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Identifier 000375367
Title Assessment of the immune responses in HLA A*0201 patients with various types of chemo-resistant advanced solid tumors after vaccination with the therapeutic telemerase -specificvaccine Vx-001. / Μαρίνα Ελένη Μελά.
Alternative Title Αξιολόγηση της ανοσολογικής απάντησης σε ασθενείς με κακοήθη νεοπλάσματα κατόπιν χορηγήσεως του θεραπευτικού εμβολίου Vx00
Author Μελά, Μαρίνα Ελένη
Thesis advisor Μαυρουδής,Δημήτρης
Reviewer Βέτσικα, Ελένη Κυριακή
Abstract Background: The human telomerase reverse transcriptase is highly expressed in most human tumours and correlates with poor prognosis. The Vx-001 is an HLA-A*0201 restricted therapeutic telomerase-specific tumour vaccine which is composed of the 9-mer cryptic hTERT572 peptide and its optimized variant hTERT572Y. Based on previous studies supporting that Vx-001 is non-toxic, highly immunogenic and its specific immune response is correlated with prolonged survival in vaccinated NSCLC patients, its specific-T cell immune response in 77 HLA-A*0201 patients with various types of chemo-resistant advanced solid tumours, was further studied. The aim of the present study was to investigate the specific -T cell immune response against Vx-001. Methods: All patients received 2 subcutaneous vaccinations with the optimized TERT572Y peptide followed by 4 vaccinations with the native TERT572 peptide at 3 week intervals. Patients who completed the six-vaccination schedule and exhibited disease stabilization received booster vaccinations with the native peptide every 3 months until disease progression. Peripheral blood mononuclear cells (PBMCs), from patients were collected before vaccination, after the 2nd and 6th vaccination and before each boost vaccination and screened for reactivity to the TERT572Y and TERT572 peptides by measuring IFN-γ production using ELISpot assay. Moreover, IFN-γ and IL-10-producing cells in response to the peptides were identified by intracellular staining (ICS) using flow cytometry. Results: TERT572Y-specific immune responses was induced in 21%, 27% and 32% of the vaccinated patients before the 1st and after the 2nd and 6th vaccination, respectively. Similarly, TERT572-specific immune responses was induced in 25%, 41% and 51% of the vaccinated patients before the 1st and after the 2nd and 6th vaccinations respectively, as assessed by IFN-γ ELISpot. These responses were confirmed by Intracellular staining for IFN-γ. Moreover, it was observed that 40% of patients with a TERT572Y-specific response after the 2nd vaccination (early response) developed a TERT572Y+/TERT572+ immune response after the 6th vaccination (late response). It was indeed a confirmation, of the initial hypothesis that the optimized TERT572Y peptide first generates peptide-specific T cells and then the stimulation with the native TERT572 peptide selects among T cells those with the specificity for the native TERT572 peptide which is presented by tumour cells. 9 Furthermore, boost vaccinations with hTERT572 every three months in responding patients maintained the number of hTERT-specific cells in most cases. Surprisingly, patients without a TERT572Y and TERT572 -specific pre-existing IFN-γ immune reactivity, responded more frequently after the 2nd vaccination than patients with a TERT572Y and TERT572 -specific pre-existing IFN-γ immune reactivity. Furthermore, the presence of IL-10 either prior to vaccination or after the 2nd and 6th vaccination, was inversely correlated with the development of vaccine-induced hTERT572-specific IFN-γ immune response. Finally, in order to determine whether there was an association between the TERT-specific-IFN-γ immune reactivity and overall survival (OS), the outcome of the patients who enrolled the vaccination protocol with clinically documented stable (SD) or progressive disease (PD) was analyzed. It was observed that OS was significantly longer in late immune TERT572-specific responding patients compared to non-late responding patients. Conclusion: The results of the current study demonstrate that Vx-001 is able to induce a TERT-specific immune response in vaccinated patients with different types of solid tumours, as our vaccination strategy circumvented the immune tolerance of TERT. The mechanisms regulating the induction of Vx-001-specific immune response need to be further investigated as this vaccine seems to be promising anticancer vaccine and may pave the way for a new era in the field of cancer immunotherapy
Language Greek
Subject Pathology
Issue date 2010-07-20
Collection   School/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
Permanent Link https://elocus.lib.uoc.gr//dlib/e/0/4/metadata-dlib-1347443063-238591-2923.tkl Bookmark and Share
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