Current Pharmaceutical Design - Volume 16, Issue 3, 2010

Active specific immunotherapy holds great potential in the search for new therapeutic approaches for patients with cancer. Much preclinical and clinical evidence has shown that the immune system can be polarized against malignant cells by several vaccination strategies. Exploiting a naturally occurring defense system, anticancer vaccination embodies an ideal non-toxic treatment for cancer that has been nourishing the hope of curing this disease for more than half a century. Despite the evidence that immune effectors can play a significant role in controlling tumor growth either in natural conditions or in response to therapeutic manipulation, the cascade of molecular events leading to tumor rejection by the immune system remains to be fully elucidated. Nevertheless, some recent tumor immunology advancements might drastically change the way to design the next generation of cancer vaccines, hopefully improving the effectiveness of this therapeutic approach. Although at present no anticancer vaccine can be recommended outside clinical trials, tumor response and immunological findings in animals and humans should prompt researchers to investigate further the potential of this biotherapy. In this issue of Current Pharmaceutical Design, the Authors address some of the most debated and crucial aspects regarding the preclinical development and clinical implementation of anticancer vaccines based on the latest tumor immunology molecular insights. In particular the articles describe the rationale of some of the most promising strategies to circumvent tumor immune escape mechanisms and thus to improve the clinical efficacy of active specific immunotherapy against malignancies. Zwirner N. and Rabinovich G. [1] from the Immunology Laboratory of the Buenos Aires University (Buenos Aires, Argentina) introduce the topic of the intricate network of interactions between tumor and immune cells that have revealed novel regulatory signals, including cell surface inhibitory receptors and costimulatory molecules, intracellular regulatory pathways, immunosuppressive cytokines and proapoptotic mediators, which may operate in concert to orchestrate tumor-immune escape. The Authors critically discuss how the control of the effector functions of innate and adaptive immune cells and the manipulation of regulatory pathways, either alone or in combination, could be exploited for therapeutic purposes in cancer patients. Dubovsky J. and Sotomayor E. [2] from the Department of Immunology and Department of Malignant Hematology of the Lee Moffitt Cancer Center (Tampa, FL, USA) focus first on the current understanding of the tenants of a good tumor antigen and how epigenetic manipulation of tumor cells might provide the long elusive “ideal antigen” with none or minimal tolerogenic potential. Then, the Authors comment on the emerging role of hystone deacetylase inhibitors and their targets in regulating inflammatory responses in antigen presenting cells as well as malignant cells themselves. The metabolic immune restraints that may hinder an appropriate immune response to anticancer vaccines - an emerging aspect of tumor immune escape - are discussed by Mocellin S. [3] from the Department of Oncological and Surgical Sciences of the University of Padova (Padova, Italy). The development of agents interfering with this phenomenon and thus potentially useful to increase the therapeutic effect of cancer vaccines is overviewed, providing readers with a comprehensive list of references regarding both preclinical and clinical evidences. Guinipero T. and Finn O. [4] from the Departments of Immunology and Pediatrics of the University of Pittsburgh (Pittsburgh, PA, USA) outline an interesting and somewhat unexpectedly neglected research field such as that of cancer vaccination in the pediatric population. Due to the greater capacity of a young immune system to recover after cancer treatment, therapeutic vaccines are expected to have a better chance to elicit protective immunity and prevent cancer recurrence in children. In this review, the Authors describe the current efforts at designing and testing cancer vaccines in children with the focus on specific tumor antigens expressed by pediatric cancers. Finally, Inoges S. and Bendandi M. [5] from Laboratory of Immunotherapy of the University of Navarra (Pamplona, Spain) and the Simmons Comprehensive Cancer Center of the University of Texas (Dallas, TX, USA) address another key issue such as the development of therapeutic vaccines against hematological cancers. In particular, the Authors focus on the preclinical evidence and clinical implementation of idiotype vaccines for B-cell malignancies, which are characterized by the unique feature of carrying tumor-specific antigenic sites such as the idiotopes found within the hypervariable regions of the immunoglobulin variable domain. Overall, this Current Pharmacology Design issue provides readers with an authoritative overview on some of the most interesting and critical aspects that must be faced by both basic researchers and clinical oncologists involved cancer vaccine development.

The improved understanding of the biochemical nature of tumor antigens and the identification of cellular and molecular mechanisms leading to activation of innate and adaptive immune cells have been of paramount importance in the progress of tumor immunology. Studies on the intricate network of interactions between tumor and immune cells have revealed novel regulatory signals, including cell surface inhibitory receptors and costimulatory molecules, intracellular regulatory pathways, immunosuppressive cytokines and proapoptotic mediators, which may operate in concert to orchestrate tumor-immune escape. This emerging portfolio of inhibitory checkpoints can influence the physiology of innate immune cells including dendritic cells, macrophages and natural killer (NK) cells, as well as different subsets of T cells to fine tune their effector function. The synergistic combination of strategies aimed at overcoming regulatory signals and/or stimulating effector pathways, may offer therapeutic advantage as adjuvants of conventional anticancer therapies. Based on this premise, we will discuss here how the control of the effector functions of innate and adaptive immune cells and the manipulation of regulatory pathways, either alone or in combination, could be exploited for therapeutic purposes in cancer patients.

