather than the concept's capacity to categorize traits as novel. This distinctive role is consistent with the definitional diversity and shows that the concept of novelty benefits ongoing investigation by focusing attention on answering different questions related to comprehending the origins of novelty. A review of recent theoretical and empirical work on evolutionary novelty confirms this interpretation. J. Exp. Zool. (Mol. Dev. Evol.) 318B:417-427, 2012. ? 2012 Wiley Periodicals, Inc.     

Cancer epigenomics: beyond genomics

For many years cancer research has focused on genetic defects, but during the last decade epigenetic deregulation has been increasingly recognized as a hallmark of cancer. The advent of genome-scale analysis techniques, including the recently developed next-generation sequencing, has enabled an invaluable advance in the molecular mechanisms underlying tumor initiation, progression, and expansion. In this review we describe recent advances in the field of cancer epigenomics concerning DNA methylation, histone modifications, and miRNAs. In the near future, this information will be used to generate novel biomarkers of relevance to diagnosis, prognosis, and chemotherapeutic response.     

Carbohydrate vaccines as immunotherapy for cancer

Carbohydrates have established themselves as the most clinically relevant antigens of those tested and subsequently developed for vaccines against infectious diseases. However, in cancer patients, many of the defined carbohydrate antigens are really altered 'self' antigens and for unclear reasons, the body does not react to them immunologically. Although these self antigens have been found to be potentially suitable targets for immune recognition and killing, the development of vaccines for cancer treatment is actually more challenging compared with those for infectious diseases mainly because of the difficulty associated with breaking the body's immunological tolerance to the antigen. These antigens lack the inherent immunogenicity associated with bacterial antigens and, therefore, methods to enhance immunological recognition and induction of immunity in vivo are under investigation. These include defining the appropriate tumour-associated antigen, successfully synthesizing the antigen to mimic the original molecule, inducing an immune response, and subsequently enhancing the immunological reactivity so that all components can work together. This has been successfully accomplished with several glycolipid and glycoprotein antigens using carriers such as keyhole limpet haemocyanin (KLH) together with a saponin adjuvant, QS-21. Not only can high titre IgM and IgG antibodies be induced, which are specific for the antigen used for immunization, but the antibodies can mediate complement lysis. The approaches for synthesis, conjugation, clinical administration and immunological potential are discussed.     

Seahawk: moving beyond HTML in Web-based bioinformatics analysis

Background  

Traditional HTML interfaces for input to and output from Bioinformatics analysis on the Web are highly variable in style, content and data formats. Combining multiple analyses can therfore be an onerous task for biologists. Semantic Web Services allow automated discovery of conceptual links between remote data analysis servers. A shared data ontology and service discovery/execution framework is particularly attractive in Bioinformatics, where data and services are often both disparate and distributed. Instead of biologists copying, pasting and reformatting data between various Web sites, Semantic Web Service protocols such as MOBY-S hold out the promise of seamlessly integrating multi-step analysis.     

Dendritic cell metabolism: moving beyond in vitro-culture-generated paradigms

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Cancer immunotherapy.

Important contributions that stimulated studies in cancer immunotherapy included: (1) the discovery of tumour-associated antigens; (2) the observation that infection with bacille Calmette-Guérin (BCG) in animals was protective against tumour challenge; and (3) the observation that immunodepression due either to malignant disease or to treatment of the disease, was, in some instances, related to prognosis. Immunotherapy trials with microbial agents have involved attempts to obtain a local effect by injecting the agent into the tumour or into the region of the tumour and to obtain a "systemic" effect distant from the site of injection. Trials with active specific immunotherapy involving tumour cells or tumour cell extracts have frequently involved the combination of these specific agents with a nonspecific adjuvant such as BCG. Recent studies with thymosin and levamisole in patients with lung cancer and other types of malignant disease have shown prolonged survival in the groups receiving immunotherapy.     

Personalized neoantigen vaccines: A new approach to cancer immunotherapy

Neoantigens arise from somatic mutations that differ from wild-type antigens and are specific to each individual patient, which provide tumor specific targets for developing personalized cancer vaccines. Decades of work has increasingly shown the potential of targeting neoantigens to generate effective clinical responses. Current clinical trials using neoantigen targeting cancer vaccines, including in combination with checkpoint blockade monoclonal antibodies, have demonstrated potent T-cell responses against those neoantigens accompanied by antitumor effects in patients. Personalized neoantigen vaccines represent a potential new class of cancer immunotherapy.     

Corn-based vaccines: current status and prospects

Planta - Corn is an attractive host for vaccine production and oral delivery. The present review provides the current outlook and perspectives for this field. Among seed-crops, corn represents a...     

Imaging of intact tissue sections: moving beyond the microscope

MALDI-imaging MS is a new molecular imaging technology for direct in situ analysis of thin tissue sections. Multiple analytes can be monitored simultaneously without prior knowledge of their identities and without the need for target-specific reagents such as antibodies. Imaging MS provides important insights into biological processes because the native distributions of molecules are minimally disturbed, and histological features remain intact throughout the analysis. A wide variety of molecules can be imaged, including proteins, peptides, lipids, drugs, and metabolites. Several specific examples are presented to highlight the utility of the technology.     

Polarity in filamentous fungi: moving beyond the yeast paradigm

Filamentous fungi grow by the polar extension of hyphae. This polar growth requires the specification of sites of germ tube or branch emergence, followed by the recruitment of the morphogenetic machinery to those sites for localized cell wall deposition. Researchers attempting to understand hyphal morphogenesis have relied upon the powerful paradigm of bud emergence in the yeast Saccharomyces cerevisiae. The yeast paradigm has provided a useful framework, however several features of hyphal morphogenesis, such as the ability to maintain multiple axes of polarity and an extremely rapid extension rate, cannot be explained by simple extrapolation from yeast models. We discuss recent polarity research from filamentous fungi focusing on the position of germ tube emergence, the relaying of positional information via RhoGTPase modules, and the recruitment of morphogenetic machinery components including cytoskeleton, polarisome and ARP2/3 complexes, and the vesicle trafficking system.