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Immunotherapeutic Approaches to Biliary Cancer

  • Upper Gastrointestinal Cancers (L Rajdev, Section Editor)
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Opinion statement

Biliary tract cancers (BTCs) are rare aggressive neoplasms with a poor prognosis and a median survival of less than 1 year in the locally advanced or metastatic setting. Among the few patients who undergo curative resection the recurrence rates are high. About 90% of patients are detected at advanced stages, and systemic chemotherapy is the mainstay of their treatment. The treatment options for these patients are limited and multiple modalities of therapy from targeted therapy to immunotherapy and combination therapies (immunotherapy, targeted therapy, and chemotherapy) have been tested in this disease. Targeted therapies have failed to show a survival benefit. The deregulation of the immune system plays a significant role in the pathogenesis of BTCs. Therefore, immunotherapy, especially, immune checkpoint inhibitors hold great promise for this group of cancers. Numerous trials of immunotherapy in BTC are currently ongoing. In this review, we will discuss the available data and evidence for immunotherapy in BTC.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as • Of importance •• Of major importance

  1. de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med. 1999;341(18):1368–78. doi:10.1056/NEJM199910283411807.

    Article  PubMed  Google Scholar 

  2. • Hezel AF, Deshpande V, Zhu AX. Genetics of biliary tract cancers and emerging targeted therapies. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28(21):3531–40. doi:10.1200/JCO.2009.27.4787. This is a summary of the molecular pathogenesis and genetics of BTCs and animal modeling and the related clinical trials with targeted agents

    Article  CAS  Google Scholar 

  3. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29. doi:10.3322/caac.21208.

    Article  PubMed  Google Scholar 

  4. Ryerson AB, Eheman CR, Altekruse SF, Ward JW, Jemal A, Sherman RL, et al. Annual report to the nation on the status of cancer, 1975–2012, featuring the increasing incidence of liver cancer. Cancer. 2016;122(9):1312–37. doi:10.1002/cncr.29936.

    Article  PubMed  PubMed Central  Google Scholar 

  5. • Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF et al. SEER Cancer Statistics Review, 1975–2013, National Cancer Institute. 2016. The statistics of cancer in the United States.

  6. Jarnagin WR, Ruo L, Little SA, Klimstra D, D'Angelica M, DeMatteo RP, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer. 2003;98(8):1689–700. doi:10.1002/cncr.11699.

    Article  PubMed  Google Scholar 

  7. Mayo SC, Shore AD, Nathan H, Edil B, Wolfgang CL, Hirose K, et al. National trends in the management and survival of surgically managed gallbladder adenocarcinoma over 15 years: a population-based analysis. J Gastrointest Surg. 2010;14(10):1578–91. doi:10.1007/s11605-010-1335-3.

    Article  PubMed  Google Scholar 

  8. Duffy A, Capanu M, Abou-Alfa GK, Huitzil D, Jarnagin W, Fong Y, et al. Gallbladder cancer (GBC): 10-year experience at memorial Sloan-Kettering cancer centre (MSKCC). J Surg Oncol. 2008;98(7):485–9. doi:10.1002/jso.21141.

    Article  CAS  PubMed  Google Scholar 

  9. Blechacz B, Komuta M, Roskams T, Gores GJ. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2011;8(9):512–22. doi:10.1038/nrgastro.2011.131.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Randi G, Malvezzi M, Levi F, Ferlay J, Negri E, Franceschi S, et al. Epidemiology of biliary tract cancers: an update. Annals of oncology: official journal of the European Society for Medical Oncology. 2009;20(1):146–59. doi:10.1093/annonc/mdn533.

    Article  CAS  Google Scholar 

  11. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–45. doi:10.1016/S0140-6736(00)04046-0.

    Article  CAS  PubMed  Google Scholar 

  12. El-Serag HB, Engels EA, Landgren O, Chiao E, Henderson L, Amaratunge HC, et al. Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: a population-based study of U.S. veterans. Hepatology. 2009;49(1):116–23. doi:10.1002/hep.22606.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer. 2004;4(9):695–706. doi:10.1038/nrc1429.

    Article  CAS  PubMed  Google Scholar 

  14. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99–109. doi:10.2147/CLEP.S37357.