In recent decades our understanding of immune cell activation and homeostasis has significantly expanded. Such progress helped to better define the cellular, molecular, and epigenetic networks involved in the immune response in the tumor microenvironment and renewed the enthusiasm towards the potential power of cancer immunotherapy. However, successful translation of novel mechanistic discoveries into effective immunotherapy was hindered by a number of obstacles, among them the ability of tumors to tolerize host lymphocytes rendering them functionally incompetent and the tumor's ability to evade antigen-specific immune recognition through a variety of genetic, epigenetic, and stromal factors. These immunosuppressive strategies have, thus far, blunted our efforts to effectively unleash anti-cancer immunity. Fortunately, the wealth of new information regarding the interactions between tumors and the immune system and the regulation of certain highly antigenic tumor proteins has led to novel approaches with the potential to render cancer cells helpless towards immune attack. Here we summarize recent findings on cancer-induced T-lymphocyte tolerance and discuss a novel “vaccinate-induce” strategy conceived to counteract these effects at an epigenetic level.

Metabolic immune restraints belong to a highly complex network of molecular mechanisms underlying the failure of naturally occurring and therapeutically induced immune responses against cancer. In the light of the disappointing results yielded so far with anticancer vaccines in the clinical setting, the dissection of the cascade of molecular events leading to tumor immune escape appears the most promising way to develop more effective immunotherapeutic strategies. Here we review the significant advances recently made in the understanding of the tumor-specific metabolic features that contribute to keep malignant cells from being recognized and destroyed by immune effectors. These mechanistic insights are fostering the development of rationally designed therapeutics aimed to revert the immunosuppressive circuits and thus to enhance the effectiveness of anticancer vaccines.

The success that vaccines have had in the fight with infectious diseases has not been mirrored in their use in the fight against cancer. The major differences are that cancer vaccines have been tested in the therapeutic rather than the prophylactic setting, and in older adults rather than in the pediatric population. Cancers, as well as current standard treatments, are highly immunosuppressive, which further compromises the success of therapeutic vaccines. Cancer is considered to be primarily a disease of the older age and yet many children suffer from or succumb to cancers such as leukemias, glioblastomas, neuroblastomas and sarcomas. Standard therapy, even when curative, is accompanied by serious side effects, including secondary tumors later in life. Due to the greater capacity of a young immune system to recover after cancer treatment, therapeutic vaccines are expected to have a better chance to elicit protective immunity and prevent cancer recurrence in children. In this review, we discuss the current efforts at designing and testing cancer vaccines in children with the focus on specific tumor antigens expressed by pediatric cancers.

After twenty years of use in humans, customized idiotypic vaccination yet remains a non-approved, experimental therapeutic option for patients with lymphoma and myeloma. Potentially applicable to all B-cell malignancies whose cells express a clonal immunoglobulin or its epitopes on their surface, this treatment is designed to prevent disease recurrence or progression. Mostly used in follicular lymphoma patients so far, idiotype vaccines have clearly shown biological efficacy, clinical efficacy and clinical benefit in this setting, although no study aiming at regulatory approval of the procedure has been able to meet its main clinical endpoints. In mantle cell lymphoma, only biological efficacy has been proven for idiotypic vaccination, while in multiple myeloma a limited number of studies support the notion of biological and perhaps even clinical efficacy, although no credible evidence of clinical benefit has still emerged. Idiotype vaccines have been produced and administered in a number of substantially different manners. Therefore, the results of most clinical trials cannot be easily compared, and even less pooled together in meaningful meta-analyses. A more creative and yet scientifically sound way to design clinical trials of customized active immunotherapies will be key to the future development of idiotype vaccines, particularly considering that we currently lack any clinical or biological indicator to possibly predict which patients are more likely to respond to idiotypic vaccination from an immunologic point of view. This review aims at summarizing the multifaceted success achieved by idiotype vaccines, as well as at outlining the challenges awaiting them in the near future: how to improve feasibility, immunogenicity and efficacy, as well as how to confirm benefit and gain regulatory approval.

