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Immunotherapy for cholangiocarcinoma: a 2021 update

    Nikolaos Charalampakis

    *Author for correspondence:

    E-mail Address: nick301178@yahoo.com

    Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece

    ,
    Georgios Papageorgiou

    Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece

    ,
    Sergios Tsakatikas

    Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece

    ,
    Rodanthi Fioretzaki

    Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece

    ,
    Christo Kole

    First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece

    ,
    Stylianos Kykalos

    Second Propedeutic Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece

    ,
    Maria Tolia

    Department of Radiation Oncology, University Hospital of Crete, Voutes, 71110, Heraklion, Crete, Greece

    &
    Dimitrios Schizas

    First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece

    Published Online:https://doi.org/10.2217/imt-2021-0126

    Cholangiocarcinoma (CCA) is a rare malignancy with generally dismal prognosis. Immunotherapy has revolutionized the management of cancer patients during the last decade, offering durable responses with an acceptable safety profile, but there are still no significant advances regarding CCA. Novel immunotherapeutic methods, such as cancer vaccines, oncolytic viruses, adoptive cell therapy and combinations of immune checkpoint inhibitors with other agents are currently under investigation and may improve prognosis. Efforts to find robust biomarkers for response are also ongoing. In this review, we discuss the rationale for the use of immunotherapy in CCA and available clinical data. Ongoing trials will also be presented, as well as key findings from each study.