    PubMed  PubMed Central  Google Scholar 

  15. Augustine MM, Fong Y. Epidemiology and risk factors of biliary tract and primary liver tumors. Surg Oncol Clin N Am. 2014;23(2):171–88. doi:10.1016/j.soc.2013.10.001.

    Article  PubMed  Google Scholar 

  16. Kabbach G, Assi HA, Bolotin G, Schuster M, Lee HJ, Tadros M. Hepatobiliary tumors: update on diagnosis and management. J Clin Transl Hepatol. 2015;3(3):169–81. doi:10.14218/JCTH.2015.00012.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. Journal of immunology research. 2014;2014:149185. doi:10.1155/2014/149185.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Nakakubo Y, Miyamoto M, Cho Y, Hida Y, Oshikiri T, Suzuoki M, et al. Clinical significance of immune cell infiltration within gallbladder cancer. Br J Cancer. 2003;89(9):1736–42. doi:10.1038/sj.bjc.6601331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. • Goeppert B, Frauenschuh L, Zucknick M, Stenzinger A, Andrulis M, Klauschen F, et al. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer. 2013;109(10):2665–74. doi:10.1038/bjc.2013.610. This paper characterizes the immune response in cholangiocarcinogenesis and identifies inflammatory cell types that influence the outcome of BTC patients

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4(1):71–8. doi:10.1038/nrc1256.

    Article  CAS  PubMed  Google Scholar 

  21. McNamara MG, Templeton AJ, Maganti M, Walter T, Horgan AM, McKeever L, et al. Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer. Eur J Cancer. 2014;50(9):1581–9. doi:10.1016/j.ejca.2014.02.015.

    Article  CAS  PubMed  Google Scholar 

  22. Lin G, Liu Y, Li S, Mao Y, Wang J, Shuang Z, et al. Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma. Oncotarget. 2016; doi:10.18632/oncotarget.7680.

  23. Dunne RF, Findeis-Hosey J, Bratton L, Figueroa N, Belt B, McMahon L et al. Association of FoxP3 expression with worse outcomes in cholangiocarcinoma: evidence to support the use of immunotherapy. J Clin Oncol. 2016;34(suppl; abstr e15631).

  24. Wada S. Clinicopathological implications of newly defined immune checkpoints in extra-hepatic cholangiocarcinoma. J Clin Oncol. 2015;33(suppl; abstr e15151).

  25. Takagi S, Miyagawa S, Ichikawa E, Soeda J, Miwa S, Miyagawa Y, et al. Dendritic cells, T-cell infiltration, and Grp94 expression in cholangiocellular carcinoma. Hum Pathol. 2004;35(7):881–6.

    Article  CAS  PubMed  Google Scholar 

  26. Wang Y, Ding M, Zhang Q, Wang J, Yang X, Zhou F, et al. Activation or suppression of the immune response mediators in biliary tract cancer (BTC) patients: a systematic review and meta-analysis. J Cancer. 2017;8(1):74–84. doi:10.7150/jca.16774.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267–96. doi:10.1146/annurev.immunol.25.022106.141609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Marks EI, Yee NS. Immunotherapeutic approaches in biliary tract carcinoma: current status and emerging strategies. World J Gastrointest Oncol. 2015;7(11):338–46. doi:10.4251/wjgo.v7.i11.338.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dong H, Chen L. B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med. 2003;81(5):281–7. doi:10.1007/s00109-003-0430-2.

    Article  CAS  PubMed  Google Scholar 

  30. Ye Y, Zhou L, Xie X, Jiang G, Xie H, Zheng S. Interaction of B7-H1 on intrahepatic cholangiocarcinoma cells with PD-1 on tumor-infiltrating T cells as a mechanism of immune evasion. J Surg Oncol. 2009;100(6):500–4. doi:10.1002/jso.21376.

    Article  PubMed  Google Scholar 

  31. Mody K, Feldman R, Reddy SK, Reynolds GA, McMillan JM, Johnson E. PD-1/PD-L1 expression and molecular associations in HPB malignancies. J Clin Oncol. 2016;34(suppl 4S; abstr 289).

