Journal of Gastrointestinal Cancer

, Volume 47, Issue 4, pp 351–357 | Cite as

Current Progress in Immunotherapy for the Treatment of Biliary Cancers

Review Article



Biliary tract cancers (BTC) remain one of the poorest groups of malignancies in terms of long-term survival, with only limited success in improvements by the use of systemic chemotherapy and our current repertoire of molecularly targeted therapies. Treatments that aim to adapt the patient’s own immune system to target cancer cell have shown tremendous promise in treating solid tumors such as melanoma and non-small cell lung cancer, and there are many recently completed and ongoing studies looking to move immunotherapy into the treatment of BTC. We review here both preclinical and early clinical studies of immune therapies for BTC, including autologous cell transfer, vaccinations, and immunomodulatory approaches (e.g., immune checkpoint inhibitors).


Published abstracts and articles from peer-reviewed journals as well as ongoing trial information were obtained from PubMed, Google Scholar, and


The use of immune-mediated or immunomodulatory therapies in BTC are supported by observations that many chronic inflammatory states are associated with their development. Although success in treating BTC by the active manipulation of the immune system has been limited to date, we note many recent and ongoing areas of preclinical and clinical investigation that may translate to further clinical trials.


As we continue to follow subgroup analyses and results from specific studies that include BTC patients, we will hopefully be able to combine these with focused preclinical investigations providing further rationale for future trial success in treating BTC.


Biliary tract cancer Immune therapy Immunotherapy Solid tumor Checkpoint inhibitor 


