The Wilms' tumor gene, WT1, encodes transcription factors that regulate cell proliferation, differentiation, and apoptosis. WT1 protein is highly expressed in malignant pleural mesothelioma (MPM), and is a rational target for immunotherapy. We have developed a vaccine comprised of four WT1 heteroclitic peptides that are given together with Montanide and GM-CSF as immunologic adjuvants. This WT1 vaccine was previously tested in a small pilot trial, and shown to be safe and immunogenic. We have chosen to test the efficacy of this vaccine in MPM patients who have minimal disease burden after completion of multimodality therapy, but remain at exceedingly high risk for recurrence. The specific aim of this project is to conduct a multicenter, blinded, randomized trial comparing treatment with the WT-1 peptide vaccine + Montanide/GM-CSF to treatment with Montanide/GM-CSF alone in patients with MPM who have completed multimodality therapy. The primary endpoint is progression free survival. The trial has opened at Memorial Sloan-Kettering and is actively enrolling patients.

关键词：疫苗；恶性胸膜间皮瘤；多学科治疗

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In the United States, annual vaccination against seasonal influenza is recommended for all persons older than 26 months. Each season since 2004-05, CDC has estimated the effectiveness of seasonal influenza vaccine to prevent influenza-associated, medically attended acute respiratory infection (ARI). This season, early data from 1,155 children and adults with ARI enrolled during December 3, 2012-January 2, 2013 were used to estimate the overall effectiveness of seasonal influenza vaccine for preventing laboratory-confirmed influenza virus infection associated with medically attended ARI. After adjustment for study site, but not for other factors, the estimated vaccine effectiveness (VE) was 62(95confidence intervals (CIs) = 51-71). This interim estimate indicates moderate effectiveness, and is similar to a summary VE estimate from a meta-analysis of randomized controlled clinical trial data; final estimates likely will differ slightly. As of January 11, 2013, 24 states and New York City were reporting high levels of influenza-like illness, 16 states were reporting moderate levels, five states were reporting low levels, and one state was reporting minimal levels. CDC and the Advisory Committee on Immunization Practices routinely recommend that annual influenza vaccination efforts continue as long as influenza viruses are circulating. Persons older than 6 months who have not yet been vaccinated this season should be vaccinated. However, these early VE estimates underscore that some vaccinated persons will become infected with influenza; therefore, antiviral medications should be used as recommended for treatment in patients, regardless of vaccination status. In addition, these results highlight the importance of continued efforts to develop more effective vaccines.

关键词：疫苗；季节性流感；美国

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This meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) is being held to discuss the use of cell lines derived from human tumors as substrates for the production of preventive viral vaccines. Over the last decade, it has become clear that the current repertoire of cell substrates is inadequate to manufacture the next generation of viral vaccines (i.e., certain viruses cannot be propagated or grow poorly in the available cell lines). Therefore, manufacturers have submitted additional cell lines to the FDA for consideration for use in the production of viral vaccines. All of the new mammalian cell lines being considered are immortal, having been transformed by various oncogenes or are spontaneously immortalized, and some are derived from human tumors. Over the last 15 years, when new types of cell substrates have been proposed, starting in 1998, CBER has presented its review approach to the Advisory Committee to address the issues raised first by the use of immortalized mammalian cell lines and then tumorigenic cell lines. The purpose of those discussions with the Advisory Committee was to obtain their input and to make public a discussion of the issues. This current VRBPAC meeting is a continuation of this process.

关键词：疫苗；人类肿瘤；FDA简报

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Tumor protein D52 (D52) is a novel self-onco-antigen involved in cellular transformation, proliferation and metastasis that is over-expressed in prostate cancer cells. The overall goal of this Award is to test the efficacy of D52-based vaccines in the TRAMP murine model of prostate cancer, and to characterize vaccine induced mechanisms of tumor immunity. Due to unforeseen circumstances during this funding period primarily involving the animal vendor and maternity leave for funded personnel we lost over 6 months of productivity. Consequently, we requested and were granted a no cost extension through 8/31/2012. Despite this unfortunate loss of time, over the past 12 months we made the following significant findings: Heterologous prime-boost vaccination induced more than 80protection from primary tumor challenge the best we have observed thus far, but only 30protection from secondary challenge about 8 months later. Similarly, if animals were immunized and rested for 8 months before challenge only about 50were protected from significant tumor growth suggesting that induction of a more durable response may require modulation of peripheral mechanisms of immune suppression as we previously reported. Finally, we demonstrated for the first time in vivo the critical importance of both CD4+ and CD8+ effector T cells in tumor protection following D52 immunization.