  32. Suleiman Y, Coppola D, Zibadi S, Dalia S, Juan T, Lee JK et al. Prognostic value of tumor-infiltrating lymphocytes (TILs) and expression of PD-L1 in cholangiocarcinoma. J Clin Oncol. 2015;33(suppl 3; abstr 294).

  33. Gani F, Nagarajan N, Kim Y, Zhu Q, Luan L, Bhaijjee F, et al. Program death 1 immune checkpoint and tumor microenvironment: implications for patients with intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2016;23(8):2610–7. doi:10.1245/s10434-016-5101-y.

    Article  PubMed  Google Scholar 

  34. Sabbatino F, Villani V, Yearley JH, Deshpande V, Cai L, Konstantinidis IT, et al. PD-L1 and HLA class I antigen expression and clinical course of the disease in intrahepatic cholangiocarcinoma. Clin Cancer Res. 2016;22(2):470–8. doi:10.1158/1078-0432.CCR-15-0715.

    Article  CAS  PubMed  Google Scholar 

  35. Lim YJ, Koh J, Kim K, Chie EK, Kim B, Lee KB, et al. High ratio of programmed cell death protein 1 (PD-1)(+)/CD8(+) tumor-infiltrating lymphocytes identifies a poor prognostic subset of extrahepatic bile duct cancer undergoing surgery plus adjuvant chemoradiotherapy. Radiother Oncol. 2015;117(1):165–70. doi:10.1016/j.radonc.2015.07.003.

    Article  CAS  PubMed  Google Scholar 

  36. Ha H, Nam AR, Bang JH, Park JE, Kim TY, Lee KH, et al. Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy. Oncotarget. 2016; doi:10.18632/oncotarget.12810.

  37. Blechacz BR, Gores GJ. Cholangiocarcinoma. Clin Liver Dis. 2008;12(1):131–150, ix. doi:10.1016/j.cld.2007.11.003.

    Article  PubMed  Google Scholar 

  38. Todoroki T. Chemotherapy for bile duct carcinoma in the light of adjuvant chemotherapy to surgery. Hepato-Gastroenterology. 2000;47(33):644–9.

    CAS  PubMed  Google Scholar 

  39. Oh D, Lim DH, Heo JS, Choi SH, Choi DW, Ahn YC, et al. The role of adjuvant radiotherapy in microscopic tumor control after extrahepatic bile duct cancer surgery. Am J Clin Oncol. 2007;30(1):21–5. doi:10.1097/01.coc.0000245467.97180.78.

    Article  PubMed  Google Scholar 

  40. Pitt HA, Nakeeb A, Abrams RA, Coleman J, Piantadosi S, Yeo CJ, et al. Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg. 1995;221(6):788–97. discussion 97-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cheng Q, Luo X, Zhang B, Jiang X, Yi B, Wu M. Predictive factors for prognosis of hilar cholangiocarcinoma: postresection radiotherapy improves survival. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2007;33(2):202–7. doi:10.1016/j.ejso.2006.09.033.

    Article  CAS  Google Scholar 

  42. •• Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2012;30(16):1934–40. doi:10.1200/JCO.2011.40.5381. This is a systematic review and meta-analysis to determine the impact of adjuvant therapy on survival

    Article  Google Scholar 

  43. Bonet Beltran M, Allal AS, Gich I, Sole JM, Carrio I. Is adjuvant radiotherapy needed after curative resection of extrahepatic biliary tract cancers? A systematic review with a meta-analysis of observational studies. Cancer Treat Rev. 2012;38(2):111–9. doi:10.1016/j.ctrv.2011.05.003.

    Article  PubMed  Google Scholar 

  44. Mantripragada KC, Hamid F, Shafqat H, Olszewski AJ. Adjuvant therapy for resected gallbladder cancer: analysis of the National Cancer Database. J Natl Cancer Inst. 2017;109(2). doi:10.1093/jnci/djw202.

  45. Hezel AF, Zhu AX. Systemic therapy for biliary tract cancers. Oncologist. 2008;13(4):415–23. doi:10.1634/theoncologist.2007-0252.

