Immune escape mechanisms and immunotherapy of urothelial bladder cancer
Background and aim: Urothelial bladder cancer (UBC) is a common malignant tumor of the urogenital system with a high rate of recurrence. Owing to the sophisticated and largely unexplored mechanisms of tumorigenesis of UBC, the classical therapeutic approaches including transurethral resection and radical cystectomy combined with chemotherapy have remained unchanged for decades. However, with increasingly in-depth understanding of the microenvironment and the composition of tumor-infiltrating lymphocytes of UBC, novel immunotherapeutic strategies have been developed. Bacillus Calmette-Guerin (BCG) therapy, immune checkpoint blockades, adoptive T cell immunotherapy, dendritic cell vaccines, etc. have all been intensively investigated as immunotherapies for UBC. This review will discuss the recent progress in immune escape mechanisms and immunotherapy of UBC.
Methods: Based on a comprehensive search of the PubMed and ClinicalTrials.gov database, this review included the literature reporting the immune escape mechanisms of UBC and clinical trials assessing the effect of immunotherapeutic strategies on tumor or immune cells in UBC patients published in English between 1999 and 2020.
Results: Immune surveillance, immune balance, and immune escape are the three major processes that occur during UBC tumorigenesis. Firstly, the role of immunosuppressive cells, immunosuppressive molecules, immunosuppressive signaling molecules and dendritic cells in tumor microenvironment are introduced elaborately in the immune escape mechanisms of UBC section. Additionally, recent progress of immunotherapies including BCG, checkpoint inhibitors, cytokines, adoptive T cell immunotherapy, dendritic cells and macrophages on UBC patients are summarized in detail. Finally, the need to explore the mechanisms, molecular characteristics and immune landscape during UBC tumorigenesis and development of novel and robust immunotherapies for UBC are also proposed and discussed.
Conclusion: Currently, BCG and immune checkpoint blockades have been approved by the US Food and Drug Administration for the treatment of UBC patients and have achieved encouraging therapeutic results, expanding the traditional chemotherapy and surgery-based treatment for UBC.
Relevance for patients: Immunotherapy has achieved desirable results in the treatment of UBC, which not only improve the overall survival but also reduce the recurrence rate and the occurrence of treatment-related adverse events (TRAEs) of UBC patients. Additionally, the indicators to predict the effectiveness and novel therapy strategies, such as combination regimen of checkpoint inhibitor with checkpoint inhibitor or chemotherapy, should be further studied.
[1] Bladder Cancer Fact Sheet; 2021. Available from: https:// www.gco.iarc.fr/today/data/factsheets/cancers/30- Bladder-fact-sheet.pdf. Last accessed on 2021 May 11.
[2] Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and Risk Factors of Urothelial Bladder Cancer. Eur Urol 2013;63:234-41.
[3] Felsenstein KM, Theodorescu D. Precision Medicine for Urothelial Bladder Cancer: Update on Tumour Genomics and Immunotherapy. Nat Rev Urol 2018;15:92-111.
[4] Herr HW. Early History of Endoscopic Treatment Of Bladder Tumors From Grunfeld’s Polypenkneipe to the Stern-McCarthy Resectoscope. J Endourol 2006;20:85-91.
[5] Wu S, Yang Z, Ye R, An D, Li C, Wang Y, et al. Novel Variants in MLL Confer to Bladder Cancer Recurrence Identified by Whole-Exome Sequencing. Oncotarget 2016;7:2629-45.
[6] Yang Z, Zhang R, Ge Y, Qin X, Kang X, Wang Y, et al. Somatic FGFR3 Mutations Distinguish a Subgroup of Muscle-Invasive Bladder Cancers with Response to Neoadjuvant Chemotherapy. EBioMedicine 2018;35:198- 203.
[7] Yang Z, Shen Z, Jin D, Zhang N, Wang Y, Lei W, et al. Mutations of METTL3 Predict Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer. J Clin Transl Res 2021;7:386-413.
[8] Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, et al. Bladder Cancer. Nat Rev Dis Primers 2017;3:17022.
[9] Svatek RS, Hollenbeck BK, Holmäng S, Lee R, Kim SP, Stenzl A, et al. The Economics of Bladder Cancer: Costs and Considerations of Caring for this Disease. Eur Urol 2014;66:253-62.
