Dissertations / Theses on the topic 'Antigeni tumore associati'
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DI, CRISTANZIANO VERONICA. "Caratterizzazione e valutazione del ruolo immunologico di un nuovo antigene associato all'adenocarcinoma del colon-retto: colorectal tumor-associated antigen 1 (COA-1)." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2008. http://hdl.handle.net/2108/432.
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Recentemente è stato identificato un nuovo antigene associato al carcinoma del colon retto
(CRC), denominato colorectal tumor-associated antigen-1 (COA-1), riconosciuto dai
linfociti T CD4+ in associazione a specifiche molecole MHC di classe II e codificato del
gene UBXD5. In questo studio abbiamo valutato se COA-1 sia in grado di evocare una
risposta immunitaria mediata da linfociti T tumore-specifici nei pazienti affetti da CRC e se
tale antigene possa rappresentare un nuovo mezzo per disegnare protocolli di
immunoterapia e un marker di progressione della malattia. A tale scopo, i PBMC isolati dai
pazienti con CRC sono stati stimolati in vitro con l’epitopo immunogenico di COA-1441-460
(FSTFPPTLYQDDTLTLQAAG) e la risposta immunitaria, sia antigene che tumore
specifica, è stata analizzata mediante rilevazione del rilascio di IFN-g, tramite saggio
ELISPOT. In tal modo, è stato possibile isolare linfociti T specifici per COA-1 e tumorereattivi
da tutti i pazienti HLA-DRb1*0402 o *1301 con malattia in progressione (7/7, stadio
C e D di Dukes), ma non dai pazienti con tumore in fase iniziale (4/4, stadio A e B di
Dukes). I linfociti T TAA-specifici hanno mostrato un fenotipo CD3+, CD4+, CD69+,
CD45RA+, compatibile con quello del subset dei linfociti T di tipo effettore. Inoltre, la
maggior parte di queste cellule ha evidenziato un’attività citotossica diretta nei confronti
delle cellule tumorali positive per COA-1 e per gli specifici elementi di restrizione di classe
II. Abbiamo anche verificato se una risposta specifica nei confronti di COA-1 potesse essere
isolata dai PBMC dei pazienti con CRC mediante l’impiego di cellule dendritiche (DC)
autologhe caricate con il lisato tumporale. I nostri dati indicano che linfociti T CD4+
specifici per COA-1 e dotati di reattività anti-CRC possono essere isolati mediante
stimolazione in vitro dei PBMC sia con le cellule tumorali intatte sia con le DC pulsate con
il lisato del tumore autologo, suggerendo che tale TAA sia in grado di generare una
risposta immunitaria dominante diretta contro il CRC. In conclusione, i risultati di questo
studio indicano che COA-1 può essere considerato un antigene rilevante per la risposta
immunitaria anti-tumorale nei pazienti con CRC, dal momento che correla con la
progressione della malattia, e ne suggeriscono un possibile impiego nei protocolli di
immunoterapia per i pazienti affetti da CRC.Recently, a new colorectal cancer (CRC)-associated antigen, denominated colorectal tumorassociated antigen-1 (COA-1), recognized by CD4+ T lymphocytes in a HLA class IIrestricted way and encoded by UBXD5 gene, was identified. In this study, we evaluated whether COA-1 can evoke a specific T cell-mediated response in CRC patients and whether this antigen can represent a tool to design new protocols of immunotherapy and a marker for the progression of the disease. Peripheral blood lymphocytes isolated from CRC patients have been in vitro stimulated with the immunogenic epitope of COA-1441-460 (FSTFPPTLYQDDTLTLQAAG) and the antigen- and tumor immunological response was analyzed by IFN-g ELISPOT assay. We could isolate COA-1 specific and tumor reactive T lymphocytes from all (n= 7) HLADRb1* 0402+ or *1301+ CRC patients with progressive disease (Dukes’ C and D), but not in patients (n= 4) with early stage tumor (Dukes’ A and B). Furthermore, these T lymphocytes had a CD3+CD4+CD69+CD45RA+ phenotype, compatible with the activated effector-type T cell subset, and most of them exerted cytotoxic activity against tumor cells expressing COA-1 and the specific MHC restriction elements. In addition, we have verified whether COA-1 specific reactivity could be isolated from PBMCs of CRC patients by the usage of autologous dendritic cells loaded with tumor lysate. Tumor reactive and COA-1 specific CD4+ T cells colud be isolated by in vitro stimulation of PBMCs either with intact tumor cells and with DC pulsed with tumor lysate, suggesting that this antigen can generate a dominant immunological response against CRC. In conclusion, the results of this study indicate that COA-1 can be a relevant antigen for the anti-tumor immune response in CRC patients, correlating with the progression of the disease, and suggest that this molecule is suitable for immunotherapeutic protocols of these patients.
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Nastke, Maria-Dorothea. "T-cell epitopes from viral and tumor associated antigens induction and analysis of antigen-specific T cells /." [S.l. : s.n.], 2005. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB12168223.
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Lotz, Carina. "Tolerance and immunity to human tumor-associated antigens." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=970660308.
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Sheu, Fong-Shyong. "Characterizations of a tumor-associated antigen COX-1." Thesis, University of British Columbia, 1991. http://hdl.handle.net/2429/30332.
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By using modified hybridoma technology, monoclonal antibodies against an ovarian tumor cell line, OC-3-VGH, were generated in Dr. Lee's laboratory. Among these antibodies, RP 215 was shown to react specifically with a tumor-associated antigen, COX-1. On SDS gel, COX-1 has a molecular weight of 60 KD and exists as an aggregate in the natural- state. A highly purified COX-1 was obtained mainly by immunoaffirtity chromatography, with RP 215 as the affinity ligand, from the shed medium of cultured tumor cells. A solid phase enzyme immunoassay was established using RP 215 as the capturing and the detecting antibody with a sensitivity of 1 AU/ml. This immunoassay kit could be used to determine the levels of COX-1 in the culture medium and in the sera of cancer patients.
COX-1 was characterized under a variety of experimental conditions. At temperatures higher than 50°C or in the presence of trypsin at 37°C, COX-1 immunoactivity was found to decrease with incubation time. However, COX-1 was not affected by incubation with carbohydrate-digestive enzymes including neuraminidase, Beta-galactosidase and fucosidase or carbohydrate modifying agents such as NaIO₄. Concanavalin A had no effect on the immunoactivity of COX-1 to RP 215. Furthermore, rabbit antisera against COX-1 were raised, and these polyclonal antisera were shown to exhibitsimilar immunoactivity to that of RP 215 monoclonal antibody.
Using the established sandwich enzyme immunoassay, serum levels of COX-1 among patients with ovarian or cervical cancers were determined retrospectively through interlaboratory evaluations and collaborations. Compared to those of normal individuals and benign tumors, serum levels of COX-1 were significantly elevated and can be correlated to the progression of the disease among cancer patients. Preliminary data indicated the COX-1 can complement other established tumor markers such as CA 125 for the purpose of monitoring patients with ovarian or cervical cancers.Medicine, Faculty of
Obstetrics and Gynaecology, Department of
Graduate
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Ullenhag, Gustav. "Vaccine Therapy of Colorectal Cancer Patients with Tumor Associated Antigens." Doctoral thesis, Uppsala University, Oncology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3399.
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In this thesis, two different vaccines were evaluated as adjuvant therapy for patients with colorectal cancer. The ability of the two candidate vaccines to generate antigen-specific cellular and humoral responses, respectively, was studied. The effectiveness of granulocyte colony stimulating factor (GM-CSF) as a cytokine adjuvant to augment the immune response was also examined.
The first vaccination strategy involved immunization with the recombinant tumor-associated protein, carcinoembryonic antigen (CEA). Recombinant CEA was administered at 4 different dose levels 7 times during one year. Peripheral blood samples were regularly analyzed during 36 months. This vaccination regimen induced a strong immunoglobulin 1 (IgG1) and IgG4 response, a moderate IgG2 response and a weak IgG3 response against CEA. GM-CSF markedly augmented the effect on IgG1 and IgG4 as well as the T cell response. In contrast, dose of rCEA had no or modest effect on induced immune responses. The response gradually increased during the 12 months immunization period. Responses of all three IgG subclasses and of T cells were protracted up to 36 months. The anti-CEA IgG titers related significantly to survival. Functional HLA-DR epitopes of CEA could be defined. These major histocompatibility class II epitopes may serve as putative components of a peptide-based vaccination strategy.
The other vaccine strategy consisted of the tumor-associated antigen epithelial cell adhesion molecule (Ep-Cam) expressed as a transgene in a viral vector, ALVAC. Patients were immunized subcutaneously/intradermally 3 times over 6 weeks and monitored for immune responses for 46 weeks. No anti-Ep-Cam specific humoral response was induced, but Ep-Cam specific type 1 T cells (interpheron-gamma production) were induced, mainly in the GM-CSF group. The cytotoxic cellular response appeared late, or a few months after the last immunization.
Both vaccines were well tolerated. Since GM-CSF was an important component for both regimens, immungenicity of this cytokine was assessed. Multiple immunizations with low dose GM-CSF were associated with a low incidence of GM-CSF antibodies that did not neutralize the biological effect of GM-CSF.
In conclusion, both vaccines are promising candidate vaccines. GM-CSF is necessary to induce a strong humoral and cellular immune response. Large clinical trials are urgently warranted to evaluate the clinical efficacy.
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Hishizawa, Masakatsu. "Identification of tumor-associated antigens in hematological malignancies by SEREX." Kyoto University, 2006. http://hdl.handle.net/2433/143835.
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Shi, Mengchao. "Design and Synthesis of a Novel Entirely Carbohydrate-Based Conjugate for Cancer Vaccine Development." University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470412718.
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Dullforce, Per. "Cytotoxicity mediated by monoclonal antibodies to tumour associated antigens." Thesis, University of Nottingham, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293660.
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Ruiz, Elena. "DNA fusion vaccines against HPV16 E7 antigen-associated cancers." Thesis, University of Southampton, 2011. https://eprints.soton.ac.uk/374745/.
