Cytokines

Renal cell carcinoma (RCC) is a chemoresistant malignancy. For many years, the only treatment for advanced disease were the cytokines IFN-α and IL-2, but these offered limited objective response rates of 10-20% and only modest survival benefits in the majority of cases. While the last decade has witnessed a marked increase in the availability of novel targeted therapies providing a meaningful impact on overall survival, high-dose IL-2 remains the only treatment modality able to induce durable complete remissions and/or cure in a small minority of patients with metastatic RCC. No clinical, molecular or immune parameters have been identified that allow reliable patient selection. The identification of molecular predictors to select patients for toxic, but potentially curative high-dose IL-2 treatment remains a priority. The combination of the antiangiogenic antibody bevacizumab with IFN-α in advanced RCC has been shown to improve response rates and progression-free survival compared with IFN-α alone; unfortunately, the lack of a third bevacizumab-alone arm prevents an evaluation of the added benefit of IFN-α over bevacizumab alone, which has known single-agent activity in RCC. Combinations with novel targeted therapies may enhance the immunomodulatory effects of cytokines and are currently under investigation. Taking IL-2 and other novel immunomodulatory therapies forward will require parallel biological studies, careful consideration for potentially severe immune-related toxicities and possibly modified immune-related response criteria.