Supported by the International Society for Translational Medicine (ISTM), Wenzhou Medical College and the First Affiliated Hospital of Wenzhou Medical College, the International Conference on Translational Medicine (ICTM) was held on October 22–23, 2011 in Wenzhou, China. Nearly 800 registrants attended the meeting, primarily representing institutes and hospitals in Europe, The United States of America, And Asia, and China. The meeting was chaired and organized by Dr. Xiangdong Wang, Xiaoming Chen, Richard Coico, Jeffrey M. Drazen, Richard Horton, Francesco M. Marincola, Laurentiu M. Popescu, Jia Qu and Aamir Shahzad.
The meeting focused on the communication of the need to foster translational medicine (TM) by building and broadening bridges between basic research and clinical studies at the international level. The meeting included distinguished TM experts from academia, the pharmaceutical and diagnostics industries, government agencies, regulators, and clinicians and provided the opportunity to identify shared interests and efforts for collaborative approaches utilizing cutting edge technologies, innovative approaches and novel therapeutic interventions. The meeting defined the concept of TM in its two-way operational scheme and emphasized the need for bed to bench efforts based directly on clinical observation.
It was the meeting participants’ realization that the shared main goals of TM include breaking the separation between clinic practice and basic research, establishing positive feedback by understanding the basis of expected and unexpected clinical outcomes and accelerating basic research relevant to human suffering. The primary objectives of the meeting were two-fold: to accelerate the two-way translation by informing the participants representing the different disciplines about the state of art activities around TM approaches; and to identify areas that need to be supported by redirecting limited resources as well as identifying new sources of funding. This report summarizes key concepts presented during the meeting representing the state-of-art translational research and salient aspects of the ensuing discussions.
Translational Medicine (TM); International Society for Translational Medicine (ISTM); the International Conference on Translational Medicine (ICTM); Biomarkers; Biobank globalization and networking
The mission of translational research involves difficult tasks to be accomplished for its ultimate goal, i.e. the introduction of novel, effective therapeutic strategies in the clinic to diminish human suffering and cure life-threatening diseases. Translational research (also referred to as translational medicine) facilitates the translation of investment in biomedical research into successful medical treatment. This includes the transfer of diagnostic and therapeutic advances by proving their efficacy in large evidence-based trials. Through the study of humans novel insights about disease are brought back to the laboratory to identify new, observation-based strategies. This “two-way road” (“bench to bedside and bedside to bench”) process includes formulating guidelines for drug development and principles for new therapeutic strategies; initiating clinical investigations that provide the biological basis for new therapies, and related clinical trials; defining therapeutic targets and clinical endpoints. It requires a systematic approach beginning with specimen sampling, patient data collection, laboratory investigations, data analysis, preclinical testing, clinical trials, treatment efficacy monitoring, and finally the evaluation of therapeutic result. The marathon well symbolizes the enormous efforts undertaken by clinicians, scientists, regulators, ethicists, patient advocates, drug developers, and others, coordinately attempting to overcome obstacles along this road toward the final “marathon goal in medicine”.
obstacles; opportunities; therapy; translational medicine; translational research
A cancer immune signature implicating good prognosis and responsiveness to immunotherapy was described that is observed also in other aspects of immune-mediated, tissue-specific destruction (TSD). Its determinism remains, however, elusive. Based on limited but unique clinical observations, we propose a multifactorial genetic model of human cancer immune responsiveness.
