Enhancing response to immunotherapy in urothelial carcinoma by targeted inhibition of the histone methyltransferase G9a pathway

Bladder cancer (BCa) is the fourth most common malignancy among men, and is the eighth most common cause of cancer death in the US (1). Once muscle-invasive, the treatment options for BCa are limited, and include radical cystectomy with or without neoadjuvant platinum-based chemotherapy or organ sparing chemoradiotherapy (2). In 2016, the treatment of metastatic BCa (mBCa) was revolutionized by results of a phase II trial of immune checkpoint programmed death-ligand 1 (PD-L1) inhibitor atezolizumab in 311 patients with mBCa who progressed after chemotherapy (3,4). The trial found a response rate of 15% in patients receiving 1,200 mg atezolizumab for 3 weeks, which was a significant improvement over systemic chemotherapy historical controls, which had a response rate of 10% (2). Several additional trials of other inhibitors of the PD-1/PD-L1 pathway in mBCa, such as pembrolizumab (5), nivolumab (6), durvalumab (7), and avelumab (8), also found sustained response in mBCa patients.