Anti-PD1 and anti-PDL1 monotherapies have shown clinical efficacy in stage IV urothelial cancer and are integrated into current clinical practice. However, only a small number of the patients treated with single-agent checkpoint blockade experience an antitumour response. Insufficient priming or inhibitory factors in the tumour immune microenvironment might have a role in the lack of response. CTLA4 is an inhibitory checkpoint on activated T cells that is being studied as a therapeutic target in combination with anti-PD1 or anti-PDL1 therapies in advanced urothelial cancer. In locally advanced urothelial cancer, this combination approach has shown encouraging antitumour effects when administered pre-operatively. We believe that the presence of pre-existing intratumoural T cell immunity is not a prerequisite for response to combination therapy and that the additional value of CTLA4 blockade might involve the broadening of peripheral T cell priming, thereby transforming immunologically cold tumours into hot tumours.
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