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To date, the success of cancer vaccines in human clinical trials has been limited. One of the reasons for this is the immunological tolerance to tumour antigens found in cancer patients. A novel DNA fusion vaccine design which links a pathogen-derived domain (DOM) of fragment C from tetanus toxin to a peptide epitope from a tumour antigen has been developed in our laboratory. The microbial sequence is able to activate a non-tolerised pool of helper T cells, providing T-cell help for immune induction against the linked tumour-specific sequence. The main aim of this project was to produce a therapeutic DNA vaccine against human papillomavirus (HPV)-associated cancers. A number of DNA fusion vaccines against the E7 antigen from HPV16 were constructed, including pDOM.E749-57, which encodes a well described H-2Db-binding epitope from E7 fused to the DOM sequence. CD8+ T-cell responses to the vaccines were demonstrated using flow cytometry and functional assays. Importantly, these responses were stronger than those induced by a published synthetic long peptide strategy. In vivo tumour challenge experiments showed that DNA vaccines had a protective and therapeutic effect. The vaccines were then tested in transgenic mice which develop spontaneous E7-expressing tumours in a setting of tolerance. DNA vaccine-mediated E7-specific CD8 + T-cell responses were successfully induced in these mice, together with a reduction in the mass of spontaneous tumours. This is the first demonstration of pDOM-epitope DNA vaccine-mediated therapy for spontaneous tumours and bodes well for translation into the clinic. One limiting factor for DNA vaccination in humans may be the delivery system. Electroporation (EP) is one approach which may overcome this. Therefore, a secondary aim of this project was to investigate the impact of EP on immune responses to DNA vaccination in more detail. EP proved essential for generating T-cell and antibody responses to the pDOM.E7 49-57 vaccine in sub-optimal conditions. This information will be crucial for the planning of therapeutic vaccination protocols in patients.
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Schecter, Robyn Lee. "A double determinant serum assay for detecting breast tumor associated antigen /." Thesis, McGill University, 1987. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=66270.
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Middleton, Catrin Heledd. "Recombinant tumor-associated antigen production and autoantibody detection in hepatocellular carcinoma." Thesis, University of Nottingham, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.595679.
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Hepatocellular carcinoma (HCC) is the sixth most common cancer and third most common cause of cancer-related death worldwide. Inadequate screening tests largely account for presentation of advanced tumours, poor prognosis and high mortality rates. Major risk factors for the development of HCC include Hepatitis B and C Virus infections and alcoholism, which lead to irreversible liver cirrhosis. Early detection of HCC amongst high-risk groups is paramount in improving prognosis, through enabling curative treatment options to be administered prior to manifestation of advanced and metastatic disease. An elicited humoral immune response, in the form of IgG autoantibodies raised to tumour-associated antigens, has been evidenced in the sera of cancer patients. Autoantibody measurements, using a minimally invasive blood test, could serve as an aid to early diagnosis by providing a window on early carcinogenesis months to years before the tumour bulk becomes otherwise clinically detectable. Autoantibody detection has previously been described in the HCC setting. Small numbers of antigens and use of sub-optimal control sera render published studies open to scrutiny. This thesis documents the research carried out in order to characterise the previously documented autoantibody response in the sera of patients with HCC and underlying liver disease. Tumour-associated antigens were produced using high-throughput recombinant technology and screened against sera from patients with HCC, liver disease and matched healthy controls. Varying autoantibody specificities and sensitivities were observed to the individual tumour-associated antigens investigated. A panel of 21 antigens achieved a specificity of 92% and sensitivity of 45% for the detection of HCC (by testing 96 cancers and 96 matched healthy controls). This same panel identified 21 % of 169 high-risk controls as having elevated autoantibody levels. This highlights the need for further investigation in order to determine whether such specificity (79%) would be deemed acceptable in a clinical setting for the application of an autoantibody test to aid in earlier cancer diagnosis. A reproducible panel of II antigens achieved a specificity of 91 % and sensitivity of 41 % for the detection of HCC, suggesting the potential held by optimised antigen production and careful panel selection. Changing autoantibody profiles in the sera of patients with stable cirrhosis and in the pre- and post-diagnostic sera of patients with HCC suggests a potential role for autoantibodies and their detection in the surveillance, diagnosis and prediction of recurrence in the HCC setting. Results are comparable to current gold standards in HCC (Ultrasonography) and to similar tests in other cancers (Early-CDT®-Lung). This simple blood test has the potential to offer a competitive advantage over currently available tools for the early identification of HCC amongst patients routinely monitored for the progression of their underlying liver disease.
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Al-Qudaihi, Ghofran. "Studies on the immunogenicity of tumour associated antigens in leukaemia." Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1254.
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There is an urgent need for the development of leukaemia-targeted immunotherapeutic approaches. Wilms’ tumour antigen (WT1), M-phase phosphoprotein 11 (MPP11) and proteinase-3 (PR-3) proteins are overexpressed in leukemic cells and represent attractive immunotherapeutic candidates. The first part of this study explored the feasibility of using an approach to develop a novel leukaemia vaccine by modifying the sequence of low avidity HLA-A*0201- restricted peptide epitopes derived from WT1 protein (WT1-126126-134 and WT1- 187187-195). The modified WT1-Db126 showed enhanced binding ability to the HLA-A*0201 molecule, increased the frequency of IFN-γ producing cytotoxic T lymphocyte (CTL), and boosted the lytic activity of the generated CTL against HLA-matched leukaemia cells. Interestingly, the CTL line generated with the modified epitope was able to recognize the wild-type peptide presented by target cells. The second part of this study identified a novel epitope derived from WT1 antigen (WT1-60237-251). This epitope was recognized by a CD4+ T cells in an HLA-DRB1*04-restricted manner and secreted Th2 cytokines (IL-5 and IL-4). The third part of the study aimed to identify potential CD8+ CTL epitopes in the sequence of MPP11 and PR-3 that may bind to HLA-A*0201 molecule and provoke specific CTL responses. A potential HLA-A*0201 binding epitope named MPP-437- 45 derived from the MPP11 protein was identified which was used to generate a CTL line. This CTL line specifically recognized peptide-loaded target cells in both ELISPOT and cytotoxic assays. Importantly, this CTL line exerted a cytotoxic effect towards the CML leukemic cell line K562-A2.1. The study also demonstrated that PR-3-derived peptides PR-129129-137 and PR-99-17 were not immunogenic since they were incapable of inducing specific CD8+ T cell responses. In conclusion, modification of the WT1-Db126 epitope resulted in enhancement of its immunogenicity without altering its antigenic specificity. The WT1-60 and MPP- 4 peptides have been identified as novel CD4 and CD8 T-cell epitopes, respectively.
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Li, Li. "Purification and characterization of tumour associated antigens 340 and 791Tgp72." Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301694.
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Dede, A. Y. "The identification of prostate cancer associated tumour antigens and biomarkers." Thesis, Nottingham Trent University, 2015. http://irep.ntu.ac.uk/id/eprint/27929/.
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The widespread use of Prostate Specific Antigen (PSA) testing has resulted in the over detection and over treatment of potentially indolent disease due to the lack of specificity of PSA for prostate cancer (PCa). PROTEOMEX, a method of tumour associated antigen (TAA) identification, combines the separation of tumour proteins by conventional proteomic methods (2-DE and mass spectrometry) with serological screening using serum antibodies, to identify immunogenic proteins in cancer. This project aims to identify TAAs and/or biomarkers for PCa which on subsequent validation, can be utilised as an improved diagnostic screening test. In pilot studies, SDS PAGE, 2-DE and OFFGEL electrophoresis were performed to identify immunogenic urine TAAs using PCa and healthy control sera. Proteins within the serum-reactive spots were either identified by Liquid Chromatography coupled to Matrix-Assisted Laser Desorption/Ionisation Time-of-Flight mass spectrometry (MALDI-TOF MS) or Electrospray Ionisation mass spectrometry (ESI MS). Among the urinary proteins separated by SDS PAGE, 2-DE and OFFGEL respectively, exclusive autoreactivity was identified in PCa sera to serum albumin and existing PCa biomarkers - human prostatic acid phosphatase & zinc-alpha-2 glycoprotein. Differential autoantibody responses were also identified to various TAAs in the PC-3 and DU-145 PCa cell lines using PCa and healthy sera. The presence of a differential TAA and autoantibody PCa serum response to one of the proteins identified by MALDI-TOF, alpha enolase, was further verified in a subset of PCa samples using immunohistochemistry, Western blotting and ELISA. In a larger sample cohort, the cytoplasmic and nuclear alpha enolase expression in a PCa TMA was assessed, where statistical significance was observed between benign controls and PCa (p=0.000003 and p=0.003 respectively), although protein expression did not correlate with any important clinico-pathological variables. Alpha enolase autoantibody expression was statistically significant between PCa and healthy controls (p=0.0038), where its expression correlated with D’Amico risk classification, indicating that alpha enolase may serve as a potential indicator of biochemical recurrence in PCa. PROTEOMEX represents a valuable approach for the identification of tumour biomarkers which may have diagnostic and/or prognostic value in PCa. Further work should identifiy more TAAs and autoantibodies associated with PCa, alongside a validation of the diagnostic utility of the identified biomarkers from this study.
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Looi, Kok Sun. "Using proteomic approach to identify tumor-associated antigens as biomarkers in hepatocellular carcinoma." To access this resource online via ProQuest Dissertations and Theses @ UTEP, 2008. http://0-proquest.umi.com.lib.utep.edu/login?COPT=REJTPTU0YmImSU5UPTAmVkVSPTI=&clientId=2515.
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Nastke, Maria-Dorothea [Verfasser], and Hans-Georg [Akademischer Betreuer] Rammensee. "T-cell epitopes from viral and tumor associated antigens : induction and analysis of antigen-specific T cells / Maria-Dorothea Nastke ; Betreuer: Hans-Georg Rammensee." Tübingen : Universitätsbibliothek Tübingen, 2005. http://d-nb.info/1162199148/34.
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Almeida, Andreia Filipa Ferreira de. "Detection of tumor-associated sialylated O-glycans by MALDI-TOF/TOF." Master's thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/10673.
