Virale und gentherapeutische Ansätze zur Chemosensibilisierung und Immunpotenzierung des experimentellen Pankreaskarzinoms

Die vorliegende Arbeit gibt eine Zusammenfassung zu verschiedenen Aspekten immun- und gentherapeutischer Ansätze für das experimentelle Pankreaskarzinom im Tiermodell. Ziel des Projektes war es erstens Strategien zur Steigerung der antineoplastischen Wirkung genotoxischer Therapien bei gleichzeitiger Verminderung der therapie-assoziierten systemischen Nebenwirkungen zu entwickeln, und zweitens immunologisch basierte Therapieansätze zur Aktivierung des Immunsystems und Steigerung der Tumorimmunogenität zu untersuchen.In summary this work describes different aspects of immune therapy and gene therapy in an experimental pancreatic carcinoma model. The aim of the project was first to develop new strategies to increase the efficacy of antitumoral chemotherapy and to prevent their related side effects and second to activate the immune system and increase the tumour immune response

Multidrug-resistance proteins are weak tumor associated antigens for colorectal carcinoma

<p>Abstract</p> <p>Background</p> <p>Multidrug resistance (MDR) is a clinically, highly relevant phenomenon. Under chemotherapy many tumors show an increasing resistance towards the applied substance(s) and to a certain extent also towards other agents. An important molecular cause of this phenomenon is an increased expression of transporter proteins. The functional relationship between high expression levels and chemotherapy resistance makes these MDR and MRP (MDR related protein) proteins to interesting therapeutic targets. We here wanted to systematically analyze, whether these proteins are tumor specific antigens which could be targeted immunologically.</p> <p>Results</p> <p>Using the reverse immunology approach, 30 HLA-A2.1 restricted MDR and MRP derived peptides (MDP) were selected. Stimulated T cell lines grew well and mainly contained activated CD8⁺cells. Peptide specificity and HLA-A2.1 restriction were proven in IFN-γ-ELISpot analyses and in cytotoxicity tests against MDP loaded target cells for a total of twelve peptides derived from MDR-1, MDR-3, MRP-1, MRP-2, MRP-3 and MRP-5. Of note, two of these epitopes are shared between MDR-1 and MDR-3 as well as MRP-2 and MRP-3. However, comparably weak cytotoxic activities were additionally observed against HLA-A2.1⁺tumor cells even after upregulation of MDR protein expression by <it>in vitro </it>chemotherapy.</p> <p>Conclusions</p> <p>Taken together, these data demonstrate that human T cells can be sensitised towards MDPs and hence, there is no absolute immunological tolerance. However, our data also hint towards rather low endogenous tumor cell processing and presentation of MDPs in the context of HLA-A2.1 molecules. Consequently, we conclude that MDR and MRP proteins must be considered as weak tumor specific antigens-at least for colorectal carcinoma. Their direct contribution to therapy-failure implies however, that it is worth to further pursue this approach.</p