Current Pharmaceutical Design - Volume 11, Issue 27, 2005

The incidence of cancer and its related morbidity and mortality remain on the increase in both developing and developed countries. Cancer remains a huge burden on the health and social welfare sectors worldwide and its prevention and cure remain two golden goals that science strives to achieve. Among the treatment options for cancer that have emerged in the past 100 years, cancer vaccine immunotherapy seems to present a promising and relatively safer approach as compared to chemotherapy and radiotherapy. The identification of different tumour antigens in the last fifteen years using a variety of techniques, together with the molecular cloning of cytotoxic T lymphocytes (CTLs)- and tumour infiltrating lymphocytes (TILs)-defined tumour antigens allowed more refining of the cancer vaccines that are currently used in different clinical trials. In a proportion of treated patients, some of these vaccines have resulted in partial or complete tumour regression, while they have increased the disease-free survival rate in others. These outcomes are more evident now in patients suffering from melanoma. This review provides an update on melanoma vaccine immunotherapy. Different cancer antigens are reviewed with a detailed description of the melanoma antigens discovered so far. The review also summarises clinical trials and individual clinical cases in which some of the old and current methods to vaccinate against or treat melanoma were used. These include vaccines made of autologous or allogenic melanoma tumour cells, melanoma peptides, recombinant bacterial or viral vectors, or dendritic cells.

Besides the traditional therapeutic options, treatment with antibodies specific for the receptor tyrosine kinase HER-2/neu has been established as a standard therapy in the clinical management of advanced breast cancer. Ongoing clinical studies focus on the improvement of application protocols in order to minimize side effects and evaluate the potential therapeutic benefit of anti-HER-2/neu antibodies in combination with conventional chemotherapy. Various similar strategies to target other tumour-associated antigens or proangiogenic factors with inhibitory antibodies are currently investigated in promising preclinical and clinical trials. In addition, research efforts are made to develop procedures to generate tumour-specific cellular immune responses in breast cancer patients. Therapeutic vaccination is, however, still at an early stage of development, despite encouraging results of animal studies. We summarise and discuss vaccination strategies with tumour-specific proteins or peptides, pulsed dendritic cells, and modified tumour cells as well as antibody-based therapeutic concepts to target HER-2/neu, EGF receptor, MUC-1, uPA/uPAR, and VEGF.

Human papillomavirus (HPV) infection represents the most important risk factor for the development of cervical dysplasia and cervical cancer. Several lines of evidence suggest that cell-mediated immune responses are important in controlling both HPV infections and HPV-associated neoplasia. Since HPV E6 and E7 oncoproteins are expressed in these lesions and are necessary for the maintenance of the malignant phenotype, these proteins might be potential tumor-specific target antigens for immunotherapy of cervical cancer. The gold standard treatment for locally advanced cervical cancer is primary radiation therapy combined with chemotherapy. A potential drawback of this potentially curative treatment is a profound and long lasting negative effect on the immune system. Treatment-induced immunosuppression combined with tumor-induced subversion of the immune system may therefore impose severe limitations on the efficacy of conventional vaccination strategies in late stage cervical cancer patients. The recognition of dendritic cells (DC) as powerful antigen-presenting cells capable of inducing primary T cell responses in vitro and in vivo, has recently generated widespread interest in DC-based immunotherapy of several human malignancies. Here, we review various therapeutic HPV vaccines being developed and implemented in human clinical trials, with a particular emphasis on the use of autologous DC pulsed with full-length HPV 16 or 18 E7 oncoproteins as a novel strategy to induce HPV E7-specific and tumor-specific T cell responses in cervical cancer patients following conventional treatment.

During the last decade, a large number of human tumour antigens have been identified. These antigens are classified as tumour-specific shared antigens, tissue-specific differentiation antigens, overexpressed antigens, tumour antigens resulting from mutations, viral antigens and fusion proteins. Antigens recognised by effectors of immune system are potential targets for antigen-specific cancer immunotherapy. However, most tumour antigens are self-proteins and are generally of low immunogenicity and the immune response elicited towards these tumour antigens is not always effective. Strategies to induce and enhance the tumour antigen-specific response are needed. This review will summarise the approaches to discovery of tumour antigens, the current status of tumour antigens, and their potential application to cancer treatment.

Historically, patients with disseminated cancer have had poor prognoses and chemotherapy has been of little benefit. However, several different avenues of clinical research are providing reasons for hope. The advent of cytokine immunotherapy, particularly in combination with chemotherapy (biochemotherapy) has seen significantly improved outcomes for metastatic disease. Early biochemotherapy trials often revealed more than 20% complete responses. Unfortunately, Phase III trials have not confirmed earlier expectations for reasons that are not clear, but may reflect the inclusion of patients with refractory brain or other metastases in later trials. More recently, cancer vaccine therapies have provided significantly improved patient survival rates. It is not uncommon for 5-year survival rates of post-surgical patients recovering from metastatic malignancy who receive cancer vaccine therapy to reach more than 50%. Cytokines have become an integral part of cancer therapy and are also under trial together with cancer vaccines as post-surgical adjuvant therapies providing significant gains in long term survival rates. New insights from several different areas of research into the properties of tumour cells and their significance for immunosurveillance point to the importance of the tumour cells themselves as antigen presenting cells. Recent developments with genetically deficient animals and cancer cells have provided greater understanding at the molecular level of the importance of a functioning antigen presenting system operating inside tumour cells. This new knowledge offers support for further enhancing patient survival by combining previous therapies such as use of cytokines in biochemotherapy together with immunization using cytokine activated whole cell cancer vaccines in the future.