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Mestrado em Bioquímica ClínicaUma das alterações fenótipicas mais comuns nos tumores são modificações no padrão de O-glicosilação na superfície da célula e nas glicoproteínas secretadas. Como consequência têm implicações nas suas funções biológicas. Em particular, tem sido descrito que algumas células tumorais sobreexpressam ou expressam de novo antigénios associados ao antigénio Thomsen-Friedenreich (TF), ou seja, sialil-Tn, sialil-T e disialyl-T. Estes epítopos resultam da paragem prematura do processo de O-glicosilação em proteínas e têm um impacto direto sobre a biologia do tumor. Assim sendo, a identificação destas modificações póstranslacionais anormais em proteínas é essencial para determinar as relações estrutura-função e descobrir novos alvos terapêuticos. Além disso, as proteínas que transportam estas alterações podem ser secretadas na corrente sanguínea, urina, e em outros fluidos corporais e, portanto, são explorados como biomarcadores em testes não invasivos. Atualmente a detecção de antigénios associados ao antigénio TF é baseado em métodos imunohistoquímicos em que, embora úteis para uma investigação de rotina, não conseguem descrever totalmente o padrão de glicosilação de uma dada proteína. Sendo assim, neste trabalho apresentamos uma abordagem analítica para determinar estes glicanos em quantidades minimas de glicoproteínas (picomole) isoladas a partir de géis SDS-PAGE. Resumidamente, as glicoproteínas são de-Oglicosiladas no gel por beta-eliminação redutiva, permetiladas e analisadas por nanoLC-MALDI-TOF/TOF. De seguida, os dados provenientes são sujeitos a uma seleção melhorada dos sinais analíticos relevantes, utilizando ferramentas de bioinformática. Esta abordagem foi, em seguida, aplicada com sucesso na validação do western blotting quanto à expressão de sialil-Tn numa glicoproteína isolada a partir da urina de ratos com tumores na bexiga induzidos quimicamente e no plasminogénio isolado a partir do soro de pacientes com lesões precursoras do cancro gástrico.
A common phenotypic change in tumors comprises alterations in the O-glycosylation of cell-surface and secreted glycoproteins with implications in their biological functions. In particular, it has been described that some tumor cells overexpress or de novo express Thomsen-Friedenreich (TF)-related antigens, namely sialyl-Tn, sialyl-T and disialyl-T. These epitopes result from a premature stop in protein Oglycosylation and have direct impact on tumor biology. As a result, the identification of these abnormal post-translational modifications of proteins is essential to determine structure-function relationships and designs novel therapeutics. Moreover, the proteins carrying these alterations can ultimately be shed into the blood stream, urine and other body fluids and thus be explored as biomarkers in non invasive tests. Currently the detection of TF-related antigens relies on immuno-based methods that, even though useful in a routine basis, often fail to fully highlight the glycosylation pattern of a given protein. Herein, we have systematized a target-driven analytical approach to determine these glycans in minute amounts of glycoproteins (picomole) isolated from SDS-PAGE gels. Briefly, the glycoproteins are to be de-O-glycosylated in-gel by reductive beta-elimination, permethylated and analyzed by nanoLC-MALDI-TOF/TOF with enhanced selection of the relevant analytical signals using bioinformatics tools. This approach was then successfully applied to validate western blotting assignments regarding the expression of sialyl-Tn in a glycoprotein isolated from the urine of rats with chemically-induced bladder tumors and in plasminogen isolated from the serum of patients with gastric cancer precursor lesions.
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Ghidouche, Abderrezak. "Nectine-4 : nouvelle cible dans l'immunothérapie du cancer du sein." Thesis, Aix-Marseille 2, 2011. http://www.theses.fr/2011AIX20677.
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Nectine-4 est une molécule d'adhérence membre de la superfamille des immunoglobulines. Elle est localisée au niveau des jonction adhérentes. Exprimée durant l'embryogenèse, nectine-4 n'est pas retrouvée dans les tissus adultes excepté la peau. Des mutations survenant au niveau du gène de la nectine-4 cause le syndrome EDSS affectant le développement de la peau. Nous avons participer à la démonstration que l'expression de nectine-4 est marqueur des carcinomes mammaires,pulmonaires et ovariens. Ainsi, nous avons étudier le role fonctionnel de l'expression de nectine-4 sur la progression tumorale. Les résultats obtenus suggèrent que nectine-4 représente une cible intéressante dans le cadre d'une stratégie d’immunothérapie anti-tumorale.Par l'utilisation d'une méthode multiplex combinant des essais biochimiques, cellulaires et algorithmiques, 5 peptides potentiellement antigéniques ont été identifiés. Toutefois,après génération de lymphocytes cytotoxiques HLA-A*0201 spécifique à partir de PBMC de donneurs sains et la mise en place" de tests de cytotoxicité dirigée; nous avons identifié un nouveau peptide antigénique produit et présenté de façon naturelle à la surface de cellules tumorales. Ce dernier est le peptide nectine-4 N°145 (VLVPPLPSL). En plus de l'identification d'un peptide antigénique, nous avons développé un anticorps monoclonal anti-nectine-4 qui a la capacité de réduire de façon spécifique et significative les capacités métastatiques des cellules tumorales nectine-4 positive.Ainsi, dans cette étude nous avons démontré que nectine-4 qui est un nouveau antigène associé aux tumeurs, affecte la progression tumorale, mais aussi il est possible de cibler cette molécule par des stratégies d'immunothérapie car nous avons pu identifiés un peptide antigénique et un anticorps monoclonal. L'efficacité d'une stratégie d'immunothérapie est en cours de réalisation actuellementNectin-4 is a cell surface adhesion molecule, member of the Ig-superfamily, and is localized at adherens junctions. Nectin4 is expressed during embryogenesis but not in adult tissues, except in the skin. Mutations in nectin-4 gene in humans cause the EDSS syndrome that affects skin development (EctoDermal and Syndactly Syndrome). We and others have recently demonstrated that nectin-4 expression was a tumoral marker of breast, lung and ovarian carcinoma. We thus started to investigate the functional role of nectin-4 overexpression in breast cancer. Using in vitro and in vivo assays, the preliminary results demonstrate that nectin-4 increased the tumorigenicity of malignant cells.Altogether, these results suggest that nectin-4 might be a candidate target forimmunotherapy (vaccination and antibody based therapy). Using a multiplex approachbased on biochemical, cellular and algorithmic assays, five relevant nectin-4 epitopes were identified. Specific cytotoxic T lymphocyte (CTL) populations from healthy donors that recognized and lyzed peptide-pulsed HLA-A*0201 tumor cells were identified. HLAA*0201-restricted CTL that recognized the N4-145 (VLVPPLPSL) nectin-4 epitope was characterized extensively. This CTL kills breast tumor cells that express nectin4, strongly demonstrating that this peptide could be naturally processed and recognized by specific CTL. In parallel, we also tested a blocking monoclonal antibody against the extracellular region of nectin-4. We next demonstrated that this antibody reduced the metastatic capacity of tumors expressing nectin4. To summarize, in this study, we identified nectin-4 as a newcell surface Tumor Associated Antigen and demonstrated its likely implication in cancertumorigenesis. In parallel, we have developed the specific tools required to conduct an effective immunotherapy targeting nectin4 over-expressing cells, which are currently under investigation
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Mathew, John. "Spectrum of autoantibody response to tumour associated antigens in normal population." Thesis, University of Nottingham, 2013. http://eprints.nottingham.ac.uk/56070/.
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Early detection and diagnosis of cancer has a significant impact on cancer specific mortality as shown in randomised screening trials for breast, colon and lung cancer. However, current screening tests have limitations as they reduce cancer specific mortality for breast, colon and lung cancer by only 24%, 16% and 20% respectively, and partly as a result cancer continues to be one of the common causes of death in the developed world(Aberle et al, 2011; Hardcastle et al, 1996; Larsson et al, 1996). One of the other problems associated with current screening tests is patient compliance (mammography, colonoscopy and CT) (Jonnalagadda et al, 2012; Maurer, 1995; Pooler et al, 2012). Diagnosing cancers with a blood test by identifying tumour associated antibodies in serum is a novel method which may allow the identification of early stage cancers and hopefully it would have greater patient acceptability. These tumour associated antibodies represent an indirect amplified signal generated as a response by the immune system to tumour associated antigens secreted early on in development of cancer. One of the common limitations of many autoantibody studies is the selection of appropriate controls - or the lack of such. One common problem is the use of limited number of normal individuals without cancer as controls, the data from which may not be representative of the normal population as a whole (Stockert et al, 1998). In addition not only the numbers of controls are often incorrect but also the age of the controls. Many studies report using 'blood donors' as controls(Guy et al, 1981) and clearly for most tumour types this involves both a younger population and also a relatively health population which may not always be reflective of the individuals to be screened (e.g. compare heavy smokers). We hypothesised that autoantibody response to cancer associated antigens may alter with demographics (age, sex, and smoking) and the aim of our study was to identify the spectrum of response of tumour associated antigens in a range of demographic groups within the normal population of the East Midlands. EarlyCDT-Lung™ is a simple commercial blood test which is reported to aid the early detection of lung cancer. The technology was initially developed in the laboratories of the Division of Breast Surgery and subsequently underwent further development by the university spinout company, Oncimmune. EarlyCDT-Lung initially measured autoantibodies (AAbs) to six cancer associated antigens (p53, NY-ESO-1, CAGE, GBU4-5, Annexinl, and SOX2) and was reported to identify up to 40% of lung cancers, at both at eariy- and late-stage disease(Boyle et al, 2011; Chapman et al, 2012; Chapman et al, 2011; Lam et al, 2011; Macdonald et al, 2012a; Macdonald et al, 2012b; Murray et al, 2010).The initial technical (Murray et al 2010) and clinical (Boyle et a;l 2011; Lam et al 2011) validation studies matched high risk individuals to every lung cancer patient. Controls were individually matched to a patient with lung cancer by age, gender and smoking history. As the 6 antigen panel had been developed and validated (Boyle et al, 2011; Murray et al, 2010) it was decided to proceed to assess the level of autoantibodies across the population and in particular to look at differences by gender and different decades of life. We used a semi-automated Enzyme linked immunosorbent assays (ELISA) to run the serum samples collected from individuals with no previous history of cancer. Informed consent was taken prior to a detailed health questionnaire and then a blood sample by standard venipunture. The information acquired in the questionnaire included age, gender, smoking history, any autoimmune disease and family history of cancer. Serum samples used in this thesis were collected from 2065 individuals. Male to female ratio was 1: 2.6(566:1487). Ratio of smoker versus ex-smokers versus non-smoker was 1: 2.4: 3.8 (285:672:1096). There was a fall in the number of smokers with increasing decade of life. The proportion of smokers and ex-smokers versus non-smokers remained approximately the same in both genders. Almost half the patients (964) had family history of some form of cancer. One hundred and eighty six subjects (9%) had personal history of autoimmune disease. Analysis of autoantibody levels revealed a small but steady increase with increasing age for 4 out of the 6 antigens (p53, NY-ESO-1, CAGE and GBU4- 5). Except for CAGE, there was no significant difference in mean optical densities between males and females. For CAGE, when analysis of variance was used to adjust for run differences, there was no significant difference in mean optical densities between males and females. Autoantibody response to all 6 cancer related antigens were consistently low in smokers. The rise in autoantibody response was more in the ex-smoker group compared to the other two groups suggesting the possibility of rebound effect when smoking is stopped. It reached statistical significance except in case of NY-ESO-1. Age matched analysis were done, and the differences were statistically significant for p53, GBU 4-5 and Annexinl. To explore further the "rebound" hypothesis further, the year of quitting for ex-smokers were extracted from the database. Any association between AAb levels and time lapse since quitting might provide support to this hypothesis. Very little difference was seen for most antigens back to 1970, but decades before that there was an observed increase in the mean AAb level for all antigens except SOX2. Further work would be required to establish such a rebound effect. Family history and history of autoimmune disease did not have a significant impact on autoantibody levels. Analysis of autoantibody levels in a large cohort of the normal population of the East Midlands revealed that age has a small but significant influence on the serum levels of certain autoantibodies to cancer related antigens. However, this could be confounded by the fact that incidence of cancer also increases with age, and would need further investigation and in particular longer followup of patients who have given blood in this research study to see which individuals have developed cancer.