[10] Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the Treatment of Superficial Bladder Tumors. J Urol 1976;116:180-3.
[11] Lamm DL, Thor DE, Harris SC, Reyna JA, Stogdill VD, Radwin HM. Bacillus Calmette-Guerin Immunotherapy of Superficial Bladder Cancer. J Urol 1980;124:38-40.
[12] Librenjak D, Situm M, Eterovic D, Dogas Z, Gotovac J. Immunoprophylactic Intravesical Application of Bacillus Calmette-Guerin after Transurethral Resection of Superficial Bladder Cancer. Croat Med J 2003;44:187-92.
[13] Meyer JP, Persad R, Gillatt DA. Use of Bacille CalmetteGuerin in Superficial Bladder Cancer. Postgrad Med J 2002;78:449-54.
[14] Ning YM, Suzman D, Maher VE, Zhang L, Tang S, Ricks T, et al. FDA Approval Summary: Atezolizumab for the Treatment of Patients with Progressive Advanced Urothelial Carcinoma after Platinum-Containing Chemotherapy. Oncologist 2017;22:743-9.
[15] FDA Approves Nivolumab for Bladder Cancer. National Cancer Institute; 2017. Available from: https://www. cancer.gov/news-events/cancer-currents-blog/2017/fdanivolumab-bladder. Last accessed on 2021 May 11.
[16] Simon S. FDA approves Bavencio (Avelumab) for Bladder Cancer. Atlanta, Georgia: American Cancer Society; 2017. Available from: https://www.cancer.org/latest-news/fdaapproves-bavencio-avelumab-for-bladder-cancer.html. Last accessed on 2021 May 11.
[17] Simon, S. FDA Approves Imfinzi (Durvalumab) for Bladder Cancer. American Cancer Society; Atlanta, Georgia: 2017. Available from: https://www.cancer.org/latest-news/fdaapproves-imfinzi-durvalumab-for-bladder-cancer.html. Last accessed on 2021 May 11.
[18] Suzman DL, Agrawal S, Ning YM, Maher VE, Fernandes LL, Karuri S, et al. FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy. Oncologist 2019;24:563-9.
[19] FDA Approves Merck’s KEYTRUDA® (Pembrolizumab) for Patients With BCG-Unresponsive, High-Risk, NonMuscle Invasive Bladder Cancer With Carcinoma In Situ With or Without Papillary Tumors Who Are Ineligible for or Have Elected Not to Undergo Cystectomy. Available from: https://www.merck.com/news/fda-approvesmercks-keytruda-pembrolizumab-for-patients-with-bcgunresponsive-high-risk-non-muscle-invasive-bladdercancer-with-carcinoma-in-situ-with-or-without-papillarytumors-wh. Last accessed on 2021 May 11.
[20] European Commission Approves BAVENCIO® (Avelumab) for First-Line Maintenance Treatment of Locally Advanced or Metastatic Urothelial Carcinoma; 2021. Available from: https://www.nasdaq.com/pressrelease/european-commission-approves-bavencioravelumab-for-first-line-maintenance-treatment. Last accessed on 2021 May 11.
[21] Topolsky DM. A Review of Immunotherapy in Advanced Bladder Cancer. Oncol Times 2018;40:6-7.
[22] Bellmunt J, Powles T, Vogelzang NJ. A Review on the Evolution of PD-1/PD-L1 Immunotherapy for Bladder Cancer: The Future is Now. Cancer Treat Rev 2017;54:58-67.
[23] Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated Regulation of Myeloid Cells by Tumours. Nat Rev Immunol 2012;12:253-68.
[24] Eruslanov E, Neuberger M, Daurkin I, Perrin GQ, Algood C, Dahm P, et al. Circulating and Tumor-infiltrating Myeloid Cell Subsets in Patients with Bladder Cancer. Int J Cancer 2012;130:1109-19.
[25] Eruslanov E, Stoffs T, Kim WJ, Daurkin I, Gilbert SM, Su LM, et al. Expansion of CCR8(+) Inflammatory Myeloid Cells in Cancer Patients with Urothelial and Renal Carcinomas. Clin Cancer Res 2013;19:1670-80.
