Chemoimmuntherapie und immunologische Bedeutung von 70 kiloDalton Hitzeschockproteinen beim metastasierten Nierenzellkarzinom
The cytokines interleukin-2 and interferon-a2a are of central importance in the treatment of patients with metastatic renal cell cancer. In the clinical part of the thesis the efficacy of chemoimmunotherapy was investigated monocentrically on 107 patients. It appeared a rate of objective remissions of 22% (95% CI 14.6 - 31.3%) and an additional rate of temporary disease stabilisations of 46%. The median survival was 19 months, with a calculated 5-year survival rate of 17%. Multivariate analysis revealed a highly significant dependence on the Karnofsky-Performance-Index of the patients. In 83 patients with Karnofsky-Performance-Index over 80% the median survival was 23 months, with a calculated 5-year survival of 21%. These results justify the further investigation of the combination of interleukin-2, interferon-a2a, and 5-fluorouracil in prospective clinical studies. In the context of the clinical aspects of cytokine-based immunotherapy it was the task of the the experimental part of the study to investigate the importance of 70 kDa heat shock proteins (HSP70) in renal cell cancer. Besides their function in cellular stress processing, members of the HSP70 family (HSP72 and HSP73) are especially important for answering questions of tumor immunology resulting from their immunological signal function, the HSP72-mediated interaction of immunological effector cells with tumor cells, and from the involvement of HSP70 in peptide processing in malignant cells. On the basis of a renal cancer cell line and of primary cells of renal carcinomas the HSP72 expression on the surface of tumor cells could be demonstrated by flow cytometry and correlated with an increased lysis of tumor cells on the cell line by interleukin-2 stimulated natural killer cells. In contrast to the findings so far reported in the literature, the present model revealed that the membrane expression of HSP72 was not limited to malignant cells but was detectable in renal cells of normal tissue too. In an immunohistochemical study on basal cytoplasmatical HSP72 expression, a univariate analysis showed a significant correlation of high HSP72 expression and patient survival. In a multivariate analysis the extent of the HSP72 expression could be identified as an independent prognostic parameter that was also correlated with the response of patients to chemoimmunotherapy. The clinical establishment of specifically effective vaccines plays a central part in the development of new treatment strategies for metastatic renal cell cancer. In this context, vaccines on the basis of HSP-peptides are of special interest. Therefore, the experimental part of the work was also aimed at developing a method for enriching HSP70-peptide complexes. With ADP affinity chromatography a method for concentrating HSP70-peptide complexes from tumor cells was created, which proved to be usable and was patented. On the one hand, HSP70-peptide complexes can be used for HSP-based vaccine programmes, on the other hand, they can serve for identifying and characterizing HSP70-bound biologically active (immunogenic) peptides. The present findings demonstrate that HSP72 per se has a prognostic value in renal cell cancer and point to the potential importance of HSP72 as an immunological target structure. The results represent new approaches to a deeper understanding of the immunological properties of renal cell carcinoma and give a basis from which to establish innovative vaccination programmes for the treatment of advanced renal cell carcinoma.
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School:Humboldt-Universität zu Berlin
Source Type:Master's Thesis
heat shock proteins
metastatic renal cell cancer
Date of Publication:04/14/2004