cancer genetics; cancer microenvironment; immune responsiveness; immunotherapy; melanoma
Recent investigations of the tumor microenvironment have shown that many tumors are infiltrated by inflammatory and lymphocytic cells. Increasing evidence suggests that the number, type and location of these tumor-infiltrating lymphocytes in primary tumors has prognostic value, and this has led to the development of an ‘immunoscore. As well as providing useful prognostic information, the immunoscore concept also has the potential to help predict response to treatment, thereby improving decision- making with regard to choice of therapy. This predictive aspect of the tumor microenvironment forms the basis for the concept of immunoprofiling, which can be described as ‘using an individual’s immune system signature (or profile) to predict that patient’s response to therapy’ The immunoprofile of an individual can be genetically determined or tumor-induced (and therefore dynamic). Ipilimumab is the first in a series of immunomodulating antibodies and has been shown to be associated with improved overall survival in patients with advanced melanoma. Other immunotherapies in development include anti-programmed death 1 protein (nivolumab), anti-PD-ligand 1, anti-CD137 (urelumab), and anti-OX40. Biomarkers that can be used as predictive factors for these treatments have not yet been clinically validated. However, there is already evidence that the tumor microenvironment can have a predictive role, with clinical activity of ipilimumab related to high baseline expression of the immune-related genes FoxP3 and indoleamine 2,3-dioxygenase and an increase in tumor-infiltrating lymphocytes. These biomarkers could represent the first potential proposal for an immunoprofiling panel in patients for whom anti-CTLA-4 therapy is being considered, although prospective data are required. In conclusion, the evaluation of systemic and local immunological biomarkers could offer useful prognostic information and facilitate clinical decision making. The challenge will be to identify the individual immunoprofile of each patient and the consequent choice of optimal therapy or combination of therapies to be used.
Tumor microenvironment; Tumor-infiltrating lymphocytes; Immunoprofiling; Immunotherapy; Ipilimumab
The functional status of circulating vaccine-induced, tumor-specific T cells has been questioned to explain their paradoxical inability to inhibit tumor growth. We enumerated with HLA-A*0201/peptide tetramers (tHLA) vaccine-elicited CD8+ T cell precursor frequency among PBMC in 13 patients with melanoma undergoing vaccination with the HLA-A*0201-associated gp100: 209–217(210 M) epitope. T cell precursor frequency increased from undetectable to 12,400 ± 3,600 × 106 CD8+ T cells after vaccination and appeared heterogeneous according to previously described functional subtypes: CD45RA+CD27+ (14 ± 2.6% of tHLA-staining T cells), naive; CD45RA−CD27+ (14 ± 3.2%), memory; CD45RA+CD27− (43 ± 6%), effector; and CD45RA−CD27− (30 ± 4.1%), memory/effector. The majority of tHLA+CD8+ T cells displayed an effector, CD27− phenotype (73%). However, few expressed perforin (17%). Epitope-specific in vitro stimulation (IVS) followed by 10-day expansion in IL-2 reversed this phenotype by increasing the number of perforin+ (84 ± 3.6%; by paired t test, p < 0.001) and CD27+ (from 28 to 67%; by paired t test, p = 0.01) tHLA+ T cells. This conversion probably represented a change in the functional status of tHLA+ T cells rather than a preferential expansion of a CD27+ (naive and/or memory) PBMC, because it was reproduced after IVS of a T cell clone bearing a classic effector phenotype (CD45RA+CD27−). These findings suggest that circulating vaccine-elicited T cells are not as functionally active as inferred by characterization of IVS-induced CTL. In addition, CD45RA/CD27 expression may be more informative about the status of activation of circulating T cells than their status of differentiation.
Human cytomegalovirus (HCMV) can cause life-threatening disease in infected hosts. Immunization with human leukocyte antigen (HLA)-restricted immunodominant synthetic peptides and adoptive transfer of epitope-specific T cells have been envisaged to generate or boost HCMV-specific cellular immunity, thereby preventing HCMV infection or reactivation. However, induction or expansion of T cells effective against HCMV are limited by the need of utilizing peptides with defined HLA restrictions. We took advantage of a combination of seven predictive algorithms to identify immunogenic peptides of potential use in the prevention or treatment of HCMV infection or reactivation. Here we describe a pp65-derived peptide (pp65340–355, RQYDPVAALFFFDIDL: RQY16-mer), characterized by peculiar features. First, RQY-16mer is able to stimulate HCMV pp65 specific responses in both CD4+ and CD8+ T cells, restricted by a wide range of HLA class I and II determinants. Second, RQY-16mer is able to induce an unusually wide range of effector functions in CD4+ T cells, including proliferation, killing of autologous HCMV-infected target cells and cytokine production. Third, and most importantly, the RQY-16mer is able to stimulate CD4+ and CD8+ T-cell responses in pharmacologically immunosuppressed patients. These data suggest that a single reagent might qualify as synthetic immunogen for potentially large populations exposed to HCMV infection or reactivation.