[26] Wu K, Tan MY, Jiang JT, Mu XY, Wang JR, Zhou WJ, et al. Cisplatin Inhibits the Progression of Bladder Cancer by Selectively Depleting G-MDSCs: A Novel Chemoimmunomodulating Strategy. Clin Immunol 2018;193:60-9.
[27] Zhang H, et al. CXCL2/MIF-CXCR2 Signaling Promotes the Recruitment of Myeloid-derived Suppressor Cells and is Correlated with Prognosis in Bladder Cancer. Oncogene 2017;36:2095-104.
[28] Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in Metastatic Urothelial Carcinoma after Platinum Therapy (CheckMate 275): A Multicentre, Single-arm, Phase 2 Trial. Lancet Oncol 2017;18:312-22.
[29] Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, et al. A New Member of the Immunoglobulin Superfamily--CTLA-4. Nature 1987;328:267-70.
[30] Horn T, Grab J, Schusdziarra J, Schmid S, Maurer T, Nawroth R, et al. Antitumor T Cell Responses in Bladder Cancer are Directed against a Limited Set of Antigens and are Modulated by Regulatory T Cells and Routine Treatment Approaches. Int J Cancer 2013;133:2145-56.
[31] Krummel MF, Allison JP. CD28 and CTLA-4 have Opposing Effects on the Response of T Cells to Stimulation. J Exp Med 1995;182:459-65.
[32] Fu LQ, Du WL, Cai MH, Yao JY, Zhao YY, Mou XZ. The Roles of Tumor-Associated Macrophages in Tumor Angiogenesis and Metastasis. Cell Immunol 2020;353:104119.
[33] Naitoh J, Franklin J, O’Donnell MA, Belldegrun AS. Interferon Alpha for the Treatment of Superficial Bladder Cancer. Adv Exp Med Biol 1999;462:371-86; discussion 387-92.
[34] Giannopoulos A, Constantinides C, Fokaeas E, Stravodimos C, Giannopoulou M, Kyroudi A, et al. The Immunomodulating Effect of Interferon-Gamma Intravesical Instillations in Preventing Bladder Cancer Recurrence. Clin Cancer Res 2003;9:5550-8.
[35] Zaharoff DA, Hoffman BS, Hooper HB, Benjamin CJ Jr., Khurana KK, Hance KW, et al. Intravesical Immunotherapy of Superficial Bladder Cancer with Chitosan/Interleukin-12. Cancer Res 2009;69:6192-9.
[36] O’Donnell MA, Luo Y, Hunter SE, Chen X, Hayes LL, Clinton SK. Interleukin-12 Immunotherapy of Murine Transitional Cell Carcinoma of the Bladder: Dose Dependent tumor Eradication and Generation of Protective Immunity. J Urol 2004;171:1330-5.
[37] Askeland EJ, Newton MR, O’Donnell MA, Luo Y. Bladder Cancer Immunotherapy: BCG and Beyond. Adv Urol 2012;2012:181987.
[38] O’Donnell MA, Luo Y, Hunter SE, Chen X, Hayes LL, Clinton SK. The Essential Role of Interferon-gamma during Interleukin-12 Therapy for Murine Transitional Cell Carcinoma of the Bladder. J Urol 2004;171:1336-42.
[39] Ostrand-Rosenberg S. CD4+ T lymphocytes: A Critical Component of Antitumor Immunity. Cancer Invest 2005;23:413-9.
[40] Wei SC, Duffy CR, Allison JP. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discov 2018;8:1069-86.
[41] O’Donnell JS, Long GV, Scolyer RA, Teng MW, Smyth MJ. Resistance to PD1/PDL1 Checkpoint Inhibition. Cancer Treat Rev 2017;52:71-81.
[42] Qian Y, Deng J, Geng L, Xie H, Jiang G, Zhou L, et al. TLR4 Signaling Induces B7-H1 Expression through MAPK Pathways in Bladder Cancer Cells. Cancer Invest 2008;26:816-21.
[43] Chopin D, Barei-Moniri R, Maillé P, Le Frère-Belda MA, Muscatelli-Groux B, Merendino N, et al. Human Urinary Bladder Transitional Cell Carcinomas Acquire the Functional Fas Ligand During Tumor Progression. Am J Pathol 2003;162:1139-49.
[44] Joshua JM, Vijayan M, Pooleri GK. A Retrospective Analysis of Patients Treated with Intravesical BCG for High-Risk Nonmuscle Invasive Bladder Cancer. Ther Adv Urol 2019;11:1756287219833056.
