{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T23:20:45Z","timestamp":1773271245857,"version":"3.50.1"},"reference-count":27,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2017,1,27]],"date-time":"2017-01-27T00:00:00Z","timestamp":1485475200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Urothelial cancer of the bladder, renal pelvis, ureter, and other urinary organs is the fifth most common cancer in the United States, and systemic platinum-based chemotherapy remains the standard of care for first-line treatment of advanced\/metastatic urothelial carcinoma (UC). Until recently, there were very limited options for patients who are refractory to chemotherapy, or do not tolerate chemotherapy due to toxicities and overall outcomes have remained very poor. While the role of immunotherapy was first established in non-muscle invasive bladder cancer in the 1970s, no systemic immunotherapy was approved for advanced disease until the recent approval of a programmed death ligand-1 (PD-L1) inhibitor, atezolizumab, in patients with advanced\/metastatic UC who have progressed on platinum-containing regimens. This represents a significant milestone in this disease after a void of over 30 years. In addition to atezolizumab, a variety of checkpoint inhibitors have shown a significant activity in advanced\/metastatic urothelial carcinoma and are expected to gain Food and Drug Administration (FDA) approval in the near future. The introduction of novel immunotherapy agents has led to rapid changes in the field of urothelial carcinoma. Numerous checkpoint inhibitors are being tested alone or in combination in the first and subsequent-line therapies of metastatic disease, as well as neoadjuvant and adjuvant settings. They are also being studied in combination with radiation therapy and for non-muscle invasive bladder cancer refractory to BCG. Furthermore, immunotherapy is being utilized for those ineligible for firstline platinum-based chemotherapy. This review outlines the novel immunotherapy agents which have either been approved, or are currently being investigated in clinical trials in UC.<\/jats:p>","DOI":"10.3390\/cancers9020015","type":"journal-article","created":{"date-parts":[[2017,1,27]],"date-time":"2017-01-27T11:23:02Z","timestamp":1485516182000},"page":"15","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Systemic Immunotherapy for Urothelial Cancer: Current Trends and Future Directions"],"prefix":"10.3390","volume":"9","author":[{"given":"Shilpa","family":"Gupta","sequence":"first","affiliation":[{"name":"Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Gill","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Austin","family":"Poole","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neeraj","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21332","article-title":"Cancer statistics, 2016","volume":"66","author":"Siegel","year":"2016","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ejca.2005.08.032","article-title":"Seven year update of an eortc phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic m-vac in advanced urothelial tract tumours","volume":"42","author":"Sternberg","year":"2006","journal-title":"Eur. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S1470-2045(10)70086-3","article-title":"Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium","volume":"11","author":"Sonpavde","year":"2010","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nature13904","article-title":"Mpdl3280a (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer","volume":"515","author":"Powles","year":"2014","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1016\/S0140-6736(16)00561-4","article-title":"Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial","volume":"387","author":"Rosenberg","year":"2016","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S1470-2045(15)70054-9","article-title":"Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial","volume":"16","author":"Rizvi","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.1200\/JCO.2016.67.9761","article-title":"Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer","volume":"34","author":"Massard","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_8","unstructured":"(2014). Merck Sharp & Dohme Corp."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4502","DOI":"10.1200\/jco.2015.33.15_suppl.4502","article-title":"Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012","volume":"33","author":"Plimack","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gupta, S., O\u2019Donnell, P.H., Plimack, E.R., Berger, R., Montgomery, B., Heath, K., Dolled-Filhart, M., Pathiraja, K., Gause, C.K., and Cheng, J. (2015, January 15\u201319). A Phase 1b Study of Pembrolizumab (Pembro; MK-3475) for Advanced Urothelial Cancer. Proceedings of the 2015 AUA Annual Meeting, New Orleans, LA, USA. Abstract MP68-11.","DOI":"10.1016\/j.juro.2015.02.2473"},{"key":"ref_11","unstructured":"Bellmunt, J., De Wit, R., Vaughn, D.J., Fradet, Y., Lee, J.L., Fong, L., Vogelzang, N.J., Climent, M.A., Petrylak, D.P., and Choueiri, T.K. (2016, January 9\u201313). Keynote-045: Open-label, phase III study of pembrolizumab versus investigator\u2019s choice of paclitaxel, docetaxel, or vinflunine for previously treated advanced urothelial cancer. Proceedings of the 2016 SITC Annual Meeting, National Harbor, MD, USA."