    Article  CAS  PubMed  Google Scholar 

  46. •• Glimelius B, Hoffman K, Sjoden PO, Jacobsson G, Sellstrom H, Enander LK, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Annals of oncology : official journal of the European Society for Medical Oncology. 1996;7(6):593–600. This study showed that chemotherapy can add to both quantity and quality of life in advanced pancreatic and biliary cancer

    Article  CAS  Google Scholar 

  47. •• Valle JW, Wasan H, Johnson P, Jones E, Dixon L, Swindell R, et al. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - the UK ABC-01 study. Br J Cancer. 2009;101(4):621–7. doi:10.1038/sj.bjc.6605211. This phase II study helped established the standard of chemotherapy and found that gemcitabine and cisplatin in combination was associated with an improved tumor control rate, time to progression and 6-month progression free survival

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. •• Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–81. doi:10.1056/NEJMoa0908721. This was the phase III study that showed that the combination of gemciatbine and cisplatin was associated with a significant survival advantage

    Article  CAS  PubMed  Google Scholar 

  49. Yang R, Wang B, Chen YJ, Li HB, Hu JB, Zou SQ. Efficacy of gemcitabine plus platinum agents for biliary tract cancers: a meta-analysis. Anti-Cancer Drugs. 2013;24(8):871–7. doi:10.1097/CAD.0b013e3283637292.

    Article  CAS  PubMed  Google Scholar 

  50. Jain A, Kwong LN, Javle M. Genomic profiling of biliary tract cancers and implications for clinical practice. Curr Treat Options in Oncol. 2016;17(11):58. doi:10.1007/s11864-016-0432-2.

    Article  Google Scholar 

  51. • Chan-On W, Nairismagi ML, Ong CK, Lim WK, Dima S, Pairojkul C, et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet. 2013;45(12):1474–8. doi:10.1038/ng.2806. This study of exome sequencing in BTCs indicates that different causative etiologies may induce distinct somatic alterations, even within the same tumor type

    Article  CAS  PubMed  Google Scholar 

  52. Jang S, Chun SM, Hong SM, Sung CO, Park H, Kang HJ, et al. High throughput molecular profiling reveals differential mutation patterns in intrahepatic cholangiocarcinomas arising in chronic advanced liver diseases. Mod Pathol. 2014;27(5):731–9. doi:10.1038/modpathol.2013.194.

    Article  CAS  PubMed  Google Scholar 

  53. Ross JS, Wang K, Virgil D, Catenacci T, Chmielecki J, Ali SM et al. Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and genomic alterations. J Clin Oncol. 2015;33(suppl 3; abstr 231).

  54. Merla A, Liu KG, Rajdev L. Targeted therapy in biliary tract cancers. Curr Treat Options in Oncol. 2015;16(10):48. doi:10.1007/s11864-015-0366-0.

    Article  Google Scholar 

  55. Pignochino Y, Sarotto I, Peraldo-Neia C, Penachioni JY, Cavalloni G, Migliardi G, et al. Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas. BMC Cancer. 2010;10:631. doi:10.1186/1471-2407-10-631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase II study of erlotinib in patients with advanced biliary cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24(19):3069–74. doi:10.1200/JCO.2005.05.3579.

    Article  CAS  Google Scholar 

  57. • Lee J, Park SH, Chang HM, Kim JS, Choi HJ, Lee MA, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. The Lancet Oncology. 2012;13(2):181–8. doi:10.1016/S1470-2045(11)70301-1. This study showed that although no significant difference in progression-free survival was noted between groups, the addition of erlotinib to gemcitabine and oxaliplatin showed antitumour activity and might be a treatment option for patients with cholangiocarcinoma

    Article  CAS  PubMed  Google Scholar 

  58. Leone F, Marino D, Cereda S, Filippi R, Belli C, Spadi R, et al. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial (Vecti-BIL study). Cancer. 2016;122(4):574–81. doi:10.1002/cncr.29778.

    Article  CAS  PubMed  Google Scholar 

  59. Malka D, Cervera P, Foulon S, Trarbach T, de la Fouchardiere C, Boucher E, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. The Lancet Oncology. 2014;15(8):819–28. doi:10.1016/S1470-2045(14)70212-8.