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Mosolits, Szilvia. "Natural and induced immunity aginst the tumour-associated antigen, Ep-CAM /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-752-5.
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Kremling, Heidi. "Expression and function of the tumor associated antigen EpCAM in early esophageal carcinoma." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-182881.
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Rojas, JoseÌ-Manuel. "Identification of novel immunogenic HLA-DR-restricted peptides from tumour-associated antigens." Thesis, Nottingham Trent University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273771.
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CD4+ T cells playa central role in antitumour immunity; not only do they provide help for the development of CTL recognising tumour antigens but they can also enhance antitumour responses via indirect cytotoxic mechanisms at the tumour site. Since CD4+ T cells recognise the antigen in the form of pep tides presented on MHC class II molecules, attention has been focused in the recent years on the identification of these peptides derived from tumour antigens. Therefore the aim of this study was to identify novel immunogenic peptides derived from tumour antigens where presentation was restricted to human MHC class II HLA-DRI and/or HLADR4 molecules. The adopted strategy consisted in predicting peptides from the tumour antigens p53, gplOO and bcr-abl(b3a2) using computer-assisted algorithms, and immunisation of HLA-DRI transgenic mice with these peptides in order to assess their immunogenicity. Immunogenic peptides in transgenic mice were then tested in human in in vitro T cell sensitisation assays. To determine peptide immunogenicity in mice, a method was optimised using the reported I-Ak-restricted peptides HEL46-61 and HEL1l 9-132. This model was then successfully established in HLA-DRI transgenic mice with the model peptide HA307- 319. Proliferative responses and IFN-y production were observed when the splenocytes of HLA-DRI transgenic mice were re-presented in vitro with the HA307-319 peptide used in immunisation. Dendritic cells (DC) were shown to be better antigen presenting cells (APC) than syngeneic splenocytes in proliferation assays; thus DC were subsequently used as APC in the all experiments. Further characterisation of DC, generated from bone marrow precursors by culture with GM-CSF, demonstrated that day 8 non-adherent cells matured with LPS were optimal for antigen presentation in this experimental setting. Immunisation of HLA-DRI transgenic mice with predicted peptides from p53, gplOO and bcr-abI(b3a2) resulted in HLA-DRlrestricted responses for two novel p53 peptides (p5363-77 and p53108-122) and two bcrabl peptides (bcr-abIGFK11 and bcr-abIATG1 8). Responses were also observed to two novel gp 100 peptides (gp 1 00194-208 and gp 100566-580). This study demonstrated that HLA-DR-restricted responses to novel peptides can be obtained in HLA-DRI transgenic mice. Furthermore, proliferative responses to p5363-77 in a HLA-DRI + donor, to gpl00566-580 in another HLA-DRl+ donor. and to p53108-122 in two HLA- -1- Abstract DR4+ donors demonstrated that these peptides were also immunogenic in human assays. Collectively, these results indicated that peptide immunisation of HLA-DRI transgenic mice could facilitate the identification of novel immunogenic HLA-DRrestricted pep tides from tumour antigens, that allow us to understand further the role of CD4+ in antitumour immunity and improve cancer immunotherapeutic strategies.
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McCurry, Dustin. "Tumor Associated Antigens Harbor Readily Defined and Universally Immunogenic Regions Relevant For Cancer Immunotherapy." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/623490.
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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.Recent advances in cancer immunology, highlighted by immune checkpoint inhibitors, have demonstrated that immunotherapy is a viable option in the oncologist’s armamentarium. Despite these advances, many patients are nonresponders. Preliminary studies have suggested that non-responders lack a de-novo anti-tumor antigen immune response that can be unmasked by checkpoint blockade; thus, strategies to induce anti-tumor immune responses are needed. We hypothesized that many tumor associated antigens (Ag) are readily susceptible to immune attack, but only in the context of identifying the tumor antigen epitopes that can reliably initiate an immune response, regardless of individual patient human leukocyte antigen (HLA) haplotype restrictions. We further hypothesized that epitope prediction strategies which seek to identify pan- or highly promiscuous-HLA binding epitopes would reduce the number of potential candidates and be more likely to accurately identify high-priority tumor Ag epitopes. Utilizing known HLA-serotype frequencies and setting a threshold of ninety percent of population coverage, regardless of race or ethnicity, twenty-nine different HLA-DRB1 haplotypes were chosen for antigen prediction utilizing the open source epitope prediction algorithm netMHCIIpan. Predictions were also performed for HLA-A serotypes utilizing the open source algorithm netMHCpan. Predicted epitopes were synthesized in the form of synthetic long peptides and tested in immune system sensitization assays involving unfractionated peripheral blood mononuclear cells (PBMC). Briefly, PBMC were subjected to a two-step culture, first synchronizing their exposure to the long peptides with aggressive surrogate activation of innate immunity, followed by IL-7-modulated T-cell hyperexpansion. Predictions resulted in identification of highly promiscuous-HLA binding epitopes. Unexpectedly, these epitopes clustered together forming high priority regions: unique “hot spots” with high densities of promiscuous HLA-binding epitopes from the widely expressed oncoproteins MUC1, HER2/neu and CMV-pp65 (p<0.0001, for predicted HLA-DRB1 binding affinities, compared to non-hot spot regions). Added synthetic long peptides (>20aa) derived from “hot spot” regions of MUC1, HER2/neu, and CMVpp65 reliably produced selective and sustained expansion of both CD4+ and CD8+ peptide-specific, interferon-γ (IFNγ)-producing Tcells when synchronized with step 2 exposure to exogenous IL-7 (p<0.0001 and p=0.0048, for CD4+ and CD8+ Ag-specific T-cells, respectively, compared to T-cells directed against peptides from non-hot spot regions). “Hot spot” peptide Ag-specific T-cells preferentially recognized endogenous tumor derived MUC1, either in MUC1 expressing tumor cell killing assays (p=0.038, compared to non-peptide Ag-specific T-cells) or as MUC1 tumor lysate when pulsed onto restimulatory PBMC (p=0.022 and 0.025, for CD4+ and CD8+ T-cells, respectively, compared to T-cells directed against peptides from non-hot spot regions). This mechanistically rational antigen selection sequence, effective even for unvaccinated donors, regardless of HLA-haplotype, enables rapid identification of tumor protein regions relevant for cancer immunology, including adoptive immunotherapy, vaccines, and even identification of tumor neo-antigens unique to each patient.
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Yamazaki, Yuji. "Investigation on Chemical and Enzymatic Synthesis of Tumor Associated Carbohydrate Antigens Triggering Immune Responses." Kyoto University, 2019. http://hdl.handle.net/2433/242472.
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Malhi, S. K. "Molecular expression and immunotherapeutic potential of the novel tumour associated antigen T21." Thesis, Nottingham Trent University, 2013. http://irep.ntu.ac.uk/id/eprint/351/.
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The application of immunotherapeutic approaches to target tumour cells by harnessing the body’s most important defence the immune system, could provide opportunities to oppose cancer. A prerequisite of tumour immunotherapy lies in the identification of antigens that are distinctively expressed in cancer and can elicit immune responses in the tumour-bearing host. Testis clone 21 (T21) was first identified as a promising prostate-associated tumour antigen identified using modified SEREX expression cloning showing restricted protein expression to normal testis and prostate, breast, kidney, ovary, melanoma, colon and stomach cancer among others. More recently, T21 was found to share significant sequence similarity with a centrosomal protein called CEP290. This study proposed to address the current understanding of T21 through analysis of gene sequence similarities observed with CEP290 and begin to extrapolate possible functional attributes of T21 and the role it may play in cancer progression. Furthermore this investigation aimed to evaluate T21 as a prospective prognostic indicator of prostate cancer and in addition, investigate T21 as a potential target for immunotherapy. In silico sequence analysis revealed that T21 contained a 93bp region, a consequence of an alternative splicing event resulting in the retention of a CEP290 intronic region making its translation to protein unique. This finding was supported by experimental observations using PCR and northern blotting. Using this T21 “unique region” sequence, T21 mRNA and protein was shown to be expressed in some normal tissues including prostate, stomach and spinal cord when compared to testis therefore T21 cannot be considered a cancer testis antigen as previously suggested. Evidence of T21 protein expression was shown in a number of cancer tissues, however a histological study demonstrated no significant discrimination between benign and prostate cancer patients. In vitro assessment of cell proliferation following T21 gene knockdown indicated an association between T21 and increased tumour cell proliferation. Expression profiling of data obtained from Next Generation Sequencing (NGS) indicated T21 function was related to cell proliferation and survival, modulation of immune responses and suppression of regulatory processes involved in tumourigenesis. Collective evidences suggest T21 activity to be independent of that of CEP290. Finally, this study identified a novel immunogenic and naturally processed peptide target using a transgenic murine model, further verified using human cancer patient PBMCs. Future studies to determine the immunotherapeutic potential of T21 would focus on providing evidence of peptide-specific tumour killing targeting this novel antigenic sequence in the first instance.