peptide cross-presentation; immunotherapy; vaccine
Translational science consists of research and development that integrates multiple resources to expedite the successful treatment of disease. The International Park of Translational BioMedicine (IPTBM) is currently being developed within the interface between Zhejiang Province and Shanghai Municipality. IPTBM has been designed to pioneer comprehensive biomedical research that spans the continuum from the education of young scientists to providing the infrastructure necessary for clinical testing and direct observation to better understand human biology while promoting viable commercial results within a vibrant biotechnology community. IPTBM’s goal is to attract global partners organized around five fundamental pillars: 1) Institutional Development, 2) Project Implementation, 3) Development and Production, 4) Investment and 5) Regulatory Clusters to address the needs of an international platform of scientists, institutes, universities, commercial enterprises, investors, politicians, and other stakeholders. The IPTBM differs from existing models including CTSA’s (US, NIH) technology because of its comprehensive approach to merge education, research, innovation, and development to translate clinical and public health needs into target-oriented and cost-efficient projects.
Translational medicine; International; Projects; Development; Management; Strategy
Tumor Ag-specific vaccines used for cancer immunotherapy can generate specific CD8 responses detectable in PBMCs and in tumor-infiltrating lymphocytes. However, human studies have shown that detection of a systemic vaccine-induced response does not necessarily correlate with the occasional instances of tumor rejection. Because this discrepancy might partially be attributable to the genetic heterogeneity of human cancers, as well as to the immunosuppressive effects of previous treatments, we turned to a mouse model in which these variables could be controlled to determine whether a relationship exists between the strength of vaccine-induced immune responses and tumor rejection. We challenged mice with the β-galactosidase (β-gal)-expressing tumor cells, C25.F6, vaccinated them with β-gal-carrying viral vectors, and used quantitative RT-PCR to measure the vaccine-induced immune response of splenocytes directly ex vivo. We found that the strength of the response increased with increasing doses of β-gal-carrying vector and/or upon boosting with a heterologous β-gal-carrying virus. Most importantly, we found that the strength of the detected immune response against this foreign Ag strongly correlated with reduction in the number of lung metastases. The results from this mouse model have major implications for the implementation of tumor vaccines in humans.
The growth of a poorly immunogenic methylcholanthrene (MCA)-induced murine (m) sarcoma genetically engineered to secrete human (h) TNF-α (MCA-102-hTNF) was studied. MCA-102-hTNF tumor cells were implanted in animals bearing three- or 7-day pulmonary metastases established with the parental line MCA-102-WT (wild type). This model approximates the clinical situation in which patients with metastatic cancer would be vaccinated with autologous tumor genetically modified to stimulate the host immune response. Reduction in the number of pulmonary metastases was occasionally seen but was not consistently reproducible. Other cytokine-producing tumors had either no effect on distant pulmonary metastases (mIL-4, IFN-γ) or a mild, inconclusive effect similar to hTNF-α (mTNF-α). Significant growth inhibition of MCA-102-hTNF was noted in animals bearing pulmonary metastases. This inhibition was: 1) tumor specific (regression occurred only in animals bearing pulmonary metastases from the same parental line), 2) TNF specific (it was inhibited by in vivo administration of anti hTNF mAbs), 3) dependent on cellular immunity (immune-depletion with anti-CD4 or CD8 mAbs permitted growth). Tumor-infiltrating lymphocytes (TIL) could not be grown from MCA-102-WT or MCA-102-hTNF tumors nor from MCA-102-WT subcutaneous implants in mice bearing MCA-102-WT pulmonary metastases. However, TIL could be grown from hTNF-secreting tumors implanted in mice bearing MCA-102-WT metastases. These TIL were therapeutic against established lung metastases from the parental tumor in adoptive immunotherapy models. These studies suggest a strategy for using gene modified tumors for the therapy of established cancer.
