Ensuring efficient development of personalized medicine by addressing regulatory needs: What role can research infrastructures play?

Personalized Medicine is a novel medical practice that uses an individual's genetic profile to guide decisions made regarding the prevention, diagnosis, and treatment of disease. Knowledge of a patient's genetic profile is crucial to support doctors in selecting the proper therapy and administer it using the correct dose or regimen. Personalized Medicine is a great opportunity to turn the "one size fits all" approach to diagnostics, therapy, and prevention, into an individualized approach. In this paper we analyze the most recent achievements and regulatory challenges in Personalized Medicine and the role that research infrastructures can play in advancing its development.

Role of type I interferon in inducing a protective immune response: perspectives for clinical applications.

Type I IFNs (IFN-I) are antiviral cytokines endowed with many biological effects, including antitumor activity. Over the last 15 years, an ensemble of studies has revealed that these cytokines play a crucial role in the induction of a protective antitumor immune response. Early in vivo studies in mouse models have been instrumental for understanding the IFN-I-induced host-mediated mechanisms. IFN-α is currently recognized as a powerful inducer of the differentiation/activation of dendritic cells (DCs) and today IFN-α-conditioned DCs represent promising DC candidates for the development of therapeutic cancer vaccines. Moreover, data from pilot clinical trials support the concept of using IFN-α as an enhancer of the response of patients to cancer vaccines. Notably, endogenous IFN-I production does also play a critical role in the antitumor response to some chemotherapeutic agents. Thus, we can now envisage new strategies of clinical use of IFN-α, based on the injection of IFN-conditioned cells as well as the usage of these cytokines as cancer vaccine adjuvants, alone or in combination with other treatments (including epigenetic drugs) to induce an immunogenic cell death and a long lasting antitumor response.

TRAIN: Training through Research Application Italian iNitiative.

Training through Research Application Italian iNitiative (TRAIN) is a mobility program financed under the EU action called "Cofinancing of regional, national and international programs" (COFUND) of the European Commission Seventh Framework Program (FP7) - People, and has been designed to encourage the promotion and development of international programs of research through mobility at various stages of research careers. The aim of TRAIN is to improve translational skills in the field of cancer by promoting a three-year international mobility program assigning a total of 51 fellowships subdivided into incoming, outgoing and reintegration fellowships.?The TRAIN proposal has been submitted in February 2009 to the European Commission in reply to the 2008 FP7-PEOPLE-COFUND call and has been successfully evaluated. TRAIN is addressed to postdoctoral scientists or scientists who have at least four years' full-time equivalent research experience and who wish to improve their careers spending one year abroad. The mobility program is open also to non-Italian experienced scientists wishing to spend one year in an Italian research center or private company. Part of the scheme is targeted to experienced Italian scientists who have completed at least three years of research in a foreign country and are interested in returning to Italy.?TRAIN is part of an overall Italian strategy outlined by the International Program of the Italian Cancer Network "Alleanza Contro il Cancro" to promote Italian participation in the building of the European Area for translational cancer research and to enhance the interaction between academy and industry.

IFN-α as a vaccine adjuvant: recent insights into the mechanisms and perspectives for its clinical use.

The IFN-α family are pleiotropic cytokines with the longest record of clinical use. Over the last decade, new biological effects of IFN-α on immune cells, including dendritic cells, have been described, supporting the concept that these cytokines can act as effective vaccine adjuvants. Recently, an important advance in our understanding of the mechanisms of interferon adjuvant activity has been achieved. Some clinical studies have been performed to assess the adjuvant activity in individuals immunized with preventive vaccines, showing variable results depending on interferon/vaccine formulation and vaccinated subjects. In spite of many data in animal models, little information is available on the possible advantage of utilizing IFN-α as an adjuvant for cancer vaccines in humans. Further clinical trials specifically designed to explore vaccine adjuvant activity are needed in order to define the best conditions for using IFN-α or IFN-α-conditioned dendritic cells for the development of therapeutic vaccines.

Translational research on advanced therapies.

Fostering translational research of advanced therapies has become a major priority of both scientific community and national governments. Advanced therapy medicinal products (ATMP) are a new medicinal product category comprising gene therapy and cell-based medicinal products as well as tissue engineered medicinal products. ATMP development opens novel avenues for therapeutic approaches in numerous diseases, including cancer and neurodegenerative and cardiovascular diseases. However, there are important bottlenecks for their development due to the complexity of the regulatory framework, the high costs and the needs for good manufacturing practice (GMP) facilities and new end-points for clinical experimentation. Thus, a strategic cooperation between different stakeholders (academia, industry and experts in regulatory issues) is strongly needed. Recently, a great importance has been given to research infrastructures dedicated to foster translational medicine of advanced therapies. Some ongoing European initiatives in this field are presented and their potential impact is discussed.

Recent advances on the immunomodulatory effects of IFN-alpha: implications for cancer immunotherapy and autoimmunity.