    Article  CAS  PubMed  Google Scholar 

  60. Gruenberger B, Schueller J, Heubrandtner U, Wrba F, Tamandl D, Kaczirek K, et al. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. The Lancet Oncology. 2010;11(12):1142–8. doi:10.1016/S1470-2045(10)70247-3.

    Article  CAS  PubMed  Google Scholar 

  61. Chen JS, Hsu C, Chiang NJ, Tsai CS, Tsou HH, Huang SF, et al. A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer. Annals of oncology : official journal of the European Society for Medical Oncology. 2015;26(5):943–9. doi:10.1093/annonc/mdv035.

    Article  CAS  Google Scholar 

  62. Hezel AF, Noel MS, Allen JN, Abrams TA, Yurgelun M, Faris JE, et al. Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer. Br J Cancer. 2014;111(3):430–6. doi:10.1038/bjc.2014.343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Jensen LH, Lindebjerg J, Ploen J, Hansen TF, Jakobsen A. Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer. Annals of oncology: official journal of the European Society for Medical Oncology. 2012;23(9):2341–6. doi:10.1093/annonc/mds008.

    Article  CAS  Google Scholar 

  64. Sohal DP, Mykulowycz K, Uehara T, Teitelbaum UR, Damjanov N, Giantonio BJ, et al. A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma. Annals of oncology : official journal of the European Society for Medical Oncology. 2013;24(12):3061–5. doi:10.1093/annonc/mdt416.

    Article  CAS  Google Scholar 

  65. Czink E, Heining C, Weber TF, Lasitschka F, Schemmer P, Schirmacher P, et al. Durable remission under dual HER2 blockade with Trastuzumab and Pertuzumab in a patient with metastatic gallbladder cancer. Z Gastroenterol. 2016;54(5):426–30. doi:10.1055/s-0042-103498.

    Article  CAS  PubMed  Google Scholar 

  66. Nam AR, Kim JW, Cha Y, Ha H, Park JE, Bang JH, et al. Therapeutic implication of HER2 in advanced biliary tract cancer. Oncotarget. 2016; doi:10.18632/oncotarget.11157.

  67. Guion-Dusserre JF, Lorgis V, Vincent J, Bengrine L, Ghiringhelli F. FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma. World J Gastroenterol. 2015;21(7):2096–101. doi:10.3748/wjg.v21.i7.2096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, et al. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(21):3491–7. doi:10.1200/JCO.2010.28.4075.

    Article  CAS  Google Scholar 

  69. Valle JW, Wasan H, Lopes A, Backen AC, Palmer DH, Morris K, et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial. The Lancet Oncology. 2015;16(8):967–78. doi:10.1016/S1470-2045(15)00139-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Buzzoni R, Pusceddu S, Bajetta E, De Braud F, Platania M, Iannacone C, et al. Activity and safety of RAD001 (everolimus) in patients affected by biliary tract cancer progressing after prior chemotherapy: a phase II ITMO study. Annals of oncology: official journal of the European Society for Medical Oncology. 2014;25(8):1597–603. doi:10.1093/annonc/mdu175.

    Article  CAS  Google Scholar 

  71. Yeung YH, Chionh FJM, Price TJ, Scott AM, Tran H, Fang G et al. Phase II study of everolimus monotherapy as first-line treatment in advanced biliary tract cancer: RADichol. J Clin Oncol. 2014;32(suppl 5s; abstr 4101).

  72. Javle MM, Shroff RT, Zhu A, Sadeghi S, Choo S, Borad MJ et al. A phase 2 study of BGJ398 in patients (pts) with advanced or metastatic FGFR-altered cholangiocarcinoma (CCA) who failed or are intolerant to platinum-based chemotherapy. J Clin Oncol. 2016;34(suppl 4S; abstr 335).

  73. Burris H, Mellinghoff I, Maher E, Wen P, Beeram M, Touat M et al. The first reported results of AG-120, a first-in-class, potent inhibitor of the IDH1 mutant protein, in a Phase I study of patients with advanced IDH1-mutant solid tumors, including gliomas. Mol Cancer Ther. 2015;14(12 Suppl 2):Abstract nr PL04–05).

  74. Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, Kauh JS, et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(17):2357–63. doi:10.1200/JCO.2010.33.9473.