To develop an effective pharmaceutical treatment for a disease, we need to fully understand the biological behavior of that disease, especially when dealing with cancer. The current available treatment for cancer may help in lessening the burden of the disease or, on certain occasions, in increasing the survival of the patient. However, a total eradication of cancer remains the researchers' hope. Some of the discoveries in the field of medicine relied on observations of natural events. Among these events is the spontaneous regression of cancer. It has been argued that such regression could be immunologically-mediated, but no direct evidence has been shown to support such an argument. We, hereby, provide compelling evidence that spontaneous cancer regression in humans is immunologically-mediated, hoping that the results from this study would stimulate the pharmaceutical industry to focus more on cancer vaccine immunotherapy. Our results showed that patients with ≥3 primary melanomas (very rare group among cancer patients) develop significant histopathological spontaneous regression of further melanomas that they could acquire during their life (P = 0.0080) as compared to patients with single primary melanoma where the phenomenon of spontaneous regression is absent or minimal. It seems that such regression resulted from the repeated exposure to the tumor which mimics a selfimmunization process. Analysis of the regressing tumors revealed heavy infiltration by T lymphocytes as compared to non-regressing tumors (P <0.0001), the predominant of which were T cytotoxic rather than T helper. Mature dendritic cells were also found in significant number (P<0.0001) in the regressing tumors as compared to the non regressing ones, which demonstrate an active involvement of the different arms of the immune system in the multiple primary melanoma patients in the process of tumor regression. Also, MHC expression was significantly higher in the regressing versus the non-regressing tumors (P<0.0001), which reflects a proper tumor antigen expression. Associated with tumor regression was also loss of the melanoma common tumor antigen Melan A/ MART-1 in the multiple primary melanoma patients as compared to the single primary ones (P = 0.0041). Furthermore, loss of Melan A/ MART-1 in the regressing tumors significantly correlated with the presence of Melan A/ MART-1-specific CTLs in the peripheral blood of these patients (P = 0.03), which adds to the evidence that the phenomenon of regression seen in these patients was immunologicallymediated and tumor-specific. Such correlation was also seen in another rare group of melanoma patients, namely those with occult primary melanoma. The lesson that we could learn from nature in this study is that inducing cancer regression using the different arms of the immune system is possible. Also, developing a novel cancer vaccine is not out of reach.

Our study focuses on the reasons for market withdrawals of drugs and drug development project terminations in clinical phases I-III from 1992 to 2002. Over 90% of the market withdrawals were caused by drug toxicity. Hepatotoxicity and cardiovascular toxicity proved to be the major causes for two out of three market withdrawals in the respective time period. In clinical phases I-III 43% of drug development project terminations were due to insufficient efficacy of the investigated compound. The second important issue, which caused one third of the projects to be closed, was toxicity. ADME parameters and economic and other reasons played a minor role. The results of our study indicate that compared with previous studies on this subject, no major improvements have been achieved in the last decade.

Schizophrenia is a severe mental illness characterized by behavioral and cognitive symptoms. Several lines of evidence focus on a direct involvement of the glutamatergic system in the pathophysiology of psychosis. The hypofunction of the ionotropic glutamate N-methyl-D-Aspartate Receptor (NMDA-R) has been proposed as a model of schizophrenia in humans. Cortical and subcortical glutamate release seems to be modulated by dopaminergic and, to a lesser extent, serotoninergic circuitries, and tuned by intracellular pathways. Although dopamine D2 receptor blockade is a crucial mechanism of antipsychotics pharmacodynamic profile, a putative glutamatergic impact of these compounds is suggested by animal pharmacological isomorphisms of psychosis as well as by clinical studies. According to this view, the balance between D2 antagonism and NMDA-R modulation may be pivotal for the improvement of both positive and negative symptoms. Recently, many pharmacological strategies involving glutamate receptors have been suggested, and novel compounds and pharmacological strategies acting on glutamate transmission are currently under evaluation: i) augmentation strategies improving NMDA-R transmission (glycine, D-serine, Dcycloserine, glycine transporter inhibitors); ii) ampakines, positive modulators of AMPA (a-amino-3-hydroxy-5-methyl- 4-isoxazole propionic acid) receptor complex; iii) agonists of glutamate metabotropic receptors; iv) drugs involved in subcellular adaptation both at pre- and post-synaptic sites. Furthermore, molecular markers, suggesting modulation of glutamate circuitries after antipsychotics administration, are an attractive tool to shed more light on glutamate involvement in antipsychotics mechanism of action. In this review we provide a critical update of recent preclinical and clinical data on dopamine-glutamate interaction and its role in new pharmacological strategies for psychosis treatment