Ivar Bleumer

A phase II trial of chimeric monoclonal antibody G250 for advanced renal cell carcinoma patients.

Chimeric monoclonal antibody G250 (WX-G250) binds to a cell surface antigen found on >90% of renal cell carcinoma (RCC). A multicentre phase II study was performed to evaluate the safety and efficacy of WX-G250 in metastatic RCC (mRCC) patients. In all, 36 patients with mRCC were included. WX-G250 was given weekly by intravenous infusion for 12 weeks. Patients with stable disease (SD) or response were eligible to receive additional treatment for 8 weeks. None of the 36 enrolled patients experienced any drug-related grade III or IV toxicity. Only three patients had grade II toxicity possibly related to the study medication. In all, 10 patients had SD and received extended treatment. One complete response and a significant regression was observed during the follow-up of the treatment. Five patients with progressive disease at study entry were stable for more than 6 months after study entry. The median survival after treatment start was 15 months. The weekly schedule of WX-G250 was well tolerated. With a median survival of 15 months after the start of this treatment and two late clinical responses, WX-G250 seems to be able to modulate mRCC. To improve the activity of WX-G250-specific antibody-dependent cellular cytotoxicity and the clinical response rate, currently combinations of WX-G250 with cytokines are in phase II trials.

Immunotherapy for renal cell carcinoma.

Renal cell carcinoma (RCC) is the most prevalent malignancy within the kidney and the incidence is rising. Due to improved radiological evaluation over 50% of the renal cancers are found incidentally. Despite the fact that these incidentalomas are often confined to the kidney, around 50% of all patients diagnosed with kidney cancer will develop systemic disease. Metastatic RCC has a poor prognosis. Traditional treatment modalities like chemo- and radiotherapy show overall response percentages of 2-6%. In view of the observed spontaneous remissions of advanced renal cancer, immune mechanisms have been suggested to play a role in the natural disease course of RCC. At present, several non-specific cytokine regimens are used in the treatment of mRCC, e.g. interleukin-2 and interferon-alpha, in combination or as monotherapy or in combination with substances like 13-cis-retinoic acid and/or 5-fluorouracil. Collective data of trials evaluating cytokine-based therapies for mRCC show an overall response rate of approximately 15%, with 5% of the patients showing complete responses. More importantly, cytokine treatment clearly translates into a significant survival benefit in a subset of patients. Nevertheless, the toxicity profile of these cytokine regimens is significant. With the enhanced knowledge of tumor-immunology, the identification of immunogenic tumor proteins, and antibodies recognizing tumor-associated antigens, new treatment strategies with increased specificity and fewer side effects are of interest. Here we review the different immunotherapeutical modalities currently used as well as new approaches for the treatment of advanced RCC.

Vaccination of patients with metastatic renal cell carcinoma with autologous dendritic cells pulsed with autologous tumor antigens in combination with interleukin-2: a phase 1 study.

Dendritic cells (DC) have been recognized as the most potent antigen presenting cells (APC) of the immune system. We performed a phase 1 study in twelve patients with metastatic renal cell carcinoma (RCC) using autologous immature DC loaded with autologous tumorlysate (TuLy) as a vaccine based on our earlier in vitro observations that such DC can activate tumor-specific cytotoxic T-lymphocytes. The treatment was combined with low-dose interleukin (IL)-2, as this has shown benefit in DC-based therapies. Patients received three intradermal vaccinations at two weekly intervals, and, after each vaccination, IL-2 was administered for 5 consecutive days. In six patients, keyhole-limpet hemocyanin (KLH) was added to the DC culture for immunologic monitoring purposes. In general, DC phenotype was CD14low, CD86high, CD40high, CD80low, and CD83low. We noticed that the number of CD14+ cultured DC increased during treatment. Nevertheless, ovalbumin uptake remained high, underlining that these cells were still functional immature DC. The vaccine was able to elicit cellular anti-KLH responses, emphasizing the ability of the injected DC to mount an immunologic response. However, proliferative responses against TuLy were not detected, and humoral responses against TuLy or KLH were absent. Objective clinical responses were not observed, but extended stable disease was noted. The absence of cellular, humoral, or clinical antitumor responses suggests that the vaccination strategy with immature DC has little benefit for patients with advanced RCC. Nevertheless, this study shows the feasibility of a completely autologous DC and tissue culture methodology for the generation of TuLy pulsed DC.

Preliminary analysis of patients with progressive renal cell carcinoma vaccinated with CA9-peptide-pulsed mature dendritic cells.

Carbonic anhydrase-IXG250/MN (CA9) is a renal cell carcinoma (RCC)-associated antigen ubiquitously expressed in the clear-cell subtype of RCC. Two CA9-derived peptides have been identified defining a cytotoxic T-lymphocyte epitope and human leukocyte antigen (HLA)-DR epitope, able to induce T-cell responses in vitro. A phase I clinical trial was performed with CA9-peptide–loaded dendritic cells (DCs) in patients with progressive, cytokine-refractory metastatic RCC to assess the safety, toxicity, and induction of CA9-specific immunity. Patients with objective progressive metastatic RCC received 5 vaccinations of mature DCs pulsed with the CA9-derived peptides and keyhole limpet hemocyanine (KLH). Peripheral blood was collected at regular intervals, delayed-type hypersensitivity (DTH) was tested at baseline and after the last vaccination, and skin biopsies of positive DTH sites were collected for immunomonitoring purposes. Patients were also monitored for clinical responses. No significant toxicity was observed. All patients developed humoral responses against KLH, and demonstrated DTH conversion. Evaluation of biopsy material suggested an increased influx of T-helper cells. In none of the immunomonitoring assays was evidence for the induction of CA9-peptide–specific immunity observed. No clinical responses were observed. The vaccination of DCs pulsed with KLH and 2 CA9-derived peptides was well tolerated. The lack of induction of CA9-peptide–specific immune responses indicates that this particular vaccine regimen is poor in inducing CA9-peptide–specific immune responses.

Tumor antigens and markers in renal cell carcinoma

Tumor markers are mainly used to diagnose specific malignancies. The methods commonly involve immunohistochemistry and cytogenetics, including FISH and RT-PCR. In RCC, the investigated tumor markers (summarized in Table 1) show additional prognostic value over classical prognostic factors such as stage and grade. These markers can be used for better patient selection, a more accurate individualization of treatment, and improved follow-up. Nevertheless, their definitive value must be reconfirmed in larger patient cohorts. Ultimately, these factors should be shown to be of value in a prospective well-controlled trial. One of the most promising new techniques involves gene expression profiling of solid tumors. This cDNA microarray technique applied in RCC has improved understanding of the molecular mechanism of the underlying tumor genesis and its correlation to the clinical course. Tumor antigens that are specific for RCC (eg, G250) and that induce a specific immune response can be used for vaccine treatment modalities. With the use of dendritic cells, antigen presentation can be improved. Several phase I studies are currently underway. More research is needed to obtain better antigens and markers in RCC to improve insight into the molecular mechanism of the development of RCC, to improve the selection of patients for treatment, and to increase its effectiveness.

Tumor Targets and Biomarkers in Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common malignancy of the kidney. Unfortunately, 50% off all patients diagnosed with this disease will develop metastasized disease for which no adequate treatment can be offered currently. Therefore, the identification of prognostic factors and biomarkers is of the greatest importance. They might show additional prognostic value over classical prognostic factors like stage and grade. Also, these markers can be used for a better patient selection, development of specific gene immunotherapy strategies, and a better follow-up. In this chapter, we review current and future biomarkers of interest in the diagnosis, treatment, and follow-up of patients with RCC.