    Article  CAS  Google Scholar 

  75. Furuse J, Nagashima F. Inhibitor of MEK1/2, selumetinib, for biliary tract cancer. Expert Rev Gastroenterol Hepatol. 2011;5(5):579–81. doi:10.1586/egh.11.58.

    Article  CAS  PubMed  Google Scholar 

  76. Santoro A, Gebbia V, Pressiani T, Testa A, Personeni N, Arrivas Bajardi E, et al. A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study. Annals of oncology : official journal of the European Society for Medical Oncology. 2015;26(3):542–7. doi:10.1093/annonc/mdu576.

    Article  CAS  Google Scholar 

  77. Moehler M, Maderer A, Schimanski C, Kanzler S, Denzer U, Kolligs FT, et al. Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme. Eur J Cancer. 2014;50(18):3125–35. doi:10.1016/j.ejca.2014.09.013.

    Article  CAS  PubMed  Google Scholar 

  78. Pauff JM, Goff LW. Current progress in immunotherapy for the treatment of biliary cancers. J Gastrointest Cancer. 2016; doi:10.1007/s12029-016-9867-8.

  79. Kaida M, Morita-Hoshi Y, Soeda A, Wakeda T, Yamaki Y, Kojima Y, et al. Phase 1 trial of Wilms tumor 1 (WT1) peptide vaccine and gemcitabine combination therapy in patients with advanced pancreatic or biliary tract cancer. J Immunother. 2011;34(1):92–9. doi:10.1097/CJI.0b013e3181fb65b9.

    Article  CAS  PubMed  Google Scholar 

  80. Yamamoto K, Ueno T, Kawaoka T, Hazama S, Fukui M, Suehiro Y, et al. MUC1 peptide vaccination in patients with advanced pancreas or biliary tract cancer. Anticancer Res. 2005;25(5):3575–9.

    CAS  PubMed  Google Scholar 

  81. Yoshitomi M, Yutani S, Matsueda S, Ioji T, Komatsu N, Shichijo S, et al. Personalized peptide vaccination for advanced biliary tract cancer: IL-6, nutritional status and pre-existing antigen-specific immunity as possible biomarkers for patient prognosis. Exp Ther Med. 2012;3(3):463–9. doi:10.3892/etm.2011.424.

    Article  CAS  PubMed  Google Scholar 

  82. Aruga A, Takeshita N, Kotera Y, Okuyama R, Matsushita N, Ohta T, et al. Long-term vaccination with multiple peptides derived from cancer-testis antigens can maintain a specific T-cell response and achieve disease stability in advanced biliary tract cancer. Clin Cancer Res. 2013;19(8):2224–31. doi:10.1158/1078-0432.CCR-12-3592.

    Article  CAS  PubMed  Google Scholar 

  83. Aruga A, Takeshita N, Kotera Y, Okuyama R, Matsushita N, Ohta T, et al. Phase I clinical trial of multiple-peptide vaccination for patients with advanced biliary tract cancer. J Transl Med. 2014;12:61. doi:10.1186/1479-5876-12-61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Lepisto AJ, Moser AJ, Zeh H, Lee K, Bartlett D, McKolanis JR, et al. A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther. 2008;6(B):955–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Shimizu K, Kotera Y, Aruga A, Takeshita N, Takasaki K, Yamamoto M. Clinical utilization of postoperative dendritic cell vaccine plus activated T-cell transfer in patients with intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2012;19(2):171–8. doi:10.1007/s00534-011-0437-y.

    Article  PubMed  Google Scholar 

  86. Nakatsuka S, Oji Y, Horiuchi T, Kanda T, Kitagawa M, Takeuchi T, et al. Immunohistochemical detection of WT1 protein in a variety of cancer cells. Mod Pathol. 2006;19(6):804–14. doi:10.1038/modpathol.3800588.

    CAS  PubMed  Google Scholar 

  87. Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004;4(1):45–60. doi:10.1038/nrc1251.

    Article  CAS  PubMed  Google Scholar 

  88. Park SY, Roh SJ, Kim YN, Kim SZ, Park HS, Jang KY, et al. Expression of MUC1, MUC2, MUC5AC and MUC6 in cholangiocarcinoma: prognostic impact. Oncol Rep. 2009;22(3):649–57.

