DANISH MEDICAL BULLETIN VOL. 54 NO . 4/N OVEMBER 2007 249 DOCTOR OF MEDICAL SCIENCE Interleukin-2 based immunotherapy in patients with metastatic renal cell carcinoma Frede Donskov This review has been accepted as a thesis together with eight previously pub- lished papers, by the University of Aarhus, November 28, and defended on August 31, 2007. Department of Oncology Aarhus University Hospital and Institute of Med- ical Microbiology and Immunology, Aarhus University, Århus, Denmark. Correspondence: Islandsgade 9, 8200 Århus N, Denmark. E-mail: fd@microbiology.au.dk Official opponents: Pieter H. De Mulder, Mogens Claesson and Jens Over- gaard. Dan Med Bull 2007;54:249-65 INTRODUCTION Renal cell carcinoma (RCC) is the most common malignancy (85%) of the kidney. The remainders are mainly transitional cell carcino- mas originating from the renal pelvis. Willms’ tumor (nephroblast- oma) is only seen in children. In the following, emphasis is re- stricted to RCC. EPIDEMIOLOGY RCC accounts for 2 percent of all cancer. Worldwide, 208,000 new cases and 102,000 deaths result each year from renal cancer [1]. The incidence varies among countries. The rates are highest in Western and Eastern Europe, North America, Australia and Scandinavia, in- termediate in Southern Europe and Japan, and low elsewhere in Asia, South America, Africa and the Pacific [2]. In the United States, the incidence has increased by 43% since 1973, and similarly, in- creased incidence rates have been observed in nearly all regions. By contrast, in Denmark and Sweden the incidence rates have remained almost unchanged [3]. The absolute numbers of new kidney cases and kidney cancer deaths in Denmark during the last 30 years are seen from Figure 1. Risk factors for developing RCC include cigarette smoking – the proportion of RCCs that could be attributed to cigarette smoking is op to 30% – hypertension, obesity and end-stage renal disease [3-5]. The median age at diagnosis is 65. The men-female ratio is 2.5:1. PATHOLOGY, GENETICS AND TUMOR BIOLOGY International agreement was reached in 1997 on the histologic clas- sification of RCC on the first international multidisciplinary work- shop held by World Health Organization (WHO) in collaboration with the Union Internationale Contre le Cancer (UICC) and Ameri- can Joint Committee on Cancer (AJCC) [6, 7]. Thus, RCC are now separated into four different cellular types: clear, papillary, chromo- phobe and collecting duct ( Table 1). The most common histological type of RCC is clear cell carcinoma (75% of cases). These tumors arise from the proximal tubule in the renal cortex (Table 1). This tu- mor type is typically sporadic, unilateral and unifocal. A large pro- portion of these tumors have mutations or hypermethylations at chromosome 3p, which contains the von Hippel-Lindau tumor sup- pressor gene. Papillary tumors occur in 15% of cases, and are the next most common histological type. Cytogenetically, these tumors frequently have trisomy of several chromosomes, as well as loss of the Y chromosome (Table 1). There are two subtypes of papillary RCC, type 1 (small cells) and type 2 (large cells with abundant eosi- nophilic cytoplasm) [8]. Inherited RCC is rare, only up to 2% of RCC cases cluster in fam- ilies [9]. Within the last decade, four genes leading to inherited forms of RCC have been identified [10]; the von Hippel-Lindau (VHL) gene leading to clear cell RCC [11] was identified on chro- mosome 3 in 1993; the c-Met gene leading to type 1 papillary RCC [12] was identified on chromosome 7 in 1997; the Fumarate hy- dratase (FH) gene leading to Type 2 papillary RCC [13] was identi- fied in 2002; and the Birt-Hogg-Dubé (BHD) gene leading to chromophobe RCC [14] was identified in 2002. During the past decade, the biology associated with the VHL gene product (pVHL) has been elucidated in inherited and sporadic RCC [8, 15]. The von Hippel-Lindau tumor suppressor gene (VHL), which resides on chromosome 3p25, is mutated or silenced in 100% of inherited and 50-85% of sporadic clear cell RCC. Mutation or methylation of VHL leads to a pseudohypoxic state in which the pVHL complex does not form and/or cannot degrade hypoxia-in- ducible factors (HIF-1α, HIF-2α and HIF-3α). Thereby, HIF over- accumulates resulting in increased transcription of a variety of genes, including vascular endothelial growth factor (VEGF), plate- let-derived growth factor B (PDGF-B), transforming growth factor- α (TGF- α), Glut 1 glucose transporter, carbonic anhydrase IX and erythropoietin (EPO) [8, 16]. Thus, VHL appears to be a critical gatekeeper for the development of clear cell RCC and for the subse- quent tumor proliferation, angiogenesis, mitogenesis, erythropoie- sis, glucose metabolism, and pH control [15, 16]. The grading of RCC began in 1932, reflecting the differentiation of the tumor cells as defined microscopically by increased nuclear size, irregularity, and nucleolar prominence [17]. Since then, several histopathological grading systems have been proposed, but cur- rently that proposed by Furhman et al [18] is the most widely used in the North America and that proposed by WHO is most widely used in Europe [17]. CLINICAL PRESENTATION In the onset of RCC, there are only few early warning signs. The classical triad of hematuria, flank pain and abdominal mass is found in less than 10% [4]. Among patients who are symptomatic, more than 50% have hematuria, approximately 40% have pain, 40% have an abdominal mass, and 10% have symptoms arising from meta- static sites. Patients also frequently have nonspecific signs and Figure 1. Incidence ( __ ) and mortality (--) of RCC in the period 1970-2000; overall (left); in men (middle); and women (right). 800 700 600 500 400 300 200 100 0 1970 1975 1980 1985 1990 1995 2000 Year Number of cases, total 800 700 600 500 400 300 200 100 0 1970 1975 1980 1985 1990 1995 2000 Year Number of RCC, men 800 700 600 500 400 300 200 100 0 1970 1975 1980 1985 1990 1995 2000 Year Number of RCC, women