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4514","DOI":"10.1200\/JCO.2016.34.15_suppl.4514","article-title":"Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: Analysis of safety, clinical activity, and PD-L1 expression","volume":"34","author":"Apolo","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1634\/theoncologist.2015-0507","article-title":"Fda approval summary: Nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy","volume":"21","author":"Kazandjian","year":"2016","journal-title":"Oncologist"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1200\/JCO.2016.34.15_suppl.4501","article-title":"Efficacy and safety of nivolumab monotherapy in metastatic urothelial cancer (mUC): Results from the phase I\/II CheckMate 032 study","volume":"34","author":"Sharma","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1016\/S1470-2045(16)30496-X","article-title":"Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (checkmate 032): A multicentre, open-label, two-stage, multi-arm, phase 1\/2 trial","volume":"17","author":"Sharma","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Galsky, M.D., Retz, M., Siefker-Radtke, A.O., Baron, A., Necchi, A., Bedke, J., Plimack, E.R., Vaena, D., Grimm, M.O., and Bracarda, S. (2016, January 7\u201311). Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results from the phase II CheckMate-275 study. Proceedings of the 2016 ESMO Congress, Copenhagen, Denmark. Abstract LBA31.","DOI":"10.1093\/annonc\/mdw435.24"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined nivolumab and ipilimumab or monotherapy in untreated melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1158\/1078-0432.CCR-10-0569","article-title":"Preoperative ctla-4 blockade: Tolerability and immune monitoring in the setting of a presurgical clinical trial","volume":"16","author":"Carthon","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1200\/jco.2016.34.2_suppl.357","article-title":"Phase II trial of gemcitabine + cisplatin + ipilimumab in patients with metastatic urothelial cancer","volume":"34","author":"Galsky","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"LBA4500","DOI":"10.1200\/JCO.2016.34.18_suppl.LBA4500","article-title":"Atezolizumab (atezo) as first-line (1L) therapy in cisplatin-ineligible locally advanced\/metastatic urothelial carcinoma (mUC): Primary analysis of IMvigor210 cohort 1","volume":"34","author":"Balar","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"LBA32_PR","DOI":"10.1093\/annonc\/mdw435.25","article-title":"Pembrolizumab (pembro) as first-line therapy for advanced\/unresectable or metastatic urothelial cancer: Preliminary results from the phase 2 keynote-052 study","volume":"27","author":"Balar","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1007\/s00262-008-0504-7","article-title":"Targeting activity of a TCR\/IL-2 fusion protein against established tumors","volume":"57","author":"Wen","year":"2008","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7765","DOI":"10.1158\/1078-0432.CCR-11-1817","article-title":"Phase I trial of ALT-801, an interleukin-2\/T-cell receptor fusion protein targeting p53 (aa264-272)\/HLA-A*0201 complex, in patients with advanced malignancies","volume":"17","author":"Fishman","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4515","DOI":"10.1200\/jco.2015.33.15_suppl.4515","article-title":"Phase Ib\/II study of an IL-2\/T-cell receptor fusion protein in combination with gemcitabine and cisplatin in advanced or metastatic chemo-refractory urothelial cancer (UC)","volume":"33","author":"Fishman","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"16130","DOI":"10.18632\/oncotarget.7470","article-title":"Il-15 superagonist\/IL-15RalphaSushi-Fc fusion complex (IL-15Sa\/IL-15RalphaSu-Fc; ALT-803) markedly enhances specific subpopulations of nk and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas","volume":"7","author":"Kim","year":"2016","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gomes-Giacoia, E., Miyake, M., Goodison, S., Sriharan, A., Zhang, G., You, L., Egan, J.O., Rhode, P.R., Parker, A.S., and Chai, K.X. (2014). Intravesical ALT-803 and bcg treatment reduces tumor burden in a carcinogen induced bladder cancer rat model; a role for cytokine production and nk cell expansion. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096705"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1002\/cncr.23848","article-title":"A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: A retrospective experience","volume":"113","author":"Dash","year":"2008","journal-title":"Cancer"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/9\/2\/15\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:27:07Z","timestamp":1760207227000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/9\/2\/15"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,27]]},"references-count":27,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,2]]}},"alternative-id":["cancers9020015"],"URL":"https:\/\/doi.org\/10.3390\/cancers9020015","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,27]]}}}