    CAS  PubMed  Google Scholar 

  89. Boonla C, Sripa B, Thuwajit P, Cha-On U, Puapairoj A, Miwa M, et al. MUC1 and MUC5AC mucin expression in liver fluke-associated intrahepatic cholangiocarcinoma. World J Gastroenterol. 2005;11(32):4939–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Matsumura N, Yamamoto M, Aruga A, Takasaki K, Nakano M. Correlation between expression of MUC1 core protein and outcome after surgery in mass-forming intrahepatic cholangiocarcinoma. Cancer. 2002;94(6):1770–6.

    Article  PubMed  Google Scholar 

  91. Higashi M, Yonezawa S, Ho JJ, Tanaka S, Irimura T, Kim YS, et al. Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: its relationship with a new morphological classification of cholangiocarcinoma. Hepatology. 1999;30(6):1347–55. doi:10.1002/hep.510300609.

    Article  CAS  PubMed  Google Scholar 

  92. Mall AS, Tyler MG, Ho SB, Krige JE, Kahn D, Spearman W, et al. The expression of MUC mucin in cholangiocarcinoma. Pathol Res Pract. 2010;206(12):805–9. doi:10.1016/j.prp.2010.08.004.

    Article  CAS  PubMed  Google Scholar 

  93. Koido S, Kan S, Yoshida K, Yoshizaki S, Takakura K, Namiki Y, et al. Immunogenic modulation of cholangiocarcinoma cells by chemoimmunotherapy. Anticancer Res. 2014;34(11):6353–61.

    CAS  PubMed  Google Scholar 

  94. Itoh K, Yamada A. Personalized peptide vaccines: a new therapeutic modality for cancer. Cancer Sci. 2006;97(10):970–6. doi:10.1111/j.1349-7006.2006.00272.x.

    Article  CAS  PubMed  Google Scholar 

  95. Noguchi M, Sasada T, Itoh K. Personalized peptide vaccination: a new approach for advanced cancer as therapeutic cancer vaccine. Cancer Immunol Immunother. 2013;62(5):919–29. doi:10.1007/s00262-012-1379-1.

    Article  CAS  PubMed  Google Scholar 

  96. Kobayashi M, Sakabe T, Abe H, Tanii M, Takahashi H, Chiba A, et al. Dendritic cell-based immunotherapy targeting synthesized peptides for advanced biliary tract cancer. J Gastrointest Surg. 2013;17(9):1609–17. doi:10.1007/s11605-013-2286-2.

    Article  PubMed  Google Scholar 

  97. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344(6184):641–5. doi:10.1126/science.1251102.

    Article  CAS  PubMed  Google Scholar 

  98. Higuchi R, Yamamoto M, Hatori T, Shimizu K, Imai K, Takasaki K. Intrahepatic cholangiocarcinoma with lymph node metastasis successfully treated by immunotherapy with CD3-activated T cells and dendritic cells after surgery: report of a case. Surg Today. 2006;36(6):559–62. doi:10.1007/s00595-006-3201-1.

    Article  PubMed  Google Scholar 

  99. Khan JA, Yaqin S. Successful immunological treatment of gallbladder cancer in India—case report. J Zhejiang Univ Sci B. 2006;7(9):719–24. doi:10.1631/jzus.2006.B0719.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Kan N, Yoshikawa K, Matsushita N, Fujii T. The case of a patient with peritoneal metastasis from cholangiocarcinoma who responded to adoptive immunotherapy and cetuximab. Gan To Kagaku Ryoho. 2013;40(12):1759–61.

    PubMed  Google Scholar 

  101. Recchia F, Sica G, Candeloro G, Bisegna R, Bratta M, Bonfili P, et al. Chemoradioimmunotherapy in locally advanced pancreatic and biliary tree adenocarcinoma: a multicenter phase II study. Pancreas. 2009;38(6):e163–8. doi:10.1097/MPA.0b013e3181abe222.

