Immunotherapy for urothelial cancer: From BCG to checkpoint inhibitors and beyond

Expert Review of Anticancer Therapy

Volumn 15, Issue 5, 2015, Pages 509-523

  Wu, Yin ^a   Enting, Deborah ^a   Rudman, Sarah ^a   Chowdhury, Simon ^a  

^a GUY S HOSPITAL   (United Kingdom)

Author keywords

CTLA 4; immune checkpoint; immunoediting; immunosurveillance; PD 1; PD L1; Th1

Indexed keywords

ANTINEOPLASTIC AGENT; BCG VACCINE; CABOZANTINIB; CISPLATIN; COBIMETINIB; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DOCETAXEL; DURVALUMAB; EPIRUBICIN; GEMCITABINE; INCB 24360202; INTERFERON; INTERLEUKIN 10 ANTIBODY; INTERLEUKIN 12; INTERLEUKIN 2; IPILIMUMAB; LIRILUMAB; MITOMYCIN; MPDL 3280 A; NIVOLUMAB; PACLITAXEL; PEMBROLIZUMAB; PF 05082566; PROGRAMMED DEATH 1 LIGAND 1; RO 7009789; TICILIMUMAB; UNCLASSIFIED DRUG; VINFLUNINE; IMMUNOLOGICAL ADJUVANT;

ANOREXIA; CANCER IMMUNOTHERAPY; CANCER PREVENTION; CANCER RECURRENCE; CLINICAL EFFECTIVENESS; CYSTITIS; CYTOTOXICITY; DOSE RESPONSE; DRUG CONTRAINDICATION; DRUG EFFICACY; DRUG INDICATION; DRUG MECHANISM; DRUG SAFETY; DRUG TARGETING; FEVER; HEMATURIA; HUMAN; IMMUNE RESPONSE; IMMUNOSURVEILLANCE; MALAISE; NAUSEA; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHASE 4 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REGULATORY MECHANISM; REVIEW; RISK ASSESSMENT; TH1 CELL; TRANSURETHRAL RESECTION; UROGENITAL TRACT CANCER; VOMITING; ANIMAL; IMMUNOLOGY; IMMUNOTHERAPY; MOLECULARLY TARGETED THERAPY; PATHOLOGY; PROCEDURES; TUMOR INVASION; URINARY BLADDER NEOPLASMS; UROTHELIUM;

ADJUVANTS, IMMUNOLOGIC; ANIMALS; BCG VACCINE; HUMANS; IMMUNOTHERAPY; MOLECULAR TARGETED THERAPY; NEOPLASM INVASIVENESS; URINARY BLADDER NEOPLASMS; UROTHELIUM;

EID: 84928632278     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1586/14737140.2015.1015419     Document Type: Review

References (118)