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Wong, Kah-Keng. "Validation of lymphoma-associated antigens identified using autoantibody profiling and protein arrays." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:51ac6bbe-2845-43cc-9b7a-cb92097155f1.
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Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma subtype with heterogeneous clinical outcome and a significant number of patients still die of their disease. Characterising lymphoma patients’ autoantibody repertoires represent one approach to improve the understanding of their disease biology. Our hypothesis was that characterisation of antigens eliciting humoural immune responses in lymphoma patients may provide insights into mechanisms of lymphomagenesis and identify novel diagnostic/therapeutic targets. HIP1R was validated as a novel B-NHL autoantigen by immunoblotting with patients’ sera. No response was identified to the related HIP1 protein. Consistent with this finding, more widespread expression of HIP1R, compared to HIP1, was observed in lymphoma cell lines. Expression studies, at both transcript (qRT-PCR and analysis of microarray datasets) and protein levels (blotting and immunolabelling), identified abundant HIP1R in normal B cells and low level expression in a poor prognosis activated B-cell (ABC)-like DLBCL subtype. Upregulation of HIP1R expression was observed in activated non-malignant B cells at both transcript and protein levels, suggesting that downregulation of HIP1R expression in ABC-DLBCL might be a disease-related process. Despite its potential for DLBCL subtyping, HIP1R protein expression was not statistically significantly associated with patients’ survival in a series of 256 DLBCL. Short FOXP1 isoforms were identified as one mechanism repressing HIP1R transcription in an ABC-DLBCL cell line. Phenotypic analysis of HIP1R-depleted B-cell lymphoma cells indicated that HIP1R silencing could increase the surface levels of B-cell receptor (BCR) components such as IgM and CD79b. HIP1R represents a novel lymphoma autoantigen and cell-of-origin marker for distinguishing germinal centre- versus ABC-DLBCL subtypes. As ABC-DLBCL survival is dependent on chronic BCR signalling, future studies will address whether HIP1R silencing plays a fundamental role in disease pathogenesis by promoting BCR signalling.
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Trabbic, Kevin R. "Approaches to Increase the Immunogenicity of Carbohydrate Antigens Using PS A1 and Subsequent Immunotherapies." University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470330973.
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Nilsson, Stinabritt. "Synthesis of blood-group and tumour-associated oligosaccaharides and a bacterial polysaccharide fragment." Lund : Organic Chemistry 2, Lund Institute of Technology, University of Lund, 1992. http://books.google.com/books?id=U-dqAAAAMAAJ.
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FERNANDEZ, S. M. ALVAREZ. "SEROLOGICAL IMMUNE RESPONSE AGAINST ADAM10 IN COLORECTAL CANCER PATIENTS IS A FAVORABLE SIGNATURE." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/243933.
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In cancer the immune system is activated in response to qualitative and quantitative aberrant expression by tumor cells of certain proteins named tumor-associated antigens (TAAs). In a previous study in the laboratory, has been investigated the presence of TAAs inducing auto-antibodies (auto-Abs) in the Colorectal cancer (Crc) by exploiting the patients serological reactivity against the surface membrane proteoma. Among several candidates, a specific immunoreactivity against A Disintegrin And Metalloprotease 10 (ADAM10) protein has been identify.ADAM10 is a disintegrin metalloprotease with a potential role in tumor progression and invasion due to its sheddase activity. ADAM10 is able to promote ERK1/2 signaling activation promoting cell proliferation by the cleavage of the extracellular domain (ECD) of the HER2 tyrosine kinase receptor, which is released in serum. Moreover, ADAM10 plays a critical physiological function in the epithelial morphogenesis since its sheddase activity is crucial for the cell migration and extracellular matrix (ECM) remodelling, a phenomenon that also drives tumor metastasis. Thus, an aberrant expression of the ADAM10 in epithelial tissues might elicit a specific serological immune response. The serological screening performed on purified ADAM10, showed a significant presence of immunoreactivity against ADAM10 in the sera from patients affected by tumors of epithelial origin like Crc, Pancreatic cancer (Pc) and Breast cancer (Brc) if compared with serological reactivity of healthy subjects. On the contrary, sera from patients affected by hematological malignancies such as chronic lymphocytic leukemia (B-CLL) and Multiple Myeloma (MM), did not showed significant immunoreactivity against ADAM10. These results suggested that the presence of auto-Abs against ADAM10 in patients sera might be a candidate biomarker for carcinomas of epithelial origin. Since it is known that ADAM10 is overexpressed in advanced stages of the Crc disease, when the lymph nodes are infiltrated by the tumor, we evaluated the disease course of this patients after surgical resection in order to define whether the presence of auto-Abs anti-ADAM10 is a favourable or detrimental signature, correlating the immunoreactivity with the patients follow-up. The results showed that the presence of auto-Abs anti-ADAM10 prolonged significantly the disease-free condition if compared with Crc patients without serological immunoreactivity against ADAM10. Thus, in order to investigate the effects of these auto-Abs, in vitro experiments of both HER2 ECD release and cell migration were performed using the Colon carcinoma cell line LoVo. Results showed that commercial anti-ADAM10 antibodies resulted to be effective in inhibiting cell migration and HER2 ECD release in LoVo cell line while IgG fraction purified from representative Crc patients did not. This lack of inhibition might be the consequence of the fact that LoVo cell line did not express the specific epitope that elicited the serological reactivity in Crc patients. In fact, Crc patients showed different expression of ADAM10 in tumoral tissues. Patients with a positive immunoreactivity against ADAM10 (Ser-ADAM10 +) showed an overexpression of the inactive form of ADAM10 and, accordingly, an high expression of the inactive HER2 (p195) isoform and a decreased expression of phosphorilated-ERK1/2. These results suggest a reduced activity of ADAM10 on the HER2 ECD cleaveage which is supported by the observation that Ser-ADAM10 + patients showed lower HER2 ECD concentrations in serum compared to Ser-ADAM10 - patients.
In conclusion, the presence of auto-antibodies anti-ADAM10 may be considered a biomarker of favourable prognosis for Crc patients at advanced stages of the disease that reflects an overexpression of inactive ADAM10 during the cell transformation and accordingly the lower protein maturation leads to a decrease of its sheddase activity which in turnt declines the proliferative and invasive capacity of tumor cells.
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Plunkett, Timothy Andrew. "Studies of the murine and human immune response to the tumour-associated antigen MUC1." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.402445.
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TARASIUK, OLGA. "Phage display selection and development of monoclonal antibodies against Protein Disulfide Isomerase, a novel tumor associated antigen and potential target for cancer immunotherapy." Doctoral thesis, Università del Piemonte Orientale, 2018. http://hdl.handle.net/11579/105204.
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Trimpe, Kevin L. "Modulation of cell-cycle associated antigen expression by the B16 melanoma : multiparameter analysis using monoclonal antibodies and flow cytometry /." The Ohio State University, 1985. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487264603217361.
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Kremling, Heidi [Verfasser], and Olivier [Akademischer Betreuer] Gires. "Expression and function of the tumor associated antigen EpCAM in early esophageal carcinoma / Heidi Kremling. Betreuer: Olivier Gires." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1071803522/34.
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Kawahara, Masahiro. "Identification of HLA class 1-restricted tumor-associated antigens in adult T cell leukemia cells by mass spectrometric analysis." Kyoto University, 2007. http://hdl.handle.net/2433/135730.
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Kleski, Kristopher A. "Progress of Entirely Carbohydrate Conjugates in Cancer Immunotherapeutics – Syntheses and Developments." University of Toledo / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1586980386810219.
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Zou, Jun. "Characterization of peptides and phage that bind galectin-3 selected from bacteriophage display libraries a study of the role of galectin-3 in metastasis-associated cancer cell adhesion /." Diss., Columbia, Mo. : University of Missouri-Columbia, 2005. http://hdl.handle.net/10355/4149.
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Thesis (Ph. D.)--University of Missouri-Columbia, 2005."December 2005" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. Includes bibliographical references.
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Writer, Michele. "Molecular analysis of the recognition of the tumour associated antigen CD55 by the mouse monoclonal antibody 791T/36." Thesis, University of Nottingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342476.
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Baxter, Katherine Elizabeth. "Developing an Oncolytic Prime-Boost Vaccine Targeting the Tumour Associated Antigen Mesothelin for the Treatment of Pancreatic Cancer." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40024.
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Pancreatic cancer (PDAC) affects 4400 Canadians each year and with 5year survival rates <8%, there is clearly an unmet need for new therapeutic approaches for treating this deadly disease. Herein I report the development of a surgical model of PDAC that recapitulates many of the hallmarks of human disease and has an immune infiltrate consisting of T cells and suppressive regulatory T cells and myeloid derived suppressor cells. This model allows the exploration of new therapeutics that can be used in combination with surgical resection of primary tumours. Furthermore, I propose that the use of neoadjuvant administration of a prime-boost oncolytic vaccine targeting a pancreatic tumour associated antigen (TAA) - mesothelin - could potentiate pancreatic tumour specific immune responses to improve patient prognosis. We demonstrate that immune tolerance to this self antigen can be broken by the complete depletion of circulating Tregs at the time of vaccination, which leads to the activation of a population of CD8+ T cells responsive to mesothelin. We demonstrate that these T cells respond to mesothelin expressing tumour cells ex vivo, and that CD8+ T cells are recruited to the site of tumour challenge. However, despite the generated CD8+ T cell response, oncolytic vaccine strategies targeting mesothelin provide no protection against Pan02 tumours, or against other mesothelin expressing murine tumour lines. I demonstrate that this is not through common tumour escape mechanisms, nor through the upregulation of suppressive immune populations. Any efficacy observed was found to be provided solely by depletion of Tregs, as the depletion of CD8+ T cells did not reduce protection from tumour outgrowth in vaccinated mice. While mesothelin represents a promising target, it is not an ideal target for oncolytic vaccine platforms, potentially due to its nature as a self antigen.
