Specific immunotherapy for renal cell carcinoma.

Abstract

Despite the fact that evaluation of cytokine-based therapies for mRCC shows that a subset of patients react favourable to immunotherapy, significant side effects do occur. With the increased knowledge of tumor-immunology, the recognition of immunogenic tumor proteins and antibodies, new treatment options with increased specificity and subsequently less side-effects are of interest. In this thesis several studies have been performed to evaluate these new treatment options. Chapter 2 discusses the need for a staging sytem that adequately discriminates patients with RCC into prognostic groups in order to provide improved counseling, follow-up evaluation and identification of high risk patients potentially suitable for adjuvant therapies and clinical trials. This chapter presents a clinical algorithm using 3 well-known prognostic factors that can be used to predict survival and stratify patients undergoing nephrectomy for localized disease into 3 risk groups. External data from 2 outside institutions suggest the validity of this algorithm with a high concordance index. These risk categories can be used in clinical trial design and interpretation as well as in clinical management areas such as surveillance. Chapters 3 & 4 discuss dendritic cell-based immunotherapy. Dendritic cells (DC) are the most potent antigen presenting cells (APC's) of the immune system with the ability to stimulate naive resting T cells to proliferate and differentiate into activated cytotoxic T cells specific against the presented antigen. Two clinical trials were performed evaluating safety and clinical or immunological responses of DC-based vaccines. Chapters 5 & 6 deal with monoclonal antibody-based immunotherapy. Currently, several monoclonal antibodies (mAb) are used in cancer treatment. In RCC the chimeric mAb G250 (WX-G250) has been identified and developed for both therapeutical and diagnostical purposes. Antibody dependent cellular cytotoxicity (ADCC) has been suggested to be the main effector mechanism of WX-G250 and in-vitro data showed that interleukin-2 (IL-2) has the capacity to up-regulate WX-G250 mediated ADCC. This led to the initiation of two successive clinical trials evaluating infusions of WX-G250 as monotherapy and the combination of WX-G250 with a low-dose IL-2 pulsing regimen