[45] Wakamatsu E, Mathis D, Benoist C. Convergent and Divergent Effects of Costimulatory Molecules in Conventional and Regulatory CD4+ T Cells. Proc Natl Acad Sci U S A 2013;110:1023-8.
[46] Leach DR, Krummel MF, Allison JP. Enhancement of Antitumor Immunity by CTLA-4 Blockade. Science 1996;271:1734-6.
[47] BCG Vaccine. Drugs and Lactation Database (LactMed). Bethesda, MD: National Library of Medicine US; 2006.
[48] Maggio E, van den Berg A, Diepstra A, Kluiver J, Visser L, Poppema S. Chemokines, Cytokines and their Receptors in Hodgkin’s Lymphoma Cell Lines and Tissues. Ann Oncol, 2002. 13 Suppl 1: p. 52-6.
[49] Yang AS, Lattime EC. Tumor-Induced Interleukin 10 Suppresses the Ability of Splenic Dendritic Cells to Stimulate CD4 and CD8 T-Cell Responses. Cancer Res 2003;63:2150-7.
[50] Troy AJ, Davidson PJ, Atkinson CH, Hart DN. CD1a Dendritic Cells Predominate in Transitional Cell Carcinoma of Bladder and Kidney but are Minimally Activated. J Urol 1999;161:1962-7.
[51] National Library of Medicine. BCG Vaccine, in Drugs and Lactation Database (LactMed). Bethesda, MD: National Library of Medicine US; 2006
[52] Shelley MD, Kynaston H, Court J, Wilt TJ, Coles B, Burgon K, et al. A Systematic Review of Intravesical Bacillus Calmette-Guerin Plus Transurethral Resection vs Transurethral Resection Alone in Ta and T1 Bladder Cancer. BJU Int 2001;88:209-16.
[53] Malmstrom PU, Sylvester RJ, Crawford DE, Friedrich M, Krege S, Rintala E, et al. An Individual Patient Data Metaanalysis of the Long-term Outcome of Randomised Studies Comparing Intravesical Mitomycin C Versus Bacillus Calmette-Guerin for Non-muscle-invasive Bladder Cancer. Eur Urol 2009;56:247-56.
[54] Sylvester RJ, van der Meijden MA, Lamm DL. Intravesical Bacillus Calmette-Guerin Reduces the Risk of Progression in Patients with Superficial Bladder Cancer: A Metaanalysis of the Published Results of Randomized Clinical Trials. J Urol 2002;168:1964-70.
[55] Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, et al. Maintenance Bacillus Calmette-Guerin Immunotherapy for Recurrent TA, T1 and Carcinoma In Situ Transitional Cell Carcinoma of the Bladder: ARandomized Southwest Oncology Group Study. J Urol 2000;163:1124-9.
[56] Herr HW, Morales A. History of Bacillus Calmette-Guerin and Bladder Cancer: An Immunotherapy Success Story. J Urol 2008;179:53-6.
[57] Kamat AM, Flaig TW, Grossman HB, Konety B, Lamm D, O’Donnell MA, et al. Expert Consensus Document: Consensus Statement on Best Practice Management Regarding the Use of Intravesical Immunotherapy with BCG for Bladder Cancer. Nat Rev Urol 2015;12:225-35.
[58] Han J, Gu X, Li Y, Wu Q. Mechanisms of BCG in the Treatment of Bladder Cancer-current Understanding and the Prospect. Biomed Pharmacother 2020;129:110393.
[59] Yu DS, Wu CL, Ping SY, Keng C, Shen KH. Bacille Calmette-Guerin can Induce Cellular Apoptosis of Urothelial Cancer Directly through Toll-like Receptor 7 Activation. Kaohsiung J Med Sci 2015;31:391-7.
[60] Sandes E, Lodillinsky C, Cwirenbaum R, Argüelles C, Casabé A, Eiján AM. Cathepsin B is Involved in the Apoptosis Intrinsic Pathway Induced by Bacillus CalmetteGuerin in Transitional Cancer Cell Lines. Int J Mol Med 2007;20:823-8.