Influenza vaccination is generally recommended for non-Hodgkin’s lymphoma (NHL) patients, but no data are available about the activity of this vaccine after treatment with rituximab-containing regimens. We evaluated the humoral response to the trivalent seasonal influenza vaccine in a group of NHL patients in complete remission for ≥6 mo (median, 29 mo) after treatment with rituximab-containing regimens (n = 31) compared with age-matched healthy subjects (n = 34). B cell populations and incidence of influenza-like illness were also evaluated. For each viral strain, the response was significantly lower in patients compared with controls and was particularly poor in patients treated with fludarabine-based regimens. In the patient group, the response to vaccination did not fulfill the immunogenic criteria based on the European Committee for Medicinal Products for Human Use requirements. Among the patients, CD27+ memory B cells were significantly reduced, and their reduction correlated with serum IgM levels and vaccine response. Episodes of influenza-like illness were recorded only in patients. These results showed that NHL patients treated with rituximab-containing regimens have persisting perturbations of B cell compartments and Ig synthesis and may be at particular risk for infection, even in long-standing complete remission.
The presentation of tumor antigen-derived peptides by human leukocyte antigen (HLA) class I surface antigens on tumor cells is a key prerequisite to trigger effective T-cell responses in cancer patients. Multiple complementary strategies like cDNA and serological expression cloning, reverse immunology and different ‘ome’-based methods have been employed to identify potential T-cell targets. This report focuses on a ligandomic profiling approach leading to the identification of 49 naturally processed HLA class I peptide ligands presented on the cell surface of renal cell carcinoma (RCC) cells. The source proteins of the defined HLA ligands are classified according to their biological function and subcellular localization. Previously established cDNA microarray data of paired tissue specimen of RCC and renal epithelium assessed the transcriptional regulation for 28 source proteins. In addition, HLA-A2-restricted, peptide-specific T cells directed against a HLA ligand derived from sulfiredoxin-1 (SRXN1) were generated, which were able to recognize and lyse ligand-presenting target cells in a HLA class I-restricted manner. Furthermore, tumor-infiltrating T cells isolated from a RCC patient were also able to kill SRXN1 expressing tumor cells. Thus, this experimental strategy might be suited to define potential candidate biomarkers and novel targets for T-cell-based immunotherapies of this disease.
Biomarkers; Cell biology; HLA antigens; Peptide ligands; Renal cell carcinoma; T-cell response
A greater understanding of the function of the human immune system at the single-cell level in healthy individuals is critical for discerning aberrant cellular behavior that occurs in settings such as autoimmunity, immunosenescence, and cancer. To achieve this goal, a systems-level approach capable of capturing the response of the interdependent immune cell types to external stimuli is required. In this study, an extensive characterization of signaling responses in multiple immune cell subpopulations within PBMCs from a cohort of 60 healthy donors was performed using single-cell network profiling (SCNP). SCNP is a multiparametric flow cytometry-based approach that enables the simultaneous measurement of basal and evoked signaling in multiple cell subsets within heterogeneous populations. In addition to establishing the interindividual degree of variation within a broad panel of immune signaling responses, the possible association of any observed variation with demographic variables including age and race was investigated. Using half of the donors as a training set, multiple age- and race-associated variations in signaling responses in discrete cell subsets were identified, and several were subsequently confirmed in the remaining samples (test set). Such associations may provide insight into age-related immune alterations associated with high infection rates and diminished protection following vaccination and into the basis for ethnic differences in autoimmune disease incidence and treatment response. SCNP allowed for the generation of a functional map of healthy immune cell signaling responses that can provide clinically relevant information regarding both the mechanisms underlying immune pathological conditions and the selection and effect of therapeutics.
Immunotherapy is an important modality in the therapy of patients with malignant melanoma. As our knowledge about this disease continues to expand, so does the immunotherapeutic armamentarium. Nevertheless, successful preclinical models do not always translate into clinically meaningful results. The authors give a comprehensive analysis of most recent advances in the immune anti-melanoma therapy, including interleukins, interferons, other cytokines, adoptive immunotherapy, biochemotherapy, as well as the use of different vaccines. We also present the fundamental concepts behind various immune enhancement strategies, passive immunotherapy, as well as the use of immune adjuvants. This review brings into discussion the results of newer and older clinical trials, as well as potential limitations and drawbacks seen with the utilization of various immune therapies in malignant melanoma. Development of novel therapeutic approaches, along with optimization of existing therapies, continues to hold a great promise in the field of melanoma therapy research. Use of anti-CTLA4 and anti-PD1 antibodies, realization of the importance of co-stimulatory signals, which translated into the use of agonist CD40 monoclonal antibodies, as well as activation of innate immunity through enhanced expression of co-stimulatory molecules on the surface of dendritic cells by TLR agonists are only a few items on the list of recent advances in the treatment of melanoma. The need to engineer better immune interactions and to boost positive feedback loops appear crucial for the future of melanoma therapy, which ultimately resides in our understanding of the complexity of immune responses in this disease.