    References

    • 1. Kendall T, Verheij J, Gaudio E et al. Anatomical, histomorphological and molecular classification of cholangiocarcinoma. Liver Int. 39(Suppl. 1), 7–18 (2019).
    • 2. Louis C, Papoutsoglou P, Coulouarn C. Molecular classification of cholangiocarcinoma. Curr. Opin. Gastroenterol. 36(2), 57–62 (2020).
    • 3. Banales JM, Marin JJG, Lamarca A et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat. Rev. Gastroenterol. Hepatol. 17(9), 557–588 (2020).
    • 4. Jusakul A, Cutcutache I, Yong CH et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 7(10), 1116–1135 (2017).
    • 5. Silva VW, Askan G, Daniel TD et al. Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency. Chin. Clin. Oncol. 5(5), 62 (2016).
    • 6. Piha-Paul SA, Oh DY, Ueno M et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int. J. Cancer 147(8), 2190–2198 (2020).
    • 7. Weinberg BA, Xiu J, Lindberg MR et al. Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets. J. Gastrointest. Oncol. 10(4), 652–662 (2019).
    • 8. Fontugne J, Augustin J, Pujals A et al. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma. Oncotarget 8(15), 24644–24651 (2017).
    • 9. Gani F, Nagarajan N, Kim Y et al. Program death 1 immune checkpoint and tumor microenvironment: implications for patients with intrahepatic cholangiocarcinoma. Ann. Surg. Oncol. 23(8), 2610–2617 (2016).
    • 10. Rizzo A, Ricci AD, Brandi G. PD-L1, TMB, MSI, and other predictors of response to immune checkpoint inhibitors in biliary tract cancer. Cancers (Basel) 13(3), 558 (2021).
    • 11. Zhai L, Ladomersky E, Lenzen A et al. IDO1 in cancer: a Gemini of immune checkpoints. Cell. Mol. Immunol. 15(5), 447–457 (2018).
    • 12. Cousin S, Bellera CA, Guégan JP et al. Regomune: a Phase II study of regorafenib + avelumab in solid tumors — results of the biliary tract cancer (BTC) cohort. J. Clin. Oncol. 39(Suppl. 15), 4096–4096 (2021).
    • 13. Vogel A, Bathon M, Saborowski A. Immunotherapies in clinical development for biliary tract cancer. Expert Opin. Investig. Drugs 30(4), 351–363 (2021).
    • 14. Jenne CN, Kubes P. Immune surveillance by the liver. Nat. Immunol. 14(10), 996–1006 (2013).
    • 15. Buonaguro L, Mauriello A, Cavalluzzo B, Petrizzo A, Tagliamonte M. Immunotherapy in hepatocellular carcinoma. Ann. Hepatol. 18(2), 291–297 (2019).
    • 16. Kasper HU, Drebber U, Stippel DL, Dienes HP, Gillessen A. Liver tumor infiltrating lymphocytes: comparison of hepatocellular and cholangiolar carcinoma. World J. Gastroenterol. 15(40), 5053–5057 (2009).
    • 17. Loeuillard E, Conboy CB, Gores GJ, Rizvi S. Immunobiology of cholangiocarcinoma. JHEP Rep. 1(4), 297–311 (2019).
    • 18. Asahi Y, Hatanaka KC, Hatanaka Y et al. Prognostic impact of CD8+ T cell distribution and its association with the HLA class I expression in intrahepatic cholangiocarcinoma. Surg. Today 50(8), 931–940 (2020).
    • 19. Diederichsen AC, Hjelmborg J, Christensen PB, Zeuthen J, Fenger C. Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol. Immunother. 52(7), 423–428 (2003).
    • 20. Goeppert B, Frauenschuh L, Zucknick M et al. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br. J. Cancer 109(10), 2665–2674 (2013).
    • 21. Job S, Rapoud D, Dos Santos A et al. Identification of four immune subtypes characterized by distinct composition and functions of tumor microenvironment in intrahepatic cholangiocarcinoma. Hepatology 72(3), 965–981 (2020).
    • 22. Saeed A, Park R, Al-Jumayli M, Al-Rajabi R, Sun W. Biologics, immunotherapy, and future directions in the treatment of advanced cholangiocarcinoma. Clin. Colorectal Cancer 18(2), 81–90 (2019).
    • 23. Rizvi S, Borad MJ, Patel T, Gores GJ. Cholangiocarcinoma: molecular pathways and therapeutic opportunities. Semin. Liver Dis. 34(4), 456–464 (2014).
    • 24. Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site – when a biomarker defines the indication. N. Engl. J. Med. 377(15), 1409–1412 (2017).
    • 25. Le DT, Durham JN, Smith KN et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357(6349), 409–413 (2017).
    • 26. Lickliter JD, Gan HK, Voskoboynik M et al. A first-in-human dose finding study of camrelizumab in patients with advanced or metastatic cancer in Australia. Drug Des. Devel. Ther. 14, 1177–1189 (2020).
    • 27. Kim RD, Chung V, Alese OB et al. A Phase II multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol. 6(6), 888–894 (2020).
    • 28. Azad NS, Gray RJ, Overman MJ et al. Nivolumab is effective in mismatch repair-deficient noncolorectal cancers: results from arm Z1D-A subprotocol of the NCI-MATCH (EAY131) study. J. Clin. Oncol. 38(3), 214–222 (2020).