1. The 20 most common cancers, UK, 2011. Cancer Research UK 2011. Available from: www.cancerresearchuk.org/cancer-info/ cancerstats/incidence/commoncancers/# Twenty [Last accessed 04 September 2014]
2. The 20 most common causes of cancer deaths, UK, 2011. Cancer Research UK, 2011. Available from: www. cancerresearchuk.org/cancer-info/cancerstats/ mortality/cancerdeaths/#Twenty [Last accessed 04 September 2014]
3. Loehrer PJ, Einhorn LH, Elson PJ, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group study. J Clin Oncol 1992;10(7):1066-73
4. Sternberg CN, de Mulder P, Schornagel JH, et al. 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. Eur J Cancer 2006;42(1):50-4
5. Galsky MD, Chowdhury S, Bellmunt J, et al. Treatment patterns and outcomes in 'real world' patients (pts) with metastatic urothelial cancer (UC). J Clin Oncol 2013; 31(15 Suppl):Abstract 4525
6. Babjuk M, Burger M, Zigeuner R, et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: update 2013. Eur Urol 2013;64(4):639-53
7. Coley WB. The Treatment of Malignant Tumors by Repeated Inoculations of Erysipelas, with a Report of Original Cases. Am J M Sc 1983;105:487-511
8. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004;21(2):137-48
9. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011;331(6024):1565-70
10. Galon J. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313(5795):1960-4
11. Galon J, Angell HK, Bedognetti D, Marincola FM. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 2013; 39(1):11-26
12. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711-23
13. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480(7378):480-9
14. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-pd-1 antibody in cancer. N Engl J Med 2012;366(26):2443-54
15. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-pd-l1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455-65
16. Pearl R. On the pathological relations between cancer and tuberculosis. Exp Biol Med 1928;26(1):73-5
17. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 1976;116(2):180-3
18. Lamm DL, Thor DE, Harris SC, et al. Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. J Urol 1980; 124(1):38-40
19. Pinsky CM, Camacho FJ, Kerr D, et al. Intravesical administration of bacillus Calmette-Guérin in patients with recurrent superficial carcinoma of the urinary bladder: report of a prospective, randomized trial. Cancer Treat Rep 1985; 69(1):47-53
20. Shelley MD, Kynaston H, Court J, et al. A systematic review of intravesical bacillus Calmette-Guérin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int 2001;88(3): 209-16
21. Sylvester RJ, van der Meijden APM, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: A meta-analysis of the published results of randomized clinical trials. J Urol 2002;168(5):1964-70
22. Böhle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: A formal meta-analysis of comparative studies on recurrence and toxicity. J Urol 2003;169(1): 90-5
23. Shelley MD, Wilt TJ, Court J, et al. Intravesical bacillus Calmette-Guérin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: A meta-analysis of randomized trials. BJU Int 2004;93(4): 485-90
24. Böhle A, Bock PR. Intravesical bacille Calmette-Guérin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology 2004;63(4): 682-6
25. Malmström P-U, Sylvester RJ, Crawford DE, et al. An Individual Patient Data Meta-Analysis of the Long-Term Outcome of Randomised Studies Comparing Intravesical Mitomycin C versus Bacillus Calmette-Guérin for Non-Muscle-Invasive Bladder Cancer. Eur Urol 2009;56(2):247-56
26. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate-And high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010:57(5):766-73
27. Oddens J, Brausi M, Sylvester R, et al. Final Results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin in intermediateand high-risk Ta, T1 Papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol 2013;63(3): 462-72
28. Shang PF, Kwong J, Wang ZP, et al. Intravesical bacillus Calmette-Guérin versus epirubicin for Ta and T1 bladder cancer. Cochrane Database Syst Rev 2011(5): CD006885
29. Yossepowitch O, Eggener SE, Bochner BH, et al. Safety and efficacy of intravesical bacillus Calmette-Guerin instillations in steroid treated and immunocompromised patients. J Urol 2006;176(2):482-5
30. Herr HW, Dalbagni G. Intravesical bacille Calmette-Guérin (BCG) in immunologically compromised patients with bladder cancer. BJU Int 2013;111(6):984-7
31. Zbar B, Bernstein ID, Bartlett GL, et al. Immunotherapy of cancer: regression of intradermal tumors and prevention of growth of lymph node metastases after intralesional injection of living Mycobacterium bovis. J Natl Cancer Inst 1972;49(1):119-30