Interferons alpha (IFNs-alpha) are pleiotropic cytokines belonging to the type I IFN family, originally described for their antiviral activity. These cytokines exhibit a long record of clinical use in patients with some types of cancer and viral diseases. Notably, certain autoimmune disorders have been postulated to be mediated by endogenous IFN-alpha and are often observed in some IFN-treated patients. IFN-alpha can induce multiple biological effects, including induction/promotion of apoptosis and inhibition of cell growth. In addition, these cytokines promote the differentiation and activity of host immune cells. Early studies in mouse tumor models showed the importance of host immune mechanisms in the generation of a long-lasting antitumor response after injection of the animals with either IFN or tumor cells genetically modified for IFN-alpha production. Several studies have shown that IFN-alpha can induce the rapid differentiation of monocytes into highly activated dendritic cells (DCs). Of note, these DCs (IFN-DCs) are particularly effective in taking up complex antigens and inducing T- and B-cell immunity. The ensemble of these results suggests that IFN-DCs can play a role in the generation of antitumor T-cell immunity, pointing out that these cells could be successfully used in strategies of cancer immunotherapy. Likewise, IFN-alpha-DC interactions could also play a role in the pathogenesis of some autoimmune disorders, often associated with IFN-alpha treatment. All this reveals the complexity of the IFN-alpha-DC interactions under normal and pathological conditions and stimulates further studies for identifying optimal modalities in either using these cytokines or controlling their production/action in patients.

Biotherapy of cancer: break the barriers to foster translation of knowledge.

Biotherapy of cancer holds great promise for its potential to lead to the identification of novel, selective, and effective treatments against cancer. However, the clinical development of biopharmaceuticals and biotherapy products is hampered by several and diverse barriers. Herein, we will address some of the critical issues identified both at the national and European level as the major obstacles for the translation of knowledge into clinical applications in the field of biotherapy and immunotherapy of cancer. We will also illustrate specific initiatives undertaken both in Europe and in Italy in order to support the translational and clinical research and that are expected to have a favorable impact on the process of clinical development of novel and more effective therapeutic interventions against cancer. The contents of this article are directly referred to the event "International Clinical Trials' Day on Biotherapy of Cancer" organized in the context of the OECI Genoa 2008, with the sponsorship of Alliance Against Cancer (ACC) and the Istituto Superiore di Sanità (ISS, the Italian National Institute of Health), and under the auspices of the European Clinical Research Infrastructures Network (ECRIN). This event sees the active participation of representatives of the ISS and of the Italian Network for Tumor Biotherapy, both involved in a project recently funded by ACC and aimed at the promotion of clinical research in the field of cancer biotherapy and immunotherapy, through the creation of a national network of clinical cancer research centers and GMP facilities dedicated to the production of biological drugs and advanced medicinal products.

Nutritional status of 8-year-old rural and urban Italian children: a study in Pistoia, Tuscany.

In this study, performed in the province of Pistoia (Italy), we tested whether 8-year-old children living in rural areas differed from their urban peers as far as nutritional status, dietary habits and physical activity are concerned. The study sample was randomly selected to include 50% of the children attending the third elementary class in the province of Pistoia during 2002. A total of 1006 children underwent an anthropometric evaluation and an assessment of dietary habits and physical activity by means of specific questionnaires. Of these children, 927 were born in Italy and are described in this report. The relationship between body mass index (BMI<5th percentile versus 5thor=95th percentile) and the environment (urban versus rural) was of borderline significance (P=0.051). However, the percentage of children with BMI>or=85th percentile was greater in rural (24%) than in urban (18%) areas (P=0.012). The choice of foods and the physical activity of rural children mirrored those of urban children. These data sound as an alarm in view of the current epidemics of obesity that are invading Italy and other Mediterranean countries.

Identification by phage display of the linear continuous MRPr1 epitope in the multidrug resistance-associated protein (MRP1).

In order to study the structure of the multidrug resistance-associated protein (MRP1), which is one of the most important members of the ATP-binding cassette (ABC) protein family acting as drug-efflux systems, we have developed an epitope mapping-based strategy. By means of the mAb MRPr1, we have immunoselected clones from two distinct random peptide libraries displayed on phages and have identified several peptide sequences mimicking the internal conformation of this 190 kDa multidrug transporter protein. Phage clones able to block the immunolabeling of the MRPr1 antibody to MRP1-overexpressing multidrug resistance (MDR) H69/AR cells were isolated and, after sequencing the corresponding inserts, their amino acid sequence was compared to that of MRP1. This analysis led to the identification of the consensus sequence L.SLNWED, corresponding to the MRP1 segment LWSLNKED (residues 241-248). This MRP1 sequence is partially overlapping with the MRPr1 epitope GSDLWSLNKE (residues 238-247) previously mapped using peptide scanning techniques. These results demonstrate the high reliability of phage display technology to study not only the topography of complex integral membrane proteins such as MRP1, but also to help identify critical residues participating in the formation of the epitope structure.