    • 29. Ueno M, Ikeda M, Morizane C et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, Phase I study. Lancet Gastroenterol. Hepatol. 4(8), 611–621 (2019).
    • 30. Yarchoan M, Cope L, Anders RA et al. Abstract CT043: a multicenter randomized Phase II trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): a NCI Experimental Therapeutics Clinical Trials Network (ETCTN) study. Cancer Res. 80(Suppl. 16), CT043–CT043 (2020).
    • 31. Ioka T, Ueno M, Oh D-Y et al. Evaluation of safety and tolerability of durvalumab (D) with or without tremelimumab (T) in patients (pts) with biliary tract cancer (BTC). J. Clin. Oncol. 37(Suppl. 4), 387–387 (2019).
    • 32. Xie C, Duffy AG, Mabry-Hrones D et al. Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer. Hepatology 69(5), 2048–2060 (2019).
    • 33. Feng K, Liu Y, Guo Y et al. Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers. Protein Cell. 9(10), 838–847 (2018).
    • 34. Qin S, Chen Z, Liu Y et al. A Phase II study of anti–PD-1 antibody camrelizumab plus FOLFOX4 or GEMOX systemic chemotherapy as first-line therapy for advanced hepatocellular carcinoma or biliary tract cancer. J. Clin. Oncol. 37(Suppl. 15), 4074–4074 (2019).
    • 35. Chen X, Wu X, Wu H et al. Camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary tract cancer: a single-arm, open-label, Phase II trial. J. Immunother. Cancer 8(2), e001240 (2020).
    • 36. Liu T, Li W, Yu Y et al. 53P Toripalimab with chemotherapy as first-line treatment for advanced biliary tract tumors: a preliminary analysis of safety and efficacy of an open-label Phase II clinical study. Ann. Oncol. 31, S261 (2020).
    • 37. Gou M, Liu Tie E, Yan H et al. PD-1 inhibitors plus nab-paclitaxel with S1 (AS) as first line in patients with advanced biliary tract cancer. J. Clin. Oncol. 38(Suppl. 15), e15195–e15195 (2020).
    • 38. Arkenau HT, Martin-Liberal J, Calvo E et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced or metastatic biliary tract cancer: nonrandomized, open-label, Phase I trial (JVDF). Oncologist 23(12), 1407–e1136 (2018).
    • 39. Zhou J, Fan J, Shi G et al. 56P Anti-PD1 antibody toripalimab, lenvatinib and gemox chemotherapy as first-line treatment of advanced and unresectable intrahepatic cholangiocarcinoma: A Phase II clinical trial. Ann. Oncol. 31, S262–S263 (2020).
    • 40. Yoo C, Oh DY, Choi HJ et al. Phase I study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1, in patients with pretreated biliary tract cancer. J. Immunother. Cancer 8(1), e000564 (2020).
    • 41. Aruga A, Takeshita N, Kotera Y, Okuyama R 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. 19(8), 2224–2231 (2013).
    • 42. Aruga A, Takeshita N, Kotera Y et al. Phase I clinical trial of multiple-peptide vaccination for patients with advanced biliary tract cancer. J. Transl. Med. 12, 61 (2014).
    • 43. Yutani S, Shirahama T, Muroya D et al. Feasibility study of personalized peptide vaccination for hepatocellular carcinoma patients refractory to locoregional therapies. Cancer Sci. 108(9), 1732–1738 (2017).
    • 44. Yoshitomi M, Yutani S, Matsueda 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. 3(3), 463–469 (2012).
    • 45. Lepisto AJ, Moser AJ, Zeh H 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. 6(B), 955–964 (2008).
    • 46. 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. 19(2), 171–178 (2012).
    • 47. Matsuyama M, Ishii H, Furuse J et al. Phase II trial of combination therapy of gemcitabine plus anti-angiogenic vaccination of elpamotide in patients with advanced or recurrent biliary tract cancer. Invest. New Drugs 33(2), 490–495 (2015).
    • 48. Kaida M, Morita-Hoshi Y, Soeda A et al. Phase I trial of Wilms tumor 1 (WT1) peptide vaccine and gemcitabine combination therapy in patients with advanced pancreatic or biliary tract cancer. J. Immunother. 34(1), 92–99 (2011).
    • 49. Guo Y, Feng K, Liu Y et al. Phase I study of chimeric antigen receptor-modified T cells in patients with EGFR-positive advanced biliary tract cancers. Clin. Cancer Res. 24(6), 1277–1286 (2018).
    • 50. Benson AB, D'Angelica MI, Abbott DE et al. Hepatobiliary cancers, version 2.2021, NCCN clinical practice guidelines in oncology. J. Natl Compr. Canc. Netw. 19(5), 541–565 (2021).
    • 51. Shen T, Zheng S, Geng L et al. Experience with anti-PD-1 antibody, camrelizumab, monotherapy for biliary tract cancer patients and literature review. Technol. Cancer Res. Treat. 19(1), doi: 10.1177/1533033820979703 (2020).
    • 52. Tan S, Liu K, Chai Y et al. Distinct PD-L1 binding characteristics of therapeutic monoclonal antibody durvalumab. Protein Cell. 9(1), 135–139 (2018).
    • 53. Yang H, Shen K, Zhu C, Li Q, Zhao Y, Ma X. Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Drug Des. Devel. Ther. 12, 2085–2096 (2018).