Schizophrenia is a psychiatric disorder demonstrating a combination of positive symptoms such as delusions and hallucinations, negative symptoms such as apathy and lack of emotion, and cognitive dysfunctions. The etiology is still unknown although there are several hypotheses such as dopamine/glutamate hypothesis. Since chlorpromazine was found to be effective for the treatment of the patients with schizophrenia over 50 years ago, the first-generation antipsychotics have demonstrated clinical efficacy mainly for positive symptoms. The main target of these antipsychotics was dopamine D2 receptor. With the introduction of the second-generation antipsychotics, side effects such as extrapyramidal symptoms, which were often observed with high doses of the first-generation antipsychotics, have been reduced. On the other hands, other side effects such as weight gain and metabolic abnormalities, have emerged, and clinical efficacy with these drugs has not been enough especially for negative symptoms and cognitive impairment. Cognitive dysfunctions are one of the critical issues to determine the morbidity of schizophrenia. Although a common main target has been dopamine D2 receptor regardless of the generation of antipsychotics, other potential targets should be investigated for the development of novel antipsychotics. In this issue, current progress and future prospects of these potential targets for novel antipsychotic drugs were reviewed. Neuronal nicotinic acetylcholine receptors (nAChR) are expected to play a role for the cognitive dysfunction. Different functions have been reported by different subtypes of nAChR. Radek et al. [1] reviewed the possibility of the alpha4 beta2 nAChR agonists for the treatment of schizophrenia. Thomsen et al. [2] reviewed the neurological properties and the cognitive effects of alpha7 nAChR activation for the drug development. Neurokinin receptors, which were considered to be related with emotional functions, are another line of important targets. Dawson and Smith [3] reviewed the neurokinin receptors widely, and preclinical and clinical findings about NK3 receptor, which is relevant to the drug development for schizophrenia. In psychiatric diseases such as schizophrenia, it is not easy to establish the animal models. One of the successful animal models for the screening of antipsychotics is the condition avoidance response (CAR) test. Wadenberg [4] reviewed the significance, accuracy and use of the CAR test as a screening tool in current and future antipsychotic drugs. The measurement of the in vivo receptor occupancy by drugs has yielded the information relevant to dose selection and pharmacokinetics of antipsychotics. Takano [5] reviewed the utility of PET technique in the development and evaluation of novel antipsychotics. I hope this issue would help the readers to understand the current and future directions of the drug development for the treatment of schizophrenia.

Schizophrenic patients exhibit debilitating impairments of intellectual function. Typical and atypical antipsychotic medications are largely ineffective at treating the cognitive deficits of schizophrenia (CDS), and efforts to discover compounds that treat these symptoms are ongoing. Considerable tobacco use in schizophrenic patients, genetic linkage, and receptor binding studies suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in schizophrenia. Neuronal α4β2 nAChRs are widely distributed in the mammalian brain, and are implicated in normal cognitive functioning in animal models. Ligands of various selectivity and potency have been used to study the role of the α4β2 subtype in schizophrenia. For instance, studies in rodents show that α4β2 agonists improve sensory gating, an information processing function that is deficient in schizophrenia. Pharmacological studies in animals also suggest that α4β2 nAChRs are involved in other cognitive domains that are impaired in schizophrenia, including speed of processing, working memory, visual learning and memory, and social cognition. The non-selective nAChR agonist nicotine has been shown to improve CDS in several human clinical studies, and recent trials have been undertaken to evaluate the efficacy of more α4β2 selective compounds. It remains to be determined whether α4β2 agonists will provide greater efficacy than nicotine for CDS or reducing tobacco use in patients. Pre-clinical evidence to date suggests that agonists of the nicotinic α4β2 subtype could be useful in improving cognitive function in schizophrenic patients.

Agonists and positive allosteric modulators of the α7 nicotinic acetylcholine receptor (nAChR) are currently being developed for the treatment of cognitive disturbances in patients with schizophrenia or Alzheimer's disease. This review describes the neurobiological properties of the α7 nAChR and the cognitive effects of α7 nAChR activation, focusing on the translational aspects in the development of these drugs. The functional properties and anatomical localization of the α7 nAChR makes it well suited to modulate cognitive function. Accordingly, systemic administration of α7 nAChR agonists improves learning, memory, and attentional function in variety of animal models, and procognitive effects of α7 nAChR agonists have recently been demonstrated in patients with schizophrenia or Alzheimer's disease. The α7 nAChR desensitizes rapidly in vitro, and this has been a major concern in the development of α7 nAChR agonists as putative drugs. Our review of the existing literature shows that development of tolerance to the behavioral effects of α7 nAChR agonists does not occur in animal models or humans. However, the long-term memory-enhancing effects seen in animal models are not mimicked in healthy humans and schizophrenic patients, where attentional improvement predominates. This discrepancy may result from inherent differences in testing methods or from species differences in the level of expression of α7 nAChRs in limbic brain regions, and may hamper preclinical evaluation of α7 nAChR activation. It is therefore important to consider the translational power of the animal models used before entering into a clinical evaluation of the pro-cognitive effects of α7 nAChR activation.