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Abdulmajed, Hind Abdulrazak Yassin. "Identification of tumour associated antigens as potential targets for the immunotherapy of B-cell chronic lymphocytic leukaemia (B-CLL)." Thesis, University of Leicester, 2008. http://hdl.handle.net/2381/9157.
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B-CLL, the most common adult B-cell malignancy in USA and the western world, is characterized by the accumulation of CD5+ mature B-cells in blood, bone marrow and lymphoid tissues. Many cases require no treatment because of an indolent course, while other patients become symptomatic or develop signs of rapid progression. Treatment is usually non-curative and is directed at reducing the symptoms. However, new therapies are currently under investigation aiming to achieve a curative therapy for B-CLL. The increasing understanding of how peptide antigens are processed, transported and presented by HLA, the identification of tumour antigens recognised by cytotoxic T lymphocytes and the identification of T-cell epitopes on human tumor cells, have opened the routes for the development of more efficient strategies for tumour immunotherapy. Several antigens have been characterized as tumour associated antigens (TAA) in B-CLL, with the potential to elicit specific anti-tumour responses. This thesis addresses the role of survivin, a member of the family of inhibitor of apoptosis proteins, as a potential target for the immunotherapy of B-CLL. Data on survivin expression showed no/ little expression of survivin in resting B-CLL, which was upregulated by in vitro activation with CD40 ligation, CpG-oligodeoxynucleotides (ODN), and with both stimulators together. CD40 ligation resulted in greater B-CLL cell activation, survivin expression, upregulation of activation markers (CD54, CD80 and CD86), and in enhanced activity of B-CLL cells to stimulate allogeneic T cell proliferation, compared to the other two ways of stimulation. Studying the induction of autologous tumour specific T cell responses in vitro, CD40L activated B-CLL cells enhanced CTL responses compared to unactivated cells. No significant difference in response of B-CLL patients T cells to survivin peptide pulsed T2 cells was found between HLA-A2+ and HLA-A2- patients, and no clear peptide specific responses were seen in either group. After investigating survivin peptides for their potential to induce cytotoxic T cell responses, generating survivin specific CTL line from a healthy donor was attempted using peptide pulsed autologous monocyte derived dendritic cells, but was unsuccessful suggesting that no T cells in the culture were able to recognise survivin peptides, or that the culture conditions used were inappropriate for the generation and maintenance of such responses. Finally, in investigation of other TAA expression in B-CLL cells, no expression of MAGE-A1, MAGE-A3, Proteinase-3, WT-1 was detected pre- and post CD40 activation. Positive PRAME expression was detected in 8 out of 20 CD40L activated CLL cells whilst NY-ESO-1 showed an upregulation in one sample. Overall results indicate that much work is still needed to study the potential of immunotherapy in the treatment of B-CLL.
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Das, Krishna [Verfasser], and Stefan [Akademischer Betreuer] Eichmüller. "Generation of a transplantable murine tumor model expressing the human breast cancer associated tumor antigen NY-BR-1 in HLA-DRB1*0401-transgenic mice / Krishna Das ; Betreuer: Stefan Eichmüller." Heidelberg : Universitätsbibliothek Heidelberg, 2017. http://d-nb.info/1178009513/34.
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Das, Krishna [Verfasser], and Stefan B. [Akademischer Betreuer] Eichmüller. "Generation of a transplantable murine tumor model expressing the human breast cancer associated tumor antigen NY-BR-1 in HLA-DRB1*0401-transgenic mice / Krishna Das ; Betreuer: Stefan Eichmüller." Heidelberg : Universitätsbibliothek Heidelberg, 2017. http://d-nb.info/1178009513/34.
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BERNARD, DOMINIQUE. "Expression des antigenes hla-dr par le tissu mammaire dans les cancers du sein." Clermont-Ferrand 2, 1986. http://www.theses.fr/1986CLF2E367.
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Mise au point d'une technique permettant le masquage de l'anticorps monoclonal anti hla-dr et de l'antigene hla-dr des cellules, l'immunoprecipitation des antigenes hla-dr, l'isolement de l'immun complexe et sa quantification par chromatofocusing. Mise en evidence de la regulation hormonale de l'expression des antigenes: en particulier role de la prolactine de l'oestradiol et de la progesterone. Effets de la gestation et de la lactation. Travail effectue sur la tumeur mammaire chimio-induite par la n-nitroso-n-methyluree chez la rate ainsi que sur un modele tumoral humain: la lignee mcf7
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Amarnath, Shoba Maria Prescilla. "Specific cytotoxic T lymphocyte immunity against hTERT in breast cancer and optimisation of dendritic cell maturation for presenting tumour associated antigens." Thesis, University of Hull, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411929.
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Perini, Silvana. "Efeito da hipoxia intermitente em marcadores de progressão de melanoma em um modelo de apneia do sono em camundongos." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/72432.
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Objetivos do Estudo: O aumento do crescimento de melanoma foi avaliado em camundongos expostos a hipóxia intermitente. As proteínas que caracterizam a agressividade do tumor ainda não foram investigadas. O estudo teve como objetivo verificar se a hipóxia intermitente simulada pela apneia do sono afeta marcadores de melanoma na progressão tumoral. Desenho: Estudo prospectivo controlado em animais. Senário: Hospital Universitário. Participantes: Doze camundongos C57BL/6. Intervenções: Camundongos foram expostos a hipóxia intermitente ou simulada. Durante 8 horas por dia, o grupo hipóxia foi submetido a um total de 480 ciclos de 30 segundos de hipóxia progressiva SpO2 nadir de 8 ± 1%, seguidos por 30 segundos de normóxia. Um milhão de células de melanoma B16F10 foi injetado por via subcutânea. No dia 14, após a eutanásia, os tumores foram removidos, fixados e corados. Médias e resultados: coloração imunohistoquímica de Ki-67, PCNA, S100-B, HMB-45, Melan-A, TGF, Caspase-1 e HIF-1α foi quantificada por dois observadores que utilizaram captura digital e processamento em três lâminas de cada animal para cada marcador. O tamanho e o peso dos tumores foram semelhantes nas experiências de hipóxia e simulada. A percentagem da mediana [25-75 quartis] de área positiva corada para Ki-67 foi de 23% [15-28] no grupo hipóxia e 0,3% [0,2-1,1] no grupo controle (P = 0,02); para PCNA, as percentagens foram 31% [25-38] e 7% [5-18], respectivamente (P = 0,009). As diferenças entre os grupos para os marcadores restantes não foram significativas. Conclusões: Os marcadores da transcrição do RNA ribossomal e da síntese de DNA são mais expressos em tumores de camundongos expostos a hipóxia intermitente do que em controles, indicando que a apneia do sono pode levar a uma maior agressividade do tumor.Study Objectives: Increased melanoma growth has been reported in mice exposed to intermittent hypoxia. Proteins that characterize tumor aggressiveness have not been investigated. The study aims to verify whether intermittent hypoxia mimicking sleep apnea affects markers of melanoma tumor progression. Design: Prospective controlled animal study. Settings: University hospital. Participants: Twelve C57bl/6 mice. Interventions: Mice were exposed to intermittent or sham hypoxia. During 8 hours per day, the hypoxia group was submitted to a total of 480 cycles of 30 seconds of progressive hypoxia to a nadir FIO2 of 8±1%, followed by 30 seconds of normoxia. One million B16F10 melanoma cells were injected subcutaneously. On the 14th day, after euthanasia, tumors were removed, fixed and stained. Measurements and Results: Immunohistochemistry staining for Ki-67, PCNA, S100-B, HMB-45, Melan-A, TGFβ, Caspase-1 and HIF-1α was quantified by two observers using digital capture and processing in three slides from each animal for each marker. The size and weight of the tumors were similar in hypoxia and simulated experiments. Median [25-75 quartiles] percentage of positive area stained for Ki-67 was 23% [15-28] in the hypoxia group and 0.3% [0.2-1.1] the control group (P=0.02); for PCNA, the percentages were 31% [25-38] e 7% [5-18], respectively (P=0.009). The differences between the groups for the remaining markers were not significant. Conclusions: Markers of ribosomal RNA transcription and of DNA synthesis are more expressed in tumors of mice exposed to intermittent hypoxia than of controls, indicating that sleep apnea can lead to greater tumor aggressiveness.
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Gardyan, Adriane [Verfasser], and Stefan [Akademischer Betreuer] Eichmüller. "Identification of CD4+ T cell epitopes specific for the breast cancer associated tumor antigen NY-BR-1 using HLA-transgenic mice / Adriane Gardyan ; Betreuer: Stefan Eichmüller." Heidelberg : Universitätsbibliothek Heidelberg, 2015. http://d-nb.info/1180499123/34.
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Bonney, Laura Catherine. "Study into the role of lactadherin as a tumour associated antigen and angiogenesis factor : investigating HuMc3 (Angiolix®) as a therapeutic antibody for cancer." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/6398.
