Phase I trial of viral vector based personalized vaccination elicits robust neoantigen specific antitumor T cell responses

Purpose: Personalized vaccines targeting multiple neoantigens (nAgs) are a promising strategy for eliciting a diversified antitumor T cell response to overcome tumor heterogeneity. NOUS-PEV is a vector based personalized vaccine, expressing 60 nAgs and consists of priming with a non-human Great Ape Adenoviral vector (GAd20) followed by boosts with Modified Vaccinia Ankara (MVA). Here, we report data of a phase Ib trial of NOUS-PEV in combination with pembrolizumab in treatment naïve metastatic melanoma patients (NCT04990479). Experimental Design: The feasibility of this approach was demonstrated by producing, releasing and administering to six patients 11 out of 12 vaccines within 8 weeks from biopsy collection to GAd20 administration. Results: The regimen was safe, with no treatment-related serious adverse events observed and mild vaccine-related reactions. Vaccine immunogenicity was demonstrated in all evaluable patients receiving the prime/boost regimen, with detection of robust neoantigen specific immune responses to multiple neoantigens comprising both CD4 and CD8 T cells. Expansion and diversification of vaccine-induced TCR clonotypes was observed in the post-treatment biopsies of patients with clinical response providing evidence of tumor infiltration by vaccine-induced neoantigen-specific T cell. Conclusions: These findings indicate the ability of NOUS-PEV to amplify and broaden the repertoire of tumor reactive T cells to empower a diverse, potent and durable antitumor immune response. Finally, a gene signature indicative for reduced presence of activated T cells together with very poor expression of the antigen processing machinery (APM) genes has been identified in pre-treatment biopsies as a potential biomarker of resistance to the treatment

Epidemiological patterns of asbestos exposure and spatial clusters of incident cases of malignant mesothelioma from the Italian national registry.

BACKGROUND: Previous ecological spatial studies of malignant mesothelioma cases, mostly based on mortality data, lack reliable data on individual exposure to asbestos, thus failing to assess the contribution of different occupational and environmental sources in the determination of risk excess in specific areas. This study aims to identify territorial clusters of malignant mesothelioma through a Bayesian spatial analysis and to characterize them by the integrated use of asbestos exposure information retrieved from the Italian national mesothelioma registry (ReNaM). METHODS: In the period 1993 to 2008, 15,322 incident cases of all-site malignant mesothelioma were recorded and 11,852 occupational, residential and familial histories were obtained by individual interviews. Observed cases were assigned to the municipality of residence at the time of diagnosis and compared to those expected based on the age-specific rates of the respective geographical area. A spatial cluster analysis was performed for each area applying a Bayesian hierarchical model. Information about modalities and economic sectors of asbestos exposure was analyzed for each cluster. RESULTS: Thirty-two clusters of malignant mesothelioma were identified and characterized using the exposure data. Asbestos cement manufacturing industries and shipbuilding and repair facilities represented the main sources of asbestos exposure, but a major contribution to asbestos exposure was also provided by sectors with no direct use of asbestos, such as non-asbestos textile industries, metal engineering and construction. A high proportion of cases with environmental exposure was found in clusters where asbestos cement plants were located or a natural source of asbestos (or asbestos-like) fibers was identifiable. Differences in type and sources of exposure can also explain the varying percentage of cases occurring in women among clusters. CONCLUSIONS: Our study demonstrates shared exposure patterns in territorial clusters of malignant mesothelioma due to single or multiple industrial sources, with major implications for public health policies, health surveillance, compensation procedures and site remediation programs

Epidemiological patterns of asbestos exposure and spatial clusters of incident cases of malignant mesothelioma from the Italian national registry

