Double Immune Checkpoint Blockade in Renal Cell Carcinoma

Long considered an immunogenic tumour, immunotherapy has been the cornerstone of systemic treatment in renal cell carcinoma (RCC) for decades. Since the introduction of interleukin 2 and interferon-alfa in the 80s to the more recently approved nivolumab (anti-PD-1) in second line setting. Moreover, on the basis that anti-CTLA-4 and anti-PD-1/PDL1 intrinsic mechanisms are different, double checkpoint inhibition was proposed to further improve anti-tumor immune response. The first trial to assess double checkpoint inhibition was the Checkmate 016 (nivolumab and ipilimumab), showing acceptable safety and promising antitumor activity that led to the first phase III trial with combination immunotherapy in RCC, the Checkmate 214. This trial showed superior overall survival and response rate of the combination immunotherapy (nivolumab and ipilimumab) versus sunitinib in intermediateand poorrisk advanced RCC, leading to its approval in this setting. Despite these advances, there is still room for improvement. In this sense, cytokines and T-cell costimulatory molecules are currently under investigation. This review summarizes the principles of immunotherapy and its role in RCC, provides an update on double checkpoint blockade and finally discusses the major challenges with double checkpoint blockade. 7