    Article  CAS  PubMed  Google Scholar 

  102. Seto K, Shoda J, Horibe T, Warabi E, Kohno M, Yanagawa T, et al. Targeting interleukin-4 receptor alpha by hybrid peptide for novel biliary tract cancer therapy. Int J Hepatol. 2014;2014:584650. doi:10.1155/2014/584650.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Janakiram M, Shah UA, Liu W, Zhao A, Schoenberg MP, Zang X. The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3. Immunol Rev. 2017;276(1):26–39. doi:10.1111/imr.12521.

    Article  CAS  PubMed  Google Scholar 

  104. Janakiram M, Pareek V, Cheng H, Narasimhulu DM, Zang X. Immune checkpoint blockade in human cancer therapy: lung cancer and hematologic malignancies. Immunotherapy. 2016;8(7):809–19. doi:10.2217/imt-2016-0001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Chinai JM, Janakiram M, Chen F, Chen W, Kaplan M, Zang X. New immunotherapies targeting the PD-1 pathway. Trends Pharmacol Sci. 2015;36(9):587–95. doi:10.1016/j.tips.2015.06.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Assal A, Kaner J, Pendurti G, Zang X. Emerging targets in cancer immunotherapy: beyond CTLA-4 and PD-1. Immunotherapy. 2015;7(11):1169–86. doi:10.2217/imt.15.78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced Nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39. doi:10.1056/NEJMoa1507643.

    Article  CAS  PubMed  Google Scholar 

  108. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35. doi:10.1056/NEJMoa1504627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13. doi:10.1056/NEJMoa1510665.

    Article  CAS  PubMed  Google Scholar 

  110. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17. doi:10.1056/NEJMoa1414428.

    Article  PubMed  Google Scholar 

  111. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9. doi:10.1056/NEJMoa1411087.

    Article  PubMed  CAS  Google Scholar 

  112. 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. The Lancet Oncology. 2016; doi:10.1016/S1470-2045(16)30496-X.

  113. Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(25):2980–7. doi:10.1200/JCO.2016.66.9929.

    Article  CAS  Google Scholar 

  114. Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(25):2969–79. doi:10.1200/JCO.2016.66.9861.

    Article  Google Scholar 

  115. Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 2016;22(4):813–20. doi:10.1158/1078-0432.CCR-15-1678.

    Article  CAS  PubMed  Google Scholar 

  116. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20. doi:10.1056/NEJMoa1500596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Le DT, Uram JN, Wang H, Kemberling H, Eyring A, Bartlett B et al. PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers. J Clin Oncol. 2016;34(suppl 4S; abstr 195).

  118. Bang YJ, Doi T, Braud FD, Piha-Paul S, Hollebecque A, Razak ARA et al. Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: Interim results of KEYNOTE-028. 2015;51(Supplement 3):S112.

  119. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837–46. doi:10.1016/S0140-6736(16)00587-0.

    Article  CAS  PubMed  Google Scholar 

  120. 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: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20. doi:10.1016/S0140-6736(16)00561-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. • Duffy AG, Makarova-Rusher OV, Pratt D, Kleiner DE, Ulahannan S et al. Tremelimumab: a monoclonal antibody against CTLA-4—In combination with subtotal ablation (trans catheter arterial chemoembolization (TACE), radiofrequency ablation (RFA) or cryoablation) in patients with hepatocellular carcinoma (HCC) and biliary tract carcinoma (BTC). J Clin Oncol. 2016;34(suppl; abstr 4073). Tremelimumab in combination with subtotal TACE, RFA or CA in patients with advanced HCC and BTC is safe and feasible.

  122. Liu WM, Fowler DW, Smith P, Dalgleish AG. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer. 2010;102(1):115–23. doi:10.1038/sj.bjc.6605465.

    Article  CAS  PubMed  Google Scholar 

  123. Lesterhuis WJ, Punt CJ, Hato SV, Eleveld-Trancikova D, Jansen BJ, Nierkens S, et al. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest. 2011;121(8):3100–8. doi:10.1172/JCI43656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Lakshmi Rajdev MD.

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Urvi A. Shah, Amara G. Nandikolla, and Lakshmi Rajdev declare they have no conflict of interest.

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Shah, U.A., Nandikolla, A.G. & Rajdev, L. Immunotherapeutic Approaches to Biliary Cancer. Curr. Treat. Options in Oncol. 18, 44 (2017). https://doi.org/10.1007/s11864-017-0486-9

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