[61] See WA, Zhang G, Chen F, Cao Y, Langenstroer P, Sandlow J. Bacille-Calmette Guerin Induces Caspase-independent Cell Death in Urothelial Carcinoma Cells Together with Release of the Necrosis-associated Chemokine High Molecular Group Box Protein 1. BJU Int 2009;103:1714-20.
[62] Ryk C, Koskela LR, Thiel T, Wiklund NP, Steineck G, Schumacher MC, et al. Outcome after BCG Treatment for Urinary Bladder Cancer may be Influenced by Polymorphisms in the NOS2 and NOS3 Genes. Redox Biol 2015;6:272-7.
[63] Thiel T, Ryk C, Chatzakos V, Grufman KH, BavandChobot N, Flygare J, et al. Secondary Stimulation from Bacillus Calmette-Guerin Induced Macrophages Induce Nitric Oxide Independent Cell-death in Bladder Cancer Cells. Cancer Lett 2014;348:119-25.
[64] Shah G, Zielonka J, Chen F, Zhang G, Cao YL, Kalyanaraman B, et al. H2 O2 generation by Bacillus Calmette-Guerin Induces the Cellular Oxidative Stress Response Required for Bacillus Calmette-Guerin Direct Effects on Urothelial Carcinoma Biology. J Urol 2014;192:1238-48.
[65] Shah G, Zhang G, Chen F, Cao Y, Kalyanaraman B, See WA. iNOS Expression and NO Production Contribute to the Direct Effects of BCG on Urothelial Carcinoma Cell Biology. Urol Oncol 2014;32:45.e1-9.
[66] Darieva Z, Lasunskaia EB, Campos MN, Kipnis TL, Da Silva WD. Activation of Phosphatidylinositol 3-Kinase and c-Jun-N-Terminal Kinase Cascades Enhances NFkappaB-dependent Gene Transcription in BCG-Stimulated Macrophages through Promotion of p65/p300 Binding. J Leukoc Biol 2004;75:689-97.
[67] Bisiaux A, Boussier J, Duffy D, Quintana-Murci L, Fontes M, Albert ML, et al. Deconvolution of the Response to Bacillus Calmette-Guerin Reveals NF-ka
[68] Umemura M, Yahagi A, Hamada S, Begum MD, Watanabe H, Kawakami K, et al. IL-17-Mediated Regulation of Innate and Acquired Immune Response against Pulmonary Mycobacterium bovis Bacille CalmetteGuerin Infection. J Immunol 2007;178:3786-96.
[69] Davis RL 3rd, Le W, Cui Z. Granulocytes as an Effector Mechanism of BCG Therapy for Bladder Cancer. Med Hypotheses 2017;104:166-9.
[70] Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 Blockade Induces Responses by Inhibiting Adaptive Immune Resistance. Nature 2014;515:568-71.
[71] Powles T, Eder JP, Fine D, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) Treatment Leads to Clinical Activity in Metastatic Bladder Cancer. Nature 2014;515:558-62.
[72] Carosella ED, Ploussard G, LeMaoult J, Desgrandchamps F. A Systematic Review of Immunotherapy in Urologic Cancer: Evolving Roles for Targeting of CTLA-4, PD-1/ PD-L1, and HLA-G. Eur Urol 2015;68:267-79.
[73] Dong H, Zhu G, Tamada K, Flies DB, van Deursen JM, Chen L. B7-H1 Determines Accumulation and Deletion of Intrahepatic CD8(+) T Lymphocytes. Immunity 2004;20:327-36.
[74] Francisco LM, Salinas VH, Brown E, Vanguri VK, Freeman GJ, Kuchroo VK, et al. PD-L1 Regulates the Development, Maintenance, and Function of Induced Regulatory T Cells. J Exp Med 2009;206:3015-29.
[75] Wang L, Wei Z, Xiong W, Bai S, Yu C, Yang Z. Bispecific Antibodies in Clinical Tumor Therapy. Sheng Wu Gong Cheng Xue Bao 2021;37:513-29.
[76] Plimack ER, Bellmunt J, Gupta S, Berger R, Chow LQ, Juco J, et al. Safety and Activity of Pembrolizumab in Patients with Locally Advanced or Metastatic Urothelial Cancer (KEYNOTE-012): A Non-randomised, Openlabel, Phase 1b Study. Lancet Oncol 2017;18:212-20.ppaB-Induced Cytokines as Autocrine Mediators of Innate Immunity. Front Immunol 2017;8:796.