32. Kelley DR, Ratliff TL, Catalona WJ, et al. Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results. J Urol 1985;134(1):48-53
33. Durek C, Brandau S, Ulmer AJ, et al. Bacillus-Calmette-Guérin (BCG) and 3D tumors: An in vitro model for the study of adhesion and invasion. J Urol 1999;162(2): 600-5
34. Huang G, Redelman-Sidi G, Rosen N, et al. Inhibition of mycobacterial infection by the tumor suppressor PTEN. J Biol Chem 2012;287(27):23196-202
35. Redelman-Sidi G, Iyer G, Solit DB, Glickman MS. Oncogenic Activation of Pak1-dependent pathway of macropinocytosis determines BCG entry into bladder cancer cells. Cancer Res 2013; 73(3):1156-67
36. Jackson AM, Alexandroff AB, Kelly RW, et al. Changes in urinary cytokines and soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after bacillus Calmette-Guérin (BCG) immunotherapy. Clin Exp Immunol 1995; 99(3):369-75
37. de Reijke TM, de Boer EC, Kurth KH, Schamhart DH. Urinary cytokines during intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: processing, stability and prognostic value. J Urol 1996; 155(2):477-82
38. Böhle A, Gerdes J, Ulmer AJ, et al. Effects of local bacillus Calmette-Guerin therapy in patients with bladder carcinoma on immunocompetent cells of the bladder wall. J Urol 1990;144(1):53-8
39. de Boer EC, De Jong WH, Van Der Meijden AP, et al. Presence of activated lymphocytes in the urine of patients with superficial bladder cancer after intravesical immunotherapy with bacillus Calmette-Guérin. Cancer Immunol Immunother 1991;33(6):411-16
40. Prescott S, James K, Hargreave TB, et al. Intravesical Evans strain BCG therapy: quantitative immunohistochemical analysis of the immune response within the bladder wall. J Urol 1992;147(6): 1636-42
41. Lima L, Dinis-Ribeiro M, Longatto-Filho A, Santos L. Predictive biomarkers of bacillus Calmette-Guérin immunotherapy response in bladder cancer: where are we now? Adv Urol 2012;2012(5):1-17
42. Kaempfer R, Gerez L, Farbstein H, et al. Prediction of response to treatment in superficial bladder carcinoma through pattern of interleukin-2 gene expression. J Clin Oncol 1996;14(6):1778-86
43. Saint F, Patard JJ, Maille P, et al. T helper 1/2 lymphocyte urinary cytokine profiles in responding and nonresponding patients after 1 and 2 courses of bacillus Calmette-Guerin for superficial bladder cancer. J Urol 2001; 166(6):2142-7
44. Nadler R, Luo Y, Zhao W, et al. Interleukin 10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumour activity. Clin Exp Immunol 2003;131(2):206-16
45. Lee S-J, Lee E-J, Kim S-K, et al. Identification of pro-inflammatory cytokines associated with muscle invasive bladder cancer; the roles of IL-5, IL-20, and IL-28A. PLoS One 2012;7(9): e40267
46. Cai T. Prediction of response to bacillus Calmette-Guerin treatment in non-muscle invasive bladder cancer patients through interleukin-6 and interleukin-10 ratio. Exp Ther Med 2012;4(3):459-64
47. Riemensberger J, Böhle A, Brandau S. IFN-gamma and IL-12 but not IL-10 are required for local tumour surveillance in a syngeneic model of orthotopic bladder cancer. Clin Exp Immunol 2002;127(1): 20-6
48. Rentsch CA, Birkhäuser FD, Biot C, et al. Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy. Eur Urol 2014;66(4):677-88
49. Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012;12(4):298-306
50. Ratliff TL, Ritchey JK, Yuan JJ, et al. T-cell subsets required for intravesical BCG immunotherapy for bladder cancer. J Urol 1993;150(3):1018-23
51. Brandau S, Riemensberger J, Jacobsen M, et al. NK cells are essential for effective BCG immunotherapy. Int J Cancer 2001; 92(5):697-702
52. Suttmann H. Neutrophil Granulocytes Are Required for Effective Bacillus Calmette-Guerin Immunotherapy of Bladder Cancer and Orchestrate Local Immune Responses. Cancer Res 2006; 66(16):8250-7
53. Sonoda T, Sugimura K, Ikemoto S-I, et al. Significance of target cell infection and natural killer cells in the anti-tumor effects of bacillus Calmette-Guerin in murine bladder cancer. Oncol Rep 2007;17(6): 1469-74
54. Biot C, Rentsch CA, Gsponer JR, et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci Transl Med 2012; 4(137):137ra72
55. Luo Y, Yamada H, Evanoff DP, Chen X. Role of Th1-stimulating cytokines in bacillus Calmette-Guerin (BCG)-induced macrophage cytotoxicity against mouse bladder cancer MBT-2 cells. CLin Exp Immunol 2006;146(1):181-8
56. Naoe M, Ogawa Y, Takeshita K, et al. Bacillus Calmette-Guérin-pulsed dendritic cells stimulate natural killer T cells and gdT cells. Int J Urol 2007;14(6):532-8
57. Ayari C, LaRue H, Hovington H, et al. Bladder tumor infiltrating mature dendritic cells and macrophages as predictors of response to bacillus Calmette-Guérin immunotherapy. Eur Urol 2009;55(6): 1386-96
58. De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 2013;23(3):277-86