malignant melanoma; immunotherapy; vaccines; cytokines; immunomodulation; dendritic cells
We have previously shown that within tumors, recombinant interleukin-2 (rIL-2, Aldesleukin) consistently activates tumor-associated macrophages and up-regulates interferon stimulated genes (ISGs) while inducing minimal migration, activation or proliferation of T-cells. These effects are independent of tumor response to treatment. Here, we prospectively evaluated transcriptional alterations induced by rIL-2 in peripheral blood mononuclear cells (PBMCs) and within melanoma metastases.
We evaluated gene expression changes by serially comparing pre- to post-treatment samples in 14 patients and also compared transcriptional differences among lesions displaying different responsiveness to therapy, focusing on 2 lesions decreasing in size and 2 remaining stable (responding lesions) compared to non-responding ones.
As previously described, the effects of rIL-2 were dramatic within PBMC, while effects within the tumor microenvironment were lesion-specific and limited. However, distinct signatures specific to response could be observed in responding lesions pre-treatment that were amplified following rIL-2 administration. These signatures match the functional profile observed in other human or experimental models in which immune-mediated tissue-specific destruction (TSD) occurs underlying a common pathways leading to rejection. Moreover, the signatures observed in pre-treatment lesions were qualitatively similar to those associated with TSD underlining a determinism to immune responsiveness that depends upon the genetic background of the host or the intrinsic genetic makeup of individual tumors.
This is the first prospectively collected insight on global transcriptional events occurring during high-dose rIL-2 therapy in melanoma metastases responding to treatment.
The dichotomy of immunology into innate and adaptive immunity has created conceptual barriers in appreciating the intrinsic two-way interaction between immune cells. An emerging body of evidence in various models of immune rejection, including cancer, indicates an indispensable regulation of innate effector functions by adaptive immune cells. This bidirectional cooperativity in innate and adaptive immune functions has broad implications for immune responses in general and for regulating the tumor-associated inflammation that overrides the protective antitumor immunity. Mechanistic understanding of this two-way immune cross-talk could provide insights into novel strategies for designing better immunotherapy approaches against cancer and other diseases that normally defy immune control.
Innate immunity; Adaptive T cells; Natural killer cells; Effector function; Immune regulation; Cancer immunotherapy
The T cell receptor (TCR) orchestrates T cell mediated-cytotoxicity through a complex interaction that results in an antigen-specific effector–target cell conjugate formation. While it is well recognized that specific TCR/antigen interactions generate the immunological synapse, their direct contribution to the effector–target cell conjugate has not been conclusively demonstrated. Moreover, since human cytotoxic T lymphocyte (CTL) clones are also susceptible to antigen-independent adhesion to target cells, it remains unclear whether effector–target cell conjugate formation can serve as an indicator of specific antigen recognition by the TCR. To address this question, a well-characterized epitope-specific CTL clone recognizing the melanoma-associated antigen epitope gp100:209–217 in association with HLA-A*0201 was tested against melanoma cell lines lacking or expressing the HLA-A*0201 allele and/or gp100. In this model, TCR/HLA/antigen interactions cooperated with accessory/adhesion molecules to facilitate effector–target cell conjugate formation. HLA-restricted antigen recognition played a dominant role resulting in up to 2-fold increases in conjugate frequency, and a 50% increase of CTL binding to tumor cells over background. The increased number of CTL contained in conjugates correlated with the number of IFN-γ producing CTL. These results warrant further investigation to evaluate conjugate assays as a potential tool to detect and isolate viable and functionally active CTL. Since conjugate formation analysis does not require knowledge of the target antigen, this assay could potentially be used for enrichment of CTL directed against novel antigens.