    • 54. Rizzo A, Ricci AD, Brandi G. Durvalumab: an investigational anti-PD-L1 antibody for the treatment of biliary tract cancer. Expert Opin. Investig. Drugs 30(4), 343–350 (2021).
    • 55. Shimomura A, Fujiwara Y, Kondo S et al. Tremelimumab-associated tumor regression following after initial progression: two case reports. Immunotherapy 8(1), 9–15 (2016).
    • 56. Liu Q, Sun Z, Chen L. Memory T cells: strategies for optimizing tumor immunotherapy. Protein Cell. 11(8), 549–564 (2020).
    • 57. Feng K, Liu Y, Zhao Y et al. Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a Phase II study. J. Immunother. Cancer 8(1), e000367 (2020).
    • 58. Sahai V, Griffith KA, Beg MS et al. A multicenter randomized Phase II study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line therapy for patients with advanced unresectable biliary tract cancer (BilT-01). J. Clin. Oncol. 38(Suppl. 15), 4582–4582 (2020).
    • 59. Oh D-Y, Lee K-H, Lee D-W et al. Phase II study assessing tolerability, efficacy, and biomarkers for durvalumab (D) ± tremelimumab (T) and gemcitabine/cisplatin (GemCis) in chemo-naïve advanced biliary tract cancer (aBTC). J. Clin. Oncol. 38(Suppl. 15), 4520–4520 (2020).
    • 60. Simone V, Brunetti O, Lupo L et al. Targeting angiogenesis in biliary tract cancers: an open option. Int. J. Mol. Sci. 18(2), (2017).
    • 61. Song IH, Jeong MS, Hong HJ et al. Development of a theranostic convergence bioradiopharmaceutical for immuno-PET based radioimmunotherapy of L1CAM in cholangiocarcinoma model. Clin. Cancer Res. 25(20), 6148–6159 (2019).
    • 62. Lin J, Shi W, Zhao S et al. Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): preliminary data and correlation with next-generation sequencing. J. Clin. Oncol. 36(Suppl. 4), 500–500 (2018).
    • 63. Kwon HC, Roh MS, Oh SY et al. Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer. Ann. Oncol. 18(3), 504–509 (2007).
    • 64. Park KW, Jung ES, Kim DG et al. ERCC1 Can be a prognostic factor in hilar cholangiocarcinoma and extrahepatic bile duct cancer, but not in intrahepatic cholangiocarcinoma. Cancer Res. Treat. 45(1), 63–69 (2013).
    • 65. He AR, Weinberg BA, Noel MS et al. Phase II study of pembrolizumab plus olaparib in the treatment of patients with advanced cholangiocarcinoma. J. Clin. Oncol. 38(Suppl. 15), TPS4659–TPS4659 (2020).
    • 66. Peyraud F, Italiano A. Combined PARP inhibition and immune checkpoint therapy in solid tumors. Cancers (Basel) 12(6), 1502 (2020).
    • 67. Friedlander M, Meniawy T, Markman B et al. Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, Phase Ia/b trial. Lancet Oncol. 20(9), 1306–1315 (2019).
    • 68. Xiong F, Gong J, Wang Q. Olaparib and pembrolizumab treatment for BRCA1-mutated and PD-L1-positive intrahepatic cholangiocarcinoma recurrence and metastasis: a case report. Onco. Targets Ther. 13, 6385–6391 (2020).
    • 69. Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Ruttinger D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5(1), 53 (2017).
    • 70. Sachdev JC, Hu-Lieskovan S, Patnaik A et al. Phase I/2a study of double immune suppression blockade by combining a CSF1R inhibitor (pexidartinib/PLX3397) with an anti PD-1 antibody (pembrolizumab) to treat advanced melanoma and other solid tumors. Gynecol. Oncol. 141, 147–148 (2016).
    • 71. Razak AR, Cleary JM, Moreno V et al. Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors. J. Immunother. Cancer 8(2), e001006 (2020).
    • 72. Ribas A, Algazi A, Ascierto PA et al. PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma. Nat. Commun. 11(1), 6262 (2020).
    • 73. Lee JW, Zhang Y, Eoh KJ et al. The combination of MEK inhibitor with immunomodulatory antibodies targeting programmed death 1 and programmed death ligand 1 results in prolonged survival in Kras/p53-driven lung cancer. J. Thorac. Oncol. 14(6), 1046–1060 (2019).
    • 74. Chen Y, Ma L, He Q, Zhang S, Zhang C, Jia W. TGF-beta1 expression is associated with invasion and metastasis of intrahepatic cholangiocarcinoma. Biol. Res. 48, 26 (2015).
    • 75. David JM, Dominguez C, Mccampbell KK, Gulley JL, Schlom J, Palena C. A novel bifunctional anti-PD-L1/TGF-beta Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells. Oncoimmunology 6(10), e1349589 (2017).
    • 76. Ferris RL, Lenz HJ, Trotta AM et al. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. Cancer Treat. Rev. 63, 48–60 (2018).
    • 77. Lan Y, Zhang D, Xu C et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-beta. Sci. Transl. Med. 10(424), eaan5488 (2018).
    • 78. Kobayashi M, Sakabe T, Abe H et al. Dendritic cell-based immunotherapy targeting synthesized peptides