59. Liao W, Lin J-X, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 2013;38(1):13-25
60. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol 2014;192(12):5451-8
61. Gomella LG, McGinnis DE, Lattime EC, et al. Treatment of transitional cell carcinoma of the bladder with intravesical interleukin-2: A pilot study. Cancer Biother 1993;8(3):223-7
62. Otter Den W, Jacobs JJL, Battermann JJ, et al. Local therapy of cancer with free IL-2. Cancer Immunol Immunother 2008;57(7): 931-50
63. Otter Den W, Van Moorselaar RJ, Jacobs JJL, et al. Role of marker lesion when applying intravesical instillations of IL-2 for non-muscle-invasive bladder cancer comparison of the therapeutic effects in two pilot studies. Anticancer Res 2013;33(5): 2099-105
64. Cockett AT, Davis RS, Cos LR, Wheeless LL. Bacillus Calmette-Guerin and interleukin-2 for treatment of superficial bladder cancer. J Urol 1991;146(3):766-9
65. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 2003;3(2): 133-46
66. Voest EE, Kenyon BM, O'Reilly MS, et al. Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 1995; 87(8):581-6
67. Horinaga M, Harsch KM, Fukuyama R, et al. Intravesical interleukin-12 gene therapy in an orthotopic bladder cancer model. Urology 2005;66(2):461-6
68. Zaharoff DA, Hoffman BS, Hooper HB, et al. Intravesical immunotherapy of superficial bladder cancer with chitosan/ interleukin-12. Cancer Res 2009;69(15): 6192-9
69. Leonard JP, Sherman ML, Fisher GL, et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood 1997;90(7):2541-8
70. Weiss GR, O'Donnell MA, Loughlin K, et al. 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(4):343-8
71. Luo Y, Chen X, Downs TM, et al. IFN-alpha 2B enhances Th1 cytokine responses in bladder cancer patients receiving Mycobacterium bovis bacillus Calmette-Guérin immunotherapy. J Immunol 1999;162(4):2399-240
72. Gan YH, Zhang Y, Khoo HE, Esuvaranathan K. Antitumour immunity of Bacillus Calmette-Guerin and interferon alpha in murine bladder cancer. Eur J Cancer 1999;35(7):1123-9
73. Portillo J, Martin B, Hernandez R, et al. Results at 43 months' follow-up of a double-blind, randomized, prospective clinical trial using intravesical interferon alpha-2b in the prophylaxis of stage pT1 transitional cell carcinoma of the bladder. Urology 1997;49(2):187-90
74. Bazarbashi S, Soudy H, Abdelsalam M, et al. Co-administration of intravesical bacillus Calmette-Guérin and interferon a-2B as first line in treating superficial transitional cell carcinoma of the urinary bladder. BJU Int 2011;108(7):1115-18
75. Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005;5(4):263-74
76. Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 2007;25(1):267-96
77. Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996;8(5): 765-72
78. Wang XB, Zheng CY, Giscombe R, Lefvert AK. Regulation of surface and intracellular expression of CTLA-4 on human peripheral T cells. Scand J Immunol 2001;54(5):453-8
79. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12(4):252-64
80. Huang X, Venet F, Wang YL, et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci USA 2009;106(15):6303-8
81. Thibult ML, Mamessier E, Gertner-Dardenne J, et al. PD-1 is a novel regulator of human B-cell activation. Int Immunol 2013;25(2):129-37
82. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26(1):677-704
83. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata. Cancer 2007;109(8):1499-505
84. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39(1):1-10
85. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515(7528):558-62
86. Plimack ER, Gupta S, Bellmunt J, et al. A Phase 1B Study of Pembrolizumab (PEMBRO; MK-3475) in Patients with Advanced Urothelial Tract Cancer. Ann Oncol 2014;25:1-41
87. A Study of Pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for participants with advanced urothelial cancer (MK-3475-045/KEYNOTE-045). Available from: https://clinicaltrials.gov/ct2/show/ NCT02256436
88. A Study of MPDL3280A compared with chemotherapy in patients with locally advanced or metastatic urothelial bladder cancer. Available from: https://clinicaltrials. gov/ct2/show/NCT02302807
89. Boorjian SA, Sheinin Y, Crispen PL, et al. T-Cell coregulatory molecule expression in urothelial cell carcinoma: clinicopathologic correlations and association with survival. Clin Cancer Res 2008;14(15):4800-8
90. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000;192(2):303-10
91. Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol 2001;1(3):220-8
92. Walker LSK, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 2011;11(12):852-63
93. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol 2014;32(18 Suppl):LBA9003
94. Ouyang W, Rutz S, Crellin NK, et al. Regulation and Functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 2011; 29(1):71-109