关键词：疫苗；前列腺癌；肿瘤蛋白

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The main objective of the study is to vaccinate patients with metastatic breast cancer with a viable dendritic cell (DC)/breast cancer fusions in conjuction with IL-12 to induce an immunological response with the hope that this combination would further enhance vaccine response by promoting Th1 cytokine induction and T cell activation. In this approach, the entire repertoire of tumor antigens, including those yet to be identified, are expressed with the immune-stimulating machinery of the DCs. The fusion cell vaccine allows for induction of helper T and CTL responses by class II presentation of exogenous protein and class I presentation of newly synthesized endogenous protein. Several of our clinical studies have demonstrated that vaccination with fusion cells was well tolerated, induced immunologic responses in a majority of patients, and results in disease regression in subset of patients. This brief report details the characterization of tumor cells and dendritic cells generated from patient BV01 with metastatic breast cancer following isolation from pleural effusions and leukapheresis, respectively.

关键词：疫苗；乳腺癌；树突状细胞

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The insulin-like growth factor (IGF) pathway plays an important role in breast cancer growth and metastasis. The IGF-I receptor (IGF-IR) is over- expressed in almost 50of triple negative breast cancers (TNBC). Thus, therapeutically targeting tumor cells which have upregulated IGF-IR may be a promising approach to treat TNBC. IGF-IR is immunogenic in breast cancer and is a potential target for active immunization. We sought to develop a vaccine that will elicit Th1 immunity to IGF-IR. Ninety-five percent of the peptides predicted to bind with high affinity to MHCII induced a Th1 immune response in human PBMC. However, since IGF-IR is a self tumor antigen, Th epitopes could potentially elicit either an inflammatory Th1 (i.e. IFN-g) or immunosuppressive Th2 (i.e. IL-10) response. A ratio of magnitude and frequency of ELISPOT responses for IFN-g and IL-10 was calculated. The peptides that demonstrated a preference to secrete IFN-g over IL-10 were located primarily in the C-terminus of IGF-IR. Vaccination with those C-terminal peptides in a mouse model of TNBC demonstrated a robust Th1 response and concomitant inhibition of tumor growth. These data suggest that more effective peptide-based vaccines could be designed when both Th1 epitopes and immunosuppressive epitopes are screened simultaneously.

关键词：疫苗；乳腺癌；靶向治疗

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To conduct for the Department of Defense, a focused and responsive world class infectious diseases research and development program leading to fielding of effective, improved means of protection and treatment to maintain maximal global operational capability with minimal morbidity and mortality - Force Health Protection--Naturally Occurring Infectious Diseases.

关键词：疫苗；传染病；军队

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This guidance is intended to alert manufacturers of active pharmaceutical ingredients (APIs), pharmaceutical and medical device manufacturers of finished products, repackers, and others to the potential risk of crude heparin contamination. This guidance provides recommendations that will help API manufacturers, pharmaceutical and medical device manufacturers of finished products, repackers, and others, to better prevent the use of crude heparin that might contain over-sulfated chondroitin sulfate (OSCS) or non-porcine ruminant material contaminants

关键词：医疗设备；肝素药品；行业指南

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The present study attempts to demonstrate precisely the following points; a) Whether cellular constitution of a clonally cancer cell population is uniform as regards the degree of natural drug resistance; b) Whether the degree of drug resistance of cancer clone fluctuates during animal passages; and c) Whether any correlation is found between the degree of drug resistance and chromosomal constitution of cells in a cancer clone. The drug resistance under question in this case is not "acquired" but natural one.

关键词：天然药物；异构单细胞；克隆

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Epigenetics refers to functionally relevant changes to the genome that do not involve a change in the nucleotide sequence. Epigenetics can also be defined as heritable and acquired changes in gene function that occur without a change in the DNA sequence. Epigenetic change is a regular and natural occurring process but it can also be influenced by factors including age, environment/lifestyle, and disease state. Examples of mechanisms that trigger such changes are DNA methylation and histone modification, each of which alters the genes expression without altering the underlying DNA sequence.

关键词：表观遗传学；功能；修改；基因组；核苷酸序列；遗传性；获得性

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