[77] Bellmunt J, de Wit R, Vaughn DJ, Y, Lee JL, Fong L, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376:1015-26.
[78] Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, et al. Randomized Phase III KEYNOTE-045 Trial of Pembrolizumab Versus Paclitaxel, Docetaxel, or Vinflunine in Recurrent Advanced Urothelial Cancer: Results of >2 Years of Follow-up. Ann Oncol 2019;30:970-6.
[79] Balar AV, Castellano D, O’Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line Pembrolizumab in Cisplatinineligible Patients with Locally Advanced and Unresectable or Metastatic Urothelial Cancer (KEYNOTE-052): A Multicentre, Single-Arm, Phase 2 Study. Lancet Oncol 2017;18:1483-92.
[80] Vuky J, Balar AV, Castellano D, O’Donnell PH, Grivas P, Bellmunt J, et al. Long-Term Outcomes in KEYNOTE-052: Phase II Study Investigating First-Line Pembrolizumab in Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol 2020;38:2658-66.
[81] Darr C, Hadaschik BA, Tschirdewahn S. Systemic Treatment of Metastatic Tumors of the Upper Urinary Tract. Urologe A 2019;58:30-3.
[82] Rexer H, Ohlmann CH, Retz M. First-line Therapy for Locally Advanced or Metastatic Urothelial Carcinoma: A Randomized, Controlled Phase III Trial Comparing Pembrolizumab with or without Platinum-based Combination Chemotherapy and Chemotherapy Only in Patients with Advanced or Metastatic Urothelial Carcinoma (Keynote 361-AB 54/16 of the AUO). Urologe A 2017;56:659-61.
[83] Rosenberg JE, Flaig TW, Friedlander TW, Milowsky MI, Srinivas S, Petrylak DP, et al. Study EV-103: Preliminary Durability Results of Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma. J Clin Oncol 2020;38 Suppl 6:441.
[84] Galsky MD, Saci A, Szabo PM, Han GC, Grossfeld G, Collette S, et al. Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275. Clin Cancer Res 2020;26:5120-8.
[85] Inman BA, Longo TA, Ramalingam S, Harrison MR. Atezolizumab: A PD-L1-Blocking Antibody for Bladder Cancer. Clin Cancer Res 2017;23:1886-90.
[86] Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as First-line Treatment in Cisplatin-ineligible Patients with Locally Advanced and Metastatic Urothelial Carcinoma: A Singlearm, Multicentre, Phase 2 Trial. Lancet 2017;389:67-76.
[87] Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in Patients with Locally Advanced and Metastatic Urothelial Carcinoma who have Progressed Following Treatment with Platinum-based Chemotherapy: ASingle-arm, Multicentre, Phase 2 Trial. Lancet 2016;387:1909-20.
[88] Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, et al. Atezolizumab Versus Chemotherapy in Patients with Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma (IMvigor211): A Multicentre, Open-label, Phase 3 Randomised Controlled Trial. Lancet 2018;391:748-57.
[89] Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients with Advanced Urothelial Bladder Cancer. J Clin Oncol 2016;34:3119-25.
[90] Powles T, O’Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, et al. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results from a Phase 1/2 Open-label Study. JAMA Oncol 2017;3:e172411.
[91] Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, et al. Avelumab, an Anti-Programmed DeathLigand 1 Antibody, in Patients with Refractory Metastatic Urothelial Carcinoma: Results from a Multicenter, Phase Ib Study. J Clin Oncol 2017;35:2117-24.
[92] Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020;383:1218-30.
[93] Wang L, Su G, Zhao X, Cai Y, Cai X, Zhang J, et al. Association between the Cytotoxic T-lymphocyte Antigen 4 +49A/G Polymorphism and Bladder Cancer Risk. Tumour Biol 2014;35:1139-42.
[94] Jaiswal PK, Singh V, Mittal RD. Cytotoxic T Lymphocyte Antigen 4 (CTLA4) Gene Polymorphism with Bladder Cancer Risk in North Indian Population. Mol Biol Rep 2014;41:799-807.
[95] Rouanne M, Roumiguié M, Houédé N, Masson-Lecomte A, Colin P, Pignot G, et al. Development of Immunotherapy in Bladder Cancer: Present and Future on Targeting PD(L)1 and CTLA-4 Pathways. World J Urol 2018;36:1727-40.
