title: Immunotherapy: a new treatment paradigm in bladder cancer.
abstract: OBJECTIVE
  T-cell checkpoint blockade has become a dynamic immunotherapy for bladder cancer. In 2016, atezolizumab, an immune checkpoint inhibitor, became the first new drug approved in metastatic urothelial carcinoma (mUC) in over 30 years. In 2017, nivolumab was also approved for the same indication. This overview of checkpoint inhibitors in clinical trials focuses on novel immunotherapy combinations, predictive biomarkers including mutational load and neoantigen identification, and an evaluation of the future of bladder cancer immunotherapy.
  
  
  RESULTS
  Programed cell death protein 1/programed death-ligand 1 (PD-1/PD-L1) checkpoint inhibitors have achieved durable clinical responses in a subset of previously treated and treatment-naïve patients with mUC. The combination of PD-1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has successfully improved response rates in multiple malignancies, and combination studies are underway in many tumor types, including bladder cancer, combining T-cell checkpoint blockade with other checkpoint agents and immunomodulatory therapies. Strong tumor responses to checkpoint blockade have been reported to be positively associated with expression of PD-L1 on tumor and tumor-infiltrating immune cells and with increased mutation-associated neoantigen load, which may lead to the development of predictive biomarkers.
  
  
  CONCLUSIONS
  Recent clinical evidence suggests that mUC is susceptible to T-cell checkpoint blockade. A global effort is underway to achieve higher response rates and more durable remissions, accelerate the development of immunotherapies, employ combination therapies, and test novel immune targets.
authors.affiliation: aGenitourinary Malignancies Branch bDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA *Nicole N. Davarpanah and Akira Yuno contributed equally to the article.
authors.forename: Nicole N
authors.initials: NN
authors.lastname: Davarpanah
authors.forename: Akira
authors.initials: A
authors.lastname: Yuno
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Apolo