Cytokine therapy for renal cell cancer: the evolving role of immunomodulation

A Leary, JM Larkin and Lisa M Pickering

Renal cell carcinoma (RCC) is a chemo-resistant malignancy. For many years the only treatment for advanced disease was immunotherapy; the cytokines IFN‑a and IL‑2 were widely used but offered limited objective response rates of 10–20% and only modest survival benefits in the majority of cases. The last decade has witnessed a marked increase in the availability of novel targeted therapies demonstrating anti-tumor activity and, more importantly, providing a meaningful impact on overall survival. However, to date, immunotherapy, in the form of high-dose IL‑2, remains the only treatment modality able to induce durable complete remissions and/or cure in metastatic RCC, albeit in a small minority of patients. A priority for immunotherapy research should be to investigate strategies that may augment the effectiveness of immunomodulation and enable a greater proportion of patients with advanced RCC to benefit from this treatment. A number of approaches are discussed; combinations with molecularly targeted agents may potentiate response and survival, immune checkpoint inhibitors such as CTLA-4 and PD1 antibodies are showing encouraging activity in early clinical trials and vaccines are of renewed interest. Taking these and other novel immunomodulatory agents forward will require the use of immune-related response criteria in clinical trial design and, most importantly, the ability to identify reliable predictors of benefit so that appropriate patients may be selected for immunotherapeutic treatments.