[96] Carthon BC, Wolchok JD, Yuan J, Kamat A, Ng Tang DS, Sun J, et al. Preoperative CTLA-4 Blockade: Tolerability and Immune Monitoring in the Setting of a Presurgical Clinical Trial. Clin Cancer Res 2010;16:2861-71.
[97] Galsky MD, Wang H, Hahn NM, Twardowski P, Pal SK, Albany C, et al. Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes. Eur Urol 2018;73:751-9.
[98] Sharma P, Siefker-Radtke A, de Braud F, Basso U, Calvo E, Bono P, et al. Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results. J Clin Oncol 2019;37:1608-16.
[99] Sharma P, Callahan MK, Bono P, Kim J, Spiliopoulou P, Calvo E, et al. Nivolumab Monotherapy in Recurrent Metastatic Urothelial Carcinoma (CheckMate 032): A Multicentre, Open-label, Two-stage, Multi-arm, Phase 1/2 Trial. Lancet Oncol 2016;17:1590-8.
[100] Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, et al. Durvalumab Alone and Durvalumab Plus Tremelimumab Versus Chemotherapy in Previously Untreated Patients with Unresectable, Locally Advanced or Metastatic Urothelial Carcinoma (DANUBE): A Randomised, Open-label, Multicentre, Phase 3 Trial. Lancet Oncol 2020;21:1574-88.
[101] Stenehjem DD, Tran D, Nkrumah MA, Gupta S. PD1/ PDL1 Inhibitors for the Treatment of Advanced Urothelial Bladder Cancer. Onco Targets Ther 2018;11:5973-89.
[102] Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, Korenstein D. Immune-related Adverse Events for AntiPD-1 and Anti-PD-L1 Drugs: Systematic Review and Meta-analysis. BMJ 2018;360:k793.
[103] Lee S, Margolin K. Cytokines in Cancer Immunotherapy. Cancers (Basel) 2011;3:3856-93.
[104] Pizza G, Berton F, Casanova S, De Vinci C, Corrado F. Interleukin-2 in the Treatment of Infiltrating Bladder Cancer. J Exp Pathol 1987;3:525-31.
[105] Weiss GR, O’Donnell MA, Loughlin K, Zonno K, LaliberteRJ, Sherman ML. Phase 1 Study of the Intravesical Administration of Recombinant Human Interleukin-12 in Patients with Recurrent Superficial Transitional Cell Carcinoma of the Bladder. J Immunother 2003;26:343-8.
[106] Sherif A, Hasan MN, Marits P, Karlsson M, Winqvist O, Thörn M, et al. Feasibility of T-Cell-Based Adoptive Immunotherapy in the First 12 Patients with Advanced Urothelial Urinary Bladder Cancer. Preliminary Data on a New Immunologic Treatment Based on the Sentinel Node Concept. Eur Urol 2010;58:105-11.
[107] Sherif A, Hasan MN, Radecka E, Rodriguez AL, Shabo S, Karlsson M, et al. Pilot Study of Adoptive Immunotherapy with Sentinel Node-Derived T Cells in Muscle-invasive Urinary Bladder Cancer. Scand J Urol 2015;49:453-62.
[108] Schraml BU, Reis e Sousa C. Defining dendritic cells. Curr Opin Immunol 2015;32:13-20.
[109] Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, et al. Immunobiology of Dendritic Cells. Annu Rev Immunol 2000;18:767-811.
[110] Gardner A, Ruffell B. Dendritic Cells and Cancer Immunity. Trends Immunol 2016;37:855-65.
[111] Nishiyama T, Tachibana M, Horiguchi Y, Nakamura K, Ikeda Y, Takesako K, et al. Immunotherapy of Bladder Cancer Using Autologous Dendritic Cells Pulsed with Human Lymphocyte Antigen-A24-specific MAGE-3 Peptide. Clin Cancer Res 2001;7:23-31.
[112] Wynn TA, Chawla A, Pollard JW. Macrophage Biology in Development, Homeostasis and Disease. Nature 2013;496:445-55.
[113] Varol C, Mildner A, Jung S. Macrophages: Development and Tissue Specialization. Annu Rev Immunol 2015;33:643-75.