Effector–target conjugate formation; HLA-restricted antigen recognition; TCR/HLA/epitopes; Intracellular cytokines; Adhesion molecules
“Today, owing to strict health and safety issues of vaccine manufacturing, vaccines must meet higher standards of safety and biochemical characterization than they did in the past.”
Despite recent advances in the understanding of the biology of renal cell carcinoma (RCC) and the implementation of novel targeted therapies, the overall 5 years’ survival rate for RCC patients remains disappointing. Late presentation, tumor heterogeneity and in particular the lack of molecular biomarkers for early detection and classification represent major obstacles. Global, untargeted comparative analysis of RCC vs tumor adjacent renal epithelium (NN) samples by high throughput analyses both at the transcriptome and proteome level have identified signatures, which might further clarify the molecular differences of RCC subtypes and might allow the identification of suitable therapeutic targets and diagnostic/prognostic biomarkers, but none thereof has yet been implemented in routine clinical use. The increasing knowledge regarding the functional role of noncoding microRNA (miR) in physiological, developmental, and pathophysiological processes by shaping the protein expression profile might provide an important link to improve the definition of disease-relevant regulatory networks. Taking into account that miR profiling of RCC and NN provides robust signatures discriminating between malignant and normal tissues, the concept of evaluating and scoring miR/protein pairs might represent a strategy for the selection and prioritization of potential biomarkers and their translation into practical use.
RCC; miR; proteomics; biomarker
We present the results of a comparative gene expression analysis of 15 metastases (10 regressing and 5 progressing) obtained from 2 melanoma patients with mixed response following different forms of immunotherapy. Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients. In contrast, progressing metastases showed low transcription levels of genes involved in these pathways. Histological analysis showed T cells and HLA-DR positive infiltrating cells in the regressing but not in the progressing metastases. Quantitative expression analysis of HLA-A, B and C genes on microdisected tumoral regions indicate higher HLA expression in regressing than in progressing metastases. The molecular signature obtained in melanoma rejection appeared to be similar to that observed in other forms of immune-mediated tissue-specific rejection such as allograft, pathogen clearance, graft versus host or autoimmune disease, supporting the immunological constant of rejection. We favor the idea that the major factor determining the success or failure of immunotherapy is the nature of HLA Class I alterations in tumor cells and not the type of immunotherapy used. If the molecular alteration is reversible by the immunotherapy, the HLA expression will be upregulated and the lesion will be recognized and rejected. In contrast, if the defect is structural the MHC Class I expression will remain unchanged and the lesion will progress.
melanoma; metastasis; immunotherapy; rejection; HLA; IRF-1
Clinical translational medicine (CTM) is an emerging area comprising multidisciplinary research from basic science to medical applications and entails a close collaboration among hospital, academia and industry.
This Session focused discussing on new models for project development and promotion in translational medicine. The conference stimulated the scientific and commercial communication of project development between academies and companies, shared the advanced knowledge and expertise of clinical applications, and created the environment for collaborations.
Although strategic collaborations between corporate and academic institutions have resulted in a state of resurgence in the market, new cooperation models still need time to tell whether they will improve the translational medicine process.
Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the ‘Immunoscore’ into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).
melanoma; immunotherapy; dendritic cells; interferon; biochemotherapy; CTLA-4
Translational Medicine (TM) in Qatar is part of a concerted effort of the Qatari medical and scientific leadership supported by a strong political will by Qatari authorities to deliver world-class health care to Qatari residents while participating in the worldwide quest to bridge the gap between bench-to-bedside-to-community. TM programs should embrace the Qatar National vision for research to become an international hub of excellence in research and development, based on intellectual merit, contributing to global knowledge and adhering to international standards, to innovate by translating new and original ideas into useful applications, to be inclusive at the national and international level, to build and maintain a competitive and diversified economy and ultimately improve the health and well-being of the Qatar’s population. Although this writing focuses on Qatar, we hope that the thoughts expressed here may be of broader use for the development of any TM program particularly in regions where an established academic community surrounded by a rich research infrastructure and/or a vibrant biotechnology enterprise is not already present.