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Lactadherin is a glycoprotein thought to have roles in cancer progression, through ligation of integrins αvβ3 and/or αvβ5 on the surface of tumour cells and their vasculature. It is thought to promote tumour growth through activation of integrin signalling pathways in both tumour and vascular endothelial cells, leading to direct tumour expansion and indirect tumour growth through stimulation of angiogenesis. HuMc3 (Angiolix®) an antibody with affinity to the integrin binding EGF-like domain of lactadherin, has been shown to inhibit lactadherin association with αv integrin expressing cell lines. This work aimed to uncover whether through its disruption of lactadherin αvβ3 and/or αvβ5 integrin ligation, HuMc3 could prevent/slow the growth of lactadherin-overexpressing tumours. This work confirmed the ability of HuMc3 to inhibit lactadherin binding to both tumour cell and vascular endothelial cell αvβ3/αvβ5 integrins. It demonstrated a concentration-dependent growth inhibition of tumour xenografts in vivo alone and a greater effect for combination with a conventional chemotherapy drug than either therapy alone. In one tumour model HuMc3 showed a similar therapeutic effect when applied alone to an approved anti-vasculature anti-cancer therapeutic bevacizumab, though a lower effect was observed when both were applied with chemotherapy. HuMc3 showed no apparent therapeutic toxicity and in biodistribution studies, no specific uptake by any normal murine tissue. In addition, the in vivo data for HuMc3 compared fairly well with that published for other anti-cancer and anti-vasculature therapeutics approved/in clinical development. HuMc3 was therefore indicated to have the potential as a successful anti-cancer therapeutic for treatment of lactadherin over-expressing cancers. Further work may determine the optimal monotherapy concentration and may uncover better combinations with other targeted agents and conventional chemotherapy/radiotherapy. A major drawback of this work was however the lack of success of the in vitro assays, so the mode of action of HuMc3 could not be confirmed. Further work may involve repeating these assays under conditions shown successful in published work with other αvβ3/αvβ5 integrin ligand-mAb combinations, as well as repeating the in vivo work with inclusion of an isotypematched control antibody, tissue analysis to examine any changes to vascular density and with examination of the importance of antibody effector functions in the in vivo effect of HuMc3
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Cescato, Valter Angelo Sperling. "Expressão dos genes relacionados à apoptose, Bcl-2, bax, e caspase-3 nos adenomas hipofisários clinicamente não funcionantes e seu potencial como marcador do comportamento tumoral." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-10052010-151708/.
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Adenomas hipofisários são tumores benignos, de crescimento lento, originados no interior da sela túrcica e constituem de 10% a 15% dos tumores intracranianos, Os adenomas clinicamente não funcionantes (ACNF), correspondem aproximadamente um terço dos adenomas em geral. Por não apresentarem síndrome clínica hormonal são geralmente diagnosticados devido a sintomas neurológicos ou oftalmológicos, como macroadenomas, com grandes dimensões, invasão de estruturas circunvizinhas e hipopituitarismo. A cirurgia é o tratamento de escolha para estes tumores e apesar de ser eficaz na resolução do quadro compressivo, a possibilidade de cura cirúrgica é reduzida principalmente em tumores invasivos. Seu acompanhamento pós-operatório é efetuado por exame de imagem, preferencialmente ressonância magnética, devido à indisponibilidade de marcadores séricos. Nesta pesquisa avaliou-se a relação da expressão dos genes relacionados à apoptose, Bcl-2, Bax e Caspase-3 e sua relação com o comportamento dos ACNF. Na Divisão de Neurocirurgia Funcional do Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo foram operados 119 doentes com tumores hipofisários, de 28/05/08 à 07/04/09, 50 deles com ACNF, 30 deles foram estudados. A ressonância magnética da região selar pré-operatória possibilitou a medida dos três maiores diâmetros do tumor, ou seja, antero-posterior (AP), crânio-caudal (CC), látero-lateral (LL) e avaliar a invasão do seios cavernoso e esfenoidal. O tamanho dos tumores foi avaliado pela soma dos três diâmetros, pelo maior diâmetro e pelo cálculo do volume, efetuado pela fórmula AP x CC x LL x 0,5. No intraoperatório foram avaliados, a consistência e invasão tumoral. A análise histológica por hematoxilina-eosina, foi efetuada em todos os tumores, assim como a análise imuno-histoquímica (IHQ) dos hormônios hipofisários, Ki-67, p53 e Bcl-2. Foi realizada a análise molecular dos genes Bcl-2, Bax e Caspase-3 por RT-PCR. Dados demográficos: 17 do sexo masculino, 13 do sexo feminino, mediana da idade foi de 54,5 anos e mediana da duração dos sintomas de 31 meses. Todos apresentavam macroadenoma, 87% deles com perda visual, 53% com cefaléia, 17% com outras alterações neurológicas e um assintomático diagnosticado incidentalmente. Avaliação hormonal, disponível em 26 doentes, confirmou deficiência em 92% deles, com mais de dois eixos acometidos em 50% dos casos. A mediana do volume dos tumores foi de 11,6 cm3, do maior diâmetro de 3,8cm e da soma dos três diâmetros de 8,6cm, observou estreita correlação significativa estatisticamente entre as três medidas. Quarenta porcento dos tumores eram gigantes (diâmetro maior ou igual a 4 cm). Consistência amolecida e invasão tumoral foram observadas em 87% e 67% dos tumores, respectivamente. Todos doentes foram operados pela via transesfenoidal, exceto um operado por craniotomia pterional. Complicações cirúrgicas ocorreram em cinco pacientes, três com fistula liquórica, dois com meningite e dois óbitos. A análise histológica confirmou o diagnóstico de adenoma hipofisário em todos os casos. A IHQ foi negativa para todos hormônios em 18 e positiva em 12 tumores (TSH, FSH, LH, GH ou ACTH). A IHQ para proteína P-53 foi negativa em todos os casos. A IHQ para KI-67 revelou ausência da proteína em 11, positividade em menos de 3% das células em 15 e em mais de 3% em 4 tumores. A IHQ para Bcl-2 foi positiva em apenas três pacientes. A análise molecular dos genes Bcl-2, Bax e Caspase-3 revelou expressão muito inferior nos tumores em relação à observada para um pool de hipófise normal. Observou-se correlação positiva estatisticamente significante entre os três genes porém não foi observada correlação entre os níveis destes três genes e nenhum fator de prognóstico tumoral estudado, quais sejam, idade, positividade para hormônios na IHQ, tamanho ou invasão tumoralPituitary adenomas are benign, slow-growing tumors that arise in the sella turcica and account for 10% to 15% of all intracranial tumors. Non-functioning pituitary adenomas (NFPA) account for around one third of all pituitary adenomas. NFPA do not clinically present as hormonal syndromes and are generally diagnosed as macroadenomas due to marked neurological and ophthalmologic symptoms and invasion of surrounding structures, beside hypopituitarism. Surgery is the gold standard to treat these tumors. It effectively relieves compressive symptoms but cure is uncommon. Despite benign in nature, NFPA usually show aggressive behavior. There are no hormonal markers and the follow-up usually is made only by magnetic resonance imaging. Apoptosis-related genes, Bcl-2, Bax, and caspase-3, were here studied in NFPA to assess their role as potential markers of tumor behavior. Out of 119 patients with pituitary adenomas treated by surgery, 30 patients (17 men, 13 women, median age 54.5 years old) harboring NFPA who underwent surgery in the Department of Functional Neurosurgery at Hospital das Clínicas Psychiatric Institute, University of S. Paulo Medical School, from August 2008 to July 2009, were studied. Information on gender, age, pituitary function, symptoms and their length was collected. Tumor dimensions were measured using magnetic resonance imaging of the sella turcica. The tumor volume was calculated by the following equation: anterior-posterior diameter x cranial-caudal diameter x lateral-lateral diameter x 0.5. Intra-operative information such as tumor invasion and consistence was recorded. Histological examination by hematoxylin-eosin staining and immunohistochemistry analysis of pituitary hormones, Ki-67, p53, and Bcl-2 were performed. The molecular analysis of Bcl-2, Bax, and caspase-3 genes was performed by real-time polymerase chain reaction (RT-PCR) in all tumor specimens collected during surgery and compared to a poll of normal pituitary gland. All patients had macroadenomas diagnosed due to visual loss (87%), headache (53%) and other neurological symptoms (17%) and one case was incidentally found. Hormonal deficits were seen in 92% of 26 cases; more than two axes were involved in half of these patients. There was found good correlation between tumor volume, largest diameter and the sum of the 3 diameters, and tumor volume was used to assess the correlations with other parameters. The median volume was 11.6 cm3. Giant tumors (4 cm) were diagnosed in 40% of the patients. Soft tumors and tumor invasion were observed in 87% and 67% of cases, respectively. A transsphenoidal approach was used in all patients, except one who had pterional craniotomy. Five patients presented post-operative complications: three had CSF leakage, two meningitis and two died. The histological examination confirmed pituitary adenoma in all cases, 18 of them were null cell and 12 showed a positive immunohistochemistry analysis for one or more hormones, mainly TSH. Immunohistochemistry analysis results for p-53 was negative in all cases; for Ki-67 was negative in 11, positive in less than 3% of the cells in 15 and positive in more than 3% of the cells in 4 cases; and for Bcl-2 was positive only in three patients. Bcl-2, Bax and caspase-3 molecular analysis revealed very low expression compared to normal pituitary values. There was found a positive correlation between these three genes but no correlation between them and age, tumor volume or invasion. The Bcl-2, Bax, and caspase-3 gene analysis by RT-PCR in NFPA did not evidence their potential as markers of tumor behavior
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Wu, Xianglei. "Évaluation concomitante des signatures fonctionnelles des réponses lymphocytaires T spécifiques des Antigènes Associés aux Tumeurs et des Cellules Tumorales Circulantes : Impact sur le pronostic des patients atteints de carcinome épidermoïde des voies aéro-digestives supérieures." Thesis, Université de Lorraine, 2017. http://www.theses.fr/2017LORR0037/document.