[114] Asano T, Ohnishi K, Shiota T, Motoshima T, Sugiyama Y, Yatsuda J, et al. CD169-Positive Sinus Macrophages in the Lymph Nodes Determine Bladder Cancer Prognosis. 2018;109:1723-30.
[115] Krpina K, Babarović E, Španjol J, Đorđević G, Maurer T, Jonjić N. Correlation of Tumor-associated Macrophages and NK Cells with Bladder Cancer Size and T Stage in Patients with Solitary Low-grade Urothelial Carcinoma. Wien Klin Wochenschr 2016;128:248-52.
[116] Miyake M, Tatsumi Y, Gotoh D, Ohnishi S, Owari T, [Iida K, et al. Regulatory T Cells and Tumor-Associated Macrophages in the Tumor Microenvironment in NonMuscle Invasive Bladder Cancer Treated with Intravesical Bacille Calmette-Guerin: A Long-Term Follow-Up Study of a Japanese Cohort. Int J Mol Sci 2017;18:2186.
[117] Wu SQ, Xu R, Li XF, Zhao XK, Qian BZ. Prognostic Roles of Tumor Associated Macrophages in Bladder Cancer: A System Review and Meta-analysis. Oncotarget 2018;9:25294-303.
[118] Liu J, Duan X. PA-MSHA Induces Apoptosis and Suppresses Metastasis by Tumor Associated Macrophages in Bladder Cancer Cells. Cancer Cell Int 2017;17:76.
[119] Tian YF, Tang K, Guan W, Yang T, Xu H, Zhuang QY, et al. OK-432 Suppresses Proliferation and Metastasis by Tumor Associated Macrophages in Bladder Cancer. Asian Pac J Cancer Prev 2015;16:4537-42.
[120] Yang H, Kim C, Kim MJ, Schwendener RA, Alitalo K, Heston W, et al. Soluble Vascular Endothelial Growth Factor Receptor-3 Suppresses Lymphangiogenesis and Lymphatic Metastasis in Bladder Cancer. Mol Cancer 2011;10:36.
[121] Kamat AM, Li R, O’Donnell MA, Black PC, Roupret M, Catto W, et al. Predicting Response to Intravesical Bacillus Calmette-Guérin Immunotherapy: Are We There Yet? A Systematic Review. Eur Urol 2018;73:738-48.
[122] Witjes JA. Management of BCG Failures in Superficial Bladder Cancer: A Review. Eur Urol 2006;49:790-7.
[123] Roupret M, Neuzillet Y, Larré S, Pignot G, Coloby P, Rébillard X, et al. Guidelines for Good Practice of Intravesical Instillations of BCG and Mitomycin C from the French National Cancer Committee (CC-AFU) for Nonmuscle Invasive Bladder Cancer. Prog Urol 2012;22:920-31.
[124] Fumet JD, Truntzer C, Yarchoan M, Ghiringhelli F. Tumour Mutational Burden as a Biomarker for Immunotherapy: Current Data and Emerging Concepts. Eur J Cancer 2020;131:40-50.
[125] Galsky MD, Arija JA, Bamias A, Davis ID, De Santis M, Kikuchi E, et al. Atezolizumab with or without Chemotherapy in Metastatic Urothelial Cancer (IMvigor130): A Multicentre, Randomised, Placebocontrolled Phase 3 Trial. Lancet 2020;395:1547-57.
[126] Rexer H, Ohlmann CH, Retz M. Erstlinientherapie Beim Lokal Fortgeschrittenen Oder Metastasierten Urothelkarzinom: Eine Randomisierte, Kontrollierte Phase-III-Studie Zum Vergleich von Pembrolizumab Mit und Ohne Platinbasierter Kombinations-Chemotherapie und der Alleinigen Chemotherapie Bei Patienten Mit Fortgeschrittenem Oder Metastasiertem Urothelkarzinom (Keynote-361) AB 54/16 der AUO [First-Line Therapy for Locally Advanced or Metastatic Urothelial Cancer: A randomized, controlled Phase III study comparing pembrolizumab with and without Platinum-Based Combination Chemotherapy and Chemotherapy Alone in Patients with Advanced or Metastatic Urothelial Cancer (Keynote-361) AB 54/16 of the AUO]. Aktuelle Urol 2018;49:21-2.
[127] Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol 2016;39:98-106.