The dopaminergic and glutamatergic hypotheses dominate current drug discovery strategies. The dopamine hypothesis states that hyperactivity of the mesolimbic dopaminergic pathway is associated with positive symptoms of the disease, whereas hypoactivity of the mesocortical dopaminergic pathway is associated with the negative and cognitive symptoms. Increasing evidence has also suggested that hypoactivity in the corticolimbic glutamatergic system may contribute to the complex interplay between dysfunctional aspects of these neurotransmitter systems, which could account for much of the symptomatology observed in schizophrenia. Current antipsychotic drugs display moderate efficacy in treating the positive symptoms and limited efficacy against the negative, cognitive, or co-morbidity symptoms of the disease. They are also associated with significant side effects such as extrapyramidal side effects and metabolic disturbances. Thus pharmacologies that are able to more selectively modulate the underlying neuronal substrates of schizophrenia may have utility as efficacious and wide spectrum antipsychotic therapies with potentially improved side effect liabilities. The neuropeptide neuromodulator / neurotransmitter class and their associated receptors have been suggested to be one such family class. One such target which has shown particular promise, and thus has gained much pharmaceutical research interest, is the neurokinin receptor family and particularly the NK3 receptor. The NK3 receptor is expressed almost exclusively within the mammalian nervous system and its localisation is commensurate with a role in modulating central monoaminergic neurotransmission. Here we will provide an introduction to both the neurokinin ligands and receptors and review current preclinical understanding of their putative biological roles and, in particular, their modulatory role in the circuitry pertinent to schizophrenia. A brief review of the available chemical strategies employed to produce selective tools and drug development candidates will also be undertaken. Finally we will summarize the available clinical information on those compounds which have progressed into patient populations and evaluate their potential therapeutic utility, and the future of the NK3 receptor target.

Schizophrenia presents with positive/psychotic, negative and cognitive symptoms. Positive symptoms seems due to a dopamine mesolimbic overreactivity, while negative/cognitive symptoms may conversely be due to mesocortical hypo-dopaminergia. Traditional dopamine D2 receptor blocking antipsychotics (e.g. haloperidol) are effective against psychotic/positive symptoms, but less so against negative/cognitive symptoms. Some D2 receptor blockage, however, seems necessary for efficacy against psychotic symptoms. Therefore, current antipsychotic drug improvement strategies include modest D2 receptor blockage, or partial D2 stimulation, combined with adjunct pharmacological properties that may enhance: i) D2 blockage efficacy; and ii) cognitive functioning. There are also strategies with no direct D2 blockage. Clinical activity is often tested in animal screening tests (so called animal models). The screening test conditioned avoidance response in rats has shown particular sensitivity, with high predictive validity, for detection of drug antipsychotic activity. The present review assessed the significance, accuracy and use of the conditioned avoidance response test as a screening tool in current antipsychotic drug development. It was found that: i) the conditioned avoidance response test holds a strong position, is frequently used in current antipsychotic drug development, and is commonly considered a reliable screening tool, with high predictive validity, for the detection of potential antipsychotic activity; ii) in current antipsychotic drug development, the conditioned avoidance response test is able to detect pharmacological properties contributing to antipsychotic activity in the presence of subtherapeutic D2 receptor blockade, as well as detecting antipsychotic activity of compounds having no direct D2 blocking properties.

Positron emission tomography (PET) is a useful technique to quantify various target molecules in vivo such as neuroreceptors, transporters and amyloid plaques using various successful radioligands. The technique has been widely used for the drug development in recent years. There are several approaches such as microdosing, measurement of in vivo receptor occupancy, and biomarkers. As for microdosing, the biodistrubution of the drugs in the human body could be evaluated in the very early phase of the drug development. The measurement of receptor occupancy in vivo could help to determine the optimal doses clinically before the largescale clinical trials are perfomred. As biomarkers, radioligands could detect the pathological changes such as the accumulation of betaamyloid and microglia. Especially the measurement of dopamine D2 receptor occupancy has been useful in the evaluation of antipsychotics. Based on it, the optimal clinical doses were evaluated and determined for the patients with schizophrenia. Although currently available antipsychotics have efficacy to the positive symptoms such as hallucination and delusion, they, regardless of the generations of antipsychotics, have only limited efficacy to the cognitive dysfunction and the negative symptoms such as apathy and social withdrawal. To aim to treat the cognitive dysfunction and negative symptoms, various targets such as glutamate receptors, tachykinin receptors, cannabinoid receptors, and nicotinic acetylcholine receptors, have been investigated recently. PET technique with the radioligands developed for these targets has potentials to rationalize and speed up the process of the drug development for the treatment of schizophrenia.