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Nous avons abordé dans l’ensemble de nos travaux deux paramètres importants pour l’immunomonitoring des patients atteints d’un cancer : les cellules tumorales circulantes (CTC) comme un indicateur de la « charge antigénique tumorale » et la réponse immune lymphocytaire T spécifique d’antigènes associés aux tumeurs (AAT). Nous avons évalué d’abord la valeur diagnostique et pronostique des CTC dans les cancers des voies aérodigestives supérieures (« HNSCC » en anglais) par une revue systématique et meta-analyse de la littérature. Les preuves actuelles identifient le test de détection de CTC comme un test extrêmement spécifique, mais de faible sensibilité dans les HNSCC. En outre, la présence de CTC indique une DFS (« disease free survival ») inférieure. Nous rapportons également pour la première fois un cas rare d’énumération extrêmement élevée de CTC détectées par le système CellSearch® chez un patient présentant un carcinome épidermoïde de la cavité buccale en utilisant. Le nombre absolu de CTC pourrait donc prédire une phase particulière de développement du cancer ainsi qu'une mauvaise survie, contribuant potentiellement à une prise en charge médicale personnalisée. De plus, nous décrivons une adaptation de la méthode CellSearch® qui nous avons développée pour détecter les cellules tumorales dans le liquide céphalo-rachidien de patients atteints de méningites carcinomateuses. Cette nouvelle approche permet une sensibilité nettement améliorée en comparaison avec la cytologie conventionnelle. La technologie CellSearch®, appliquée à des volumes limités des échantillons et permettant une augmentation du temps pré-analytique, pourrait ainsi avoir un grand intérêt dans le diagnostic de métastases leptoméningées chez les patients atteints d’un cancer d’origine épithéliale. Par une évaluation concomitante des CTC et des réponses lymphocytaires spécifiques aux AAT chez 24 patients avec HNSCC, nous avons trouvé que les CTC pourraient être un indicateur indépendant de la charge tumorale immunogène. L'absence de CTC, la présence de lymphocytes T spécifiques aux AAT, ou la combinaison de ceux-ci, étaient tous des paramètres montrant une tendance pour une meilleure survie globale ou une survie sans maladie. L’amplitude et les signatures fonctionnelles des lymphocytes T spécifiques aux AAT chez les patients atteints de HNSCC étaient associées à la présence de CTC. Ces résultats suggèrent qu’une évaluation concomitante de ces deux paramètres pourrait être plus informative sur le pronostic et potentiellement sur l’impact des traitements (notamment dans la perspective d’un traitement par des « immune checkpoints »)We have evaluated herein two important parameters in the immunomonitoring of cancer patients: circulating tumor cells (CTC) as an indicator of “tumoral antigenic load” and tumor-associated antigens (TAA) specific T-cells. We firstly evaluated the diagnostic and prognostic value of CTC in Head and Neck Squamous Cell Carcinoma (HNSCC) by a systematic review and meta-analysis. We came to the conclusion that current evidence identifies the CTC detection test as an extremely specific but low sensitive test in HNSCC. In addition, the presence of CTC indicates a worse disease-free disease (DFS). Also, we report for the first time a rare case of extremely high enumeration of circulating tumor cells detected in a patient with squamous cell carcinoma of the oral cavity using the CellSearch® system. The absolute number of CTC could therefore predict a particular phase of cancer development as well as a poor survival, potentially contributing to personalized health. In addition, we describe an adaptation of the CellSearch® method that we have developed for detecting tumor cells in the cerebrospinal fluid of patients with carcinomatous meningitis. This new approach reaches a significantly improved sensitivity compared to conventional cytology. CellSearch® technology, applied to limited sample volumes and allowing an increased pre-analytical time, may be of great interest in the diagnosis of leptomeningeal metastases in patients with epithelial cancer. By a concomitant evaluation of CTC and TAA-specific lymphocyte responses in 24 HNSCC patients, we describe that CTC could be an independent indicator of immunogenic tumor burden. The absence of CTC, the presence of TAA-specific T-cells, or the combination of these, were all parameters showing a trend for a better overall survival or DFS. The amplitude and functional signatures of TAA-specific T-lymphocytes in patients with HNSCC were associated with the presence of CTC. These results suggest that a concomitant evaluation of these two parameters may be more pertinent for prognosis assessment as well as for treatment impact, especially in “checkpoint-inhibitors” new immunotherapies
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Mustafa, Mohammad Zahid. "Autoantibody signatures defined by serological proteome analysis in sera of patients with cholangiocarcinoma." Phd thesis, Université Paris Sud - Paris XI, 2014. http://tel.archives-ouvertes.fr/tel-01058149.
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Cholangiocarcinoma (CC) is a rare but fatal primary liver cancer and accounts for an estimated 15% of primary liver cancer worldwide. It is associated with high mortality due to the lack of established diagnostic approaches. Autoantibodies can be used clinically as diagnostic markers for early cancer detection of cholangiocarcinoma. Studies, indicating the presence of auto-antibodies (AAbs) in CC have not been reported yet. No immunological biomarker, correlated to the disease, has been identified. The objective of our study was to identify cellular proteins from liver tissues (tumoral and non tumoral) and cholangiocarcinoma cell lines which could be recognized by antibody of CC patients. We used serological proteome analysis (SERPA) technique which leads us to suggest some molecules as potential biomarkers for the early diagnosis of CC. Proteins from different origins were 2DE separated: CCSW1 and CCLP1 tumor cell lines, five different samples of hepatectomies for CC with respect to their tumoral and non-tumoral counterparts and a normal liver from amyloid neuropathy. Sera from 13 CC patients and a pool of 10 healthy subjects were probed on immunoblot performed with these different separations. Comparison of immunoblotting patterns given by patient's sera compared to patterns given by controls allowed to define immunoreactive spots of interest and those reacting with more than one-third of sera were identified by orbitrap type mass spectrometry. In this way we identified 10, 11, 9, 14 and 16 proteins from CCSW1, CCLP1, tumor part, non-tumor counterpart and normal liver antigenic extracts respectively. Different patterns of reactivity were observed according to sera on the same antigenic extract, and for a same serum, according to the antigenic extract, even though few common patterns were also observed. This widespread of reactivity is not unusual and reported earlier in several studies of this sort. It is indicated that a single AAb have an ability to identify only a small proportion of patient. For this reason, several antibodies in combination must be used to ensure sensitivity and specificity of assays used in the daily clinic.Identified proteins were then categorized by gene ontology analysis by which they fall into three main groups; biological process and molecular functions, protein class and molecular pathway and cellular component, according to the Panther classification. By Gene Ontology classification, two different patterns of targeted antigens were observed. The vast majority of targeted-proteins with catalytic activity were found in normal liver or non-tumor specimens. The second pattern was mainly represented by targeted proteins categorized as structural proteins extracted from CC cell lines and tumor tissues. Proteins identified with catalytic activity were: alpha-enolase, fructose biphosphate aldolase B and glyceraldedyde 3-phosphate dehydrogenase; which were reactive with more than 50% of CC sera. Proteins identified with structural activity, and detected with high rates by using cell lines and tumor tissues, were: vimentin, prelamine A/C, annexin A2 and actin; reactivity of each protein was higher than 62% with CC sera. Serotranferrin, identified under the category of transfer/carrier proteins, recognized by 100% of CC sera by using tumor tissues.High sensitivity and specificity is a prime requisite of AAbs that might be used as CC biomarkers for CC diagnosis. Most of the AAbs detected in this study had previously been reported in other cancers and auto-immune disorders. Hence it is essential to prove the specificity of antigenic proteins, a combination of various antigens therefore needs to be tested to enable the development of new biomarkers for the diagnosis and prognosis of CC.In conclusion, the proposed potential biomarkers need to be tested in a variety of different combinations with a panel of significant number of patients and using the most appropriate substrate defined during this study.
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Azria, David. "Association du facteur de nécrose tumorale (TNFα) et de la radiothérapie dans les cancers digestifs exprimant l'antigène carcinoembryonnaire (ACE) : intérêts d'un anticorps bispécifique anti-ACE/anti-TNFα." Montpellier 1, 2004. http://www.theses.fr/2004MON1T005.
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LE FACTEUR DE NECROSE TUMORALE ALPHA (TNFalpha) A MONTRE UN EFFET RADIOSENSIBILISANT DANS PLUSIEURS MODELES IN VITRO ET IN VIVO. EN CLINIQUE, SON UTILISATION SYSTEMIQUE A ETE MARQUEE PAR UNE TOXICITE MAJEURE. NOTRE METHODE DE CIBLAGE PAR LES ANTICORPS BISPECIFIQUES (AcBs) A PERMIS DE DELIVRER LE TNFalpha AU SEIN DE LA TUMEUR EN CIBLANT L'ANTIGENE CARCINOEMBRYONNAIRE (ACE). LE PREMIER OBJECTIF A ETE DE MONTRER L'EFFET RADIOSENSIBILISANT DU TNFalpha IN VITRO DANS DIFFERENTS MODELES DE CANCERS DIGESTIFS EXPRIMANT L'ACE EN ESSAYANT D'ANALYSER LE MECANISME IMPLIQUE, EN PARTICULIER, CONCERNANT LE CYCLE CELLULAIRE. LE SECOND OBJECTIF A ETE DE TRANSPOSER CES RESULATS IN VIVO DANS DIFFERENTS MODELES PRE-CLINIQUES EN UTILISANT UN AcBs ANTI-ACE/ANTI-TNFalpha. IN VITRO, NOUS AVONS MONTRE UN EFFET ADDITIF DE L'ASSOCIATION RADIOTHERAPIE (RT) + TNFalpha DANS DEUX MODELES DE TUMEUR HUMAINE EXPRIMANT L'ACE : LES LIGNEES COLIQUE LS174T ET PANCREATIQUE BxPC-3. APRES TRAITEMENT PAR LE TNFalpha, L'ETUDE DU CYCLE CELLULAIRE A MIS EN EVIDENCE UNE DIMINUTION DE L'ARRET EN G2 RADIO-INDUIT ET DE LA PHASE S AU DEPEND D'UNE AUGMENTATION DU NOMBRE DE CELLULES DANS LA PHASE G1. IN VIVO, DES SOURIS NUES GREFFEES ONT RECU DIFFERENTS TRAITEMENTS : SERUM PHYSIOLOGIQUE (NaCI), TNFalpha, AcBs, TNFalpha + AcBs, RT + NaCI, RT + TNFalpha + AcBs. UNE DIFFERENCE SIGNIFICATIVE DU DELAI DE PROGRESSION TUMORALE A ETE MISE EN EVIDENCE ENTRE LE GROUPE RT + NaCI ET LE GROUPE RT + AcBs + TNFalpha. DES EXPERIENCES AVEC DES SOURIS TRANSGENIQUES POUR L'ACE GREFFEES AVEC DES TUMEURS COLIQUES MURINES TRANSFECTEES AVEC LE GENE DE L'ACE ONT MONTRE UN DELAI DE PROGRESSION TUMORALE NETTEMENT INFERIEUR DANS LE GROUPE RT + TNFalpha HUMAIN + AcBS DONT DEUX GUERISONS. DES EXPERIENCES UTILISANT UN TNFalpha MURIN SONT EGALEMENT EN COURS AFIN D'EVALUER TOUT LE POTENTIEL THERAPEUTIQUE ET LES TOXICITES LIMITANTES DE CETTE STRATEGIE DANS UN MODELE ANIMAL IMMUNOCOMPETENT AVANT L'OUVERTURE D'UNE ETUDE CLINIQUE DE PHASE I.