95. Newton MR, Askeland EJ, Andresen ED, et al. Anti-interleukin-10R1 monoclonal antibody in combination with bacillus Calmette-Guérin is protective against bladder cancer metastasis in a murine orthotopic tumour model and demonstrates systemic specific anti-tumour immunity. Clin Exp Immunol 2014;177(1):261-8
96. Herbst RS, Soria J-C, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515(7528): 563-7
97. Gajewski TF, Schreiber H, Fu Y-X. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013; 14(10):1014-22
98. Bellmunt J, Petrylak DP, Powles T, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic urothelial bladder cancer (UBC). Ann Oncol 2014;25:280-304
99. Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol 2013;31(5):616-22
100. Yamamoto T, Hagiwara M, Nakazono M, Yamamoto H. [Intravesical bacillus Calmette-Guerin (BCG) in the treatment of superficial bladder cancer. Prospective randomized study for prophylactic effect]. Nippon Hinyokika Gakkai Zasshi 1990; 81(7):997-1001
101. Pagano F, Bassi P, Milani C, et al. A low dose bacillus Calmette-Guerin regimen in superficial bladder cancer therapy: is it effective? J Urol 1991;146(1):32-5
102. Lamm DL, Blumenstein BA, David Crawford E, et al. Randomized intergroup comparison of Bacillus Calmette-Guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder a southwest oncology group study. Urol Oncol 1995;1(3):119-26
103. Malmström PU, Wijkström H, Lundholm C, et al. 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. Swedish-Norwegian Bladder Cancer Study Group. J Urol 1999;161(4): 1124-7
104. Järvinen R, Kaasinen E, Sankila A, Rintala E. Long-term efficacy of maintenance bacillus Calmette-Guérin versus maintenance mitomycin c instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: A subgroup analysis of the prospective, randomised FinnBladder I study with a 20-Year Follow-up. Eur Urol 2009;56(2): 260-5
105. Duchek M, Johansson R, Jahnson S, et al. Bacillus Calmette-Guérin is superior to a combination of epirubicin and interferon-a2b in the intravesical treatment of patients with stage t1 urinary bladder cancer. A prospective, randomized, Nordic study. Eur Urol 2010;57(1):25-31
106. A Study of MPDL3280A in patients with locally advanced or metastatic urothelial bladder cancer. Available from: https://clinicaltrials.gov/ct2/show/ NCT02108652
107. First-line gemcitabine, cisplatin + ipilimumab for metastatic urothelial carcinoma. Available from: https://clinicaltrials.gov/ct2/show/ NCT01524991
108. A Phase 1/2, Open-label study of nivolumab monotherapy or nivolumab combined with ipilimumab in subjects with advanced or metastatic solid tumors. Available from: https://clinicaltrials.gov/ct2/ show/NCT01928394
109. A Phase 1 Study of (Cabozantinib) Plus Nivolumab (CaboNivo) alone or in combination with ipilimumab (CaboNivoIpi) in patients with advanced/ metastatic urothelial carcinoma and other genitourinary tumors. Available from: http://apps.who.int/trialsearch/Trial2.aspx? TrialID=NCT02308943
110. Safety Study of Anti-LAG-3 with and without anti-PD-1 in the treatment of solid tumors. Available from: https://clinicaltrials. gov/ct2/show/NCT01968109
111. Study of Pembrolizumab (MK-3475) in participants with advanced solid tumors (MK-3475-012/KEYNOTE-012). Available from: https://clinicaltrials.gov/ct2/show/ NCT01848834
112. A Phase 1 study of MPDL3280A (an Engineered Anti-PDL1 Antibody) in patients with locally advanced or metastatic solid tumors. Available from: https://clinicaltrials.gov/ct2/show/ NCT01375842
113. A Study of RO7009789 in combination with mpdl3280a in patients with locally advanced and metastatic solid tumors. Available from: https://clinicaltrials.gov/ct2/ show/NCT02304393
114. A Phase 1b Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) in combination with cobimetinib in patients with locally advanced or metastatic solid tumors. Available from: https://clinicaltrials. gov/ct2/show/NCT01988896
115. A Phase 1 Study of MEDI4736 in combination with tremelimumab in subjects with advanced solid tumors. Available from: https://clinicaltrials.gov/ct2/show/ NCT02261220
116. A Study Of 4-1BB Agonist PF-05082566 Plus PD-1 Inhibitor MK-3475 In Patients With Solid Tumors (B1641003/KEYNOTE-0036). Available from: https://clinicaltrials.gov/ct2/show/ NCT02179918
117. A Phase I study of an anti-KIR antibody in combination with an anti-PD1 antibody in patients with advanced solid tumors. Available from: https://clinicaltrials.gov/ct2/ show/NCT01714739
118. A Phase 1/2 study exploring the safety, tolerability, and efficacy of MK-3475 in combination with INCB024360 in subjects with selected solid tumors and advanced NSCLC (INCB 24360-202/ MK-3475-037/ KEYNOTE-037). Available from: https:// clinicaltrials.gov/ct2/show/NCT02178722