  1. 1.
    Kabbach G, Assi HA, Bolotin G, Schuster M, Lee HJ, Tadros M (2015) Hepatobiliary tumors: update on diagnosis and management. J Clin Transl Hepatol 3(3):169–81. doi: 10.14218Google Scholar
  2. 2.
    Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet. 2014;383(9935):2168–79. doi:10.1016/S0140-6736(13)61903-0.
  3. 3.
    Misra S, Chaturvedi A, Misra NC, Sharma ID. Carcinoma of the gallbladder. Lancet Oncol. 2003;4(3):167–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Schweitzer N, Vogel A. Systemic therapy of cholangiocarcinoma: from chemotherapy to targeted therapies. Best Pract Res Clin Gastroenterol. 2015;29(2):345–53. doi:10.1016/j.bpg.2015.01.002.
  5. 5.
    Andersen JB, Thorgeirsson SS. A perspective on molecular therapy in cholangiocarcinoma: present status and future directions. Hepat Oncol. 2014;1(1):143–57.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Malka D, Cervera P, Foulon S, Trarbach T, de la Fouchardière C, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15(8):819–28. doi:10.1016/S1470-2045(14)70212-8.
  7. 7.
    Leone F, Marino D, Cereda S, Filippi R, Belli C, 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. 2015. doi:10.1002/cncr.29778.
  8. 8.
    Javle M, Churi C, Kang HC, Shroff R, Janku F, et al. HER2/neu-directed therapy for biliary tract cancer. J Hematol Oncol. 2015:8–58. doi:10.1186/s13045-015-0155-z.
  9. 9.
    Valle JW, Wasan H, Lopes A, Backen AC, Palmer DH, 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. Lancet Oncol. 2015;16(8):967–78. doi:10.1016/S1470-2045(15)00139-4.
  10. 10.
    Mahipal A, Shibata D, Siegel E, Springett G, Almhanna K, et al. Phase I trial of combination of FOLFIRI and pasireotide, a somatostatin analogue, in advanced gastrointestinal malignancies. Investig New Drugs. 2015;33(5):1093–9. doi:10.1007/s10637-015-0277-8.
  11. 11.
    Bekaii ST, Phelps MA, Li X, Saji M, Goff L, et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol. 2011;29(17):2357–63. doi:10.1200/JCO.2010.33.9473.
  12. 12.
    Santoro A, Gebbia V, Pressiani T, Testa A, Personeni N, 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. Ann Oncol. 2015;26(3):542–7. doi:10.1093/annonc/mdu576.
  13. 13.
    Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815–22.CrossRefPubMedGoogle Scholar
  14. 14.
    Dougan M, Dranoff G. Immune therapy for cancer. Annu Rev Immunol. 2009;27:83–117. doi:10.1146/annurev.immunol.021908.132544.
  15. 15.
    Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33. doi:10.1056/NEJMoa1103849.
  16. 16.
    El-Serag HB, Engels EA, Landgren O, Chiao E, Henderson L, 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.
  17. 17.
    Goeppert B, Frauenschuh L, Zucknick M, Stenzinger A, Andrulis M, 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.
  18. 18.
    Nakakubo Y, Miyamoto M, Cho Y, Hida Y, Oshikiri T, et al. Clinical significance of immune cell infiltration within gallbladder cancer. Br J Cancer. 2003;89(9):1736–42.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Oshikiri T, Miyamoto M, Shichinohe T, Suzuoki M, Hiraoka K, et al. Prognostic value of intratumoral CD8+ T lymphocyte in extrahepatic bile duct carcinoma as essential immune response. J Surg Oncol. 2003;84(4):224–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.CrossRefPubMedGoogle Scholar
  21. 21.
    Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, et al. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas. 2004;28(1):e26–31.CrossRefPubMedGoogle Scholar
  22. 22.
    Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, et al. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009;15(17):5323–37. doi:10.1158/1078-0432.CCR-09-0737.
  23. 23.
    Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704–15. doi:10.1056/NEJMra072739.
  24. 24.
    Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480–9. doi:10.1038/nature10673.
  25. 25.
    Aruga A, Takeshita N, Kotera Y, Okuyama R, Matsushita N, 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.
  26. 26.
    Nakatsuka S, Oji Y, Horiuchi T, Kanda T, Kitagawa M, et al. Immunohistochemical detection of WT1 protein in a variety of cancer cells. Mod Pathol. 2006;19(6):804–14.PubMedGoogle Scholar
  27. 27.
    Ghosh M, Kamma H, Kawamoto T, Koike N, Miwa M, et al. MUC 1 core protein as a marker of gallbladder malignancy. Eur J Surg Oncol. 2005;31(8):891–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Kobayashi M, Sakabe T, Abe H, Tanii M, Takahashi H, 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.
  29. 29.
    Kaida M, Morita-Hoshi Y, Soeda A, Wakeda T, Yamaki 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.
  30. 30.
    Okusaka T, Ueno M, Sato T, Heike Y. Possibility of immunotherapy for biliary tract cancer: how do we prove efficacy? Introduction to a current ongoing phase I and randomized phase II study to evaluate the efficacy and safety of adding Wilms tumor 1 peptide vaccine to gemcitabine and cisplatin for the treatment of advanced biliary tract cancer (WT-BT trial). J Hepatobiliary Pancreat Sci. 2012;19(4):314–8. doi:10.1007/s00534-011-0495-1.
  31. 31.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22. doi:10.1056/NEJMoa1001294.
  32. 32.
    Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, 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.
  33. 33.
    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.
  34. 34.
    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8. doi:10.1126/science.aaa1348.
  35. 35.
    Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189–99. doi:10.1056/NEJMoa1406498.
  36. 36.
    Koido S, Kan S, Yoshida K, Yoshizaki S, Takakura K, et al. Immunogenic modulation of cholangiocarcinoma cells by chemoimmunotherapy. Anticancer Res. 2014;34(11):6353–61.PubMedGoogle Scholar
  37. 37.
    Oikawa T, Takahashi H, Ishikawa T, Hokari A, Otsuki N, et al. Intrahepatic expression of the co-stimulatory molecules programmed death-1, and its ligands in autoimmune liver disease. Pathol Int. 2007;57(8):485–92.CrossRefPubMedGoogle Scholar
  38. 38.
    Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003–10. doi:10.1038/ng.3375.
  39. 39.
    Sabbatino F, Villani V, Yearley JH, Deshpande V, Cai L, 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.
  40. 40.
    Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346–57.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8(4):299–308. doi:10.1038/nrc2355.
  42. 42.
    Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313(23):1485–92.CrossRefPubMedGoogle Scholar
  43. 43.
    Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, 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.
  44. 44.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. doi:10.1056/NEJMoa1003466.
  45. 45.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, et al. Combined nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. doi:10.1056/NEJMoa1504030.
  46. 46.
    Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 2015;14(8):561–84. doi:10.1038/nrd4591.
  47. 47.
    Cook AM, Lesterhuis WJ, Nowak AK, Lake RA. Chemotherapy and immunotherapy: mapping the road ahead. Opin ImmunolCurr. 2015;39:23–9. doi:10.1016/j.coi.2015.12.003.

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Internal Medicine, Division of Hematology and OncologyVanderbilt UniversityNashvilleUSA

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