Abstract BACKGROUND: Previous ecological spatial studies of malignant mesothelioma cases, mostly based on mortality data, lack reliable data on individual exposure to asbestos, thus failing to assess the contribution of different occupational and environmental sources in the determination of risk excess in specific areas. This study aims to identify territorial clusters of malignant mesothelioma through a Bayesian spatial analysis and to characterize them by the integrated use of asbestos exposure information retrieved from the Italian national mesothelioma registry (ReNaM). METHODS: In the period 1993 to 2008, 15,322 incident cases of all-site malignant mesothelioma were recorded and 11,852 occupational, residential and familial histories were obtained by individual interviews. Observed cases were assigned to the municipality of residence at the time of diagnosis and compared to those expected based on the age-specific rates of the respective geographical area. A spatial cluster analysis was performed for each area applying a Bayesian hierarchical model. Information about modalities and economic sectors of asbestos exposure was analyzed for each cluster. RESULTS: Thirty-two clusters of malignant mesothelioma were identified and characterized using the exposure data. Asbestos cement manufacturing industries and shipbuilding and repair facilities represented the main sources of asbestos exposure, but a major contribution to asbestos exposure was also provided by sectors with no direct use of asbestos, such as non-asbestos textile industries, metal engineering and construction. A high proportion of cases with environmental exposure was found in clusters where asbestos cement plants were located or a natural source of asbestos (or asbestos-like) fibers was identifiable. Differences in type and sources of exposure can also explain the varying percentage of cases occurring in women among clusters. CONCLUSIONS: Our study demonstrates shared exposure patterns in territorial clusters of malignant mesothelioma due to single or multiple industrial sources, with major implications for public health policies, health surveillance, compensation procedures and site remediation programs

Chimpanzee adenoviral vectors as vaccines–challenges to move the technology into the fast lane

In recent years, replication-defective chimpanzee-derived adenoviruses have been extensively evaluated as genetic vaccines. These vectors share desirable properties with human adenoviruses like the broad tissue tropism and the ease of large-scale manufacturing. Additionally, chimpanzee adenoviruses have the advantage to overcome the negative impact of pre-existing anti-human adenovirus immunity. Areas covered: Here the authors review current pre-clinical research and clinical trials that utilize chimpanzee-derived adenoviral vectors as vaccines. A wealth of studies are ongoing to evaluate different vector backbones and administration routes with the aim of improving immune responses. The challenges associated with the identification of an optimal chimpanzee vector and immunization strategies for different immunological outcomes will be discussed. Expert commentary: The demonstration that chimpanzee adenoviruses can be safely used in humans has paved the way to the use of a whole new array of vectors of different serotypes. However, so far no predictive signature of vector immunity in humans has been identified. The high magnitude of T cell responses elicited by chimpanzee adenoviruses has allowed dissecting the qualitative aspects that may be important for protective immunity. Ultimately, only the results from the most clinically advanced products will help establish the efficacy of the vaccine vector platform in the field of disease prevention

Investigation of APC mutations in a Turkish familial adenomatous polyposis family by heterodublex analysis

Bu çalışma, 25-28 Mayıs 2002 tarihleri arasında Strasbourg[Fransa]’da düzenlenen European-Society-of-Human-Genetics European Human Genetics Conference in Conjuction With European Meeting on Psychosocial Aspects of Genetics’ da bildiri olarak sunulmuştur.PURPOSE: Familial adenomatous polyposis is an autosomal dominant disease characterized by the presence of 100 or more colorectal adenomatous polyps. Mutations in the adenomatous polyposis coli gene are primarily responsible for the development of this disease. This study was designed to investigation of adenomatous polyposis coli (APC) gene mutations in members of familial adenomatous polyposis family to identify individuals at risk of the disease. METHODS: We examined one patient with familial adenomatous polyposis and 21 family members including one affected person from familial adenomatous polyposis and 20 nonsymptomatic persons. We studied E, D, F, and G segments of exon 15 of the adenomatous polyposis coli gene by heteroduplex analysis. RESULTS: We used silver staining method for staining. We found a mutation for five persons at segment F of exon 15 of the adenomatous polyposis coli gene. Two of them were affected by colorectal cancer, one of whom was the proband, and the other three were non-symptomatic family members. The pathogenetic mutation was a T deletion at codon 1172, causing a frameshift in the adenomatous polyposis coli gene, as a result of the sequencing analysis of these cases. CONCLUSIONS: Investigation of adenomatous polyposis coli gene mutations is very important for the identification of genetic susceptibility to colorectal cancer and for the definition of tumor developing at an early stage. Furthermore, the identification of this mutation for the first time in a Turkish family will be useful to foster further studies on familial adenomatous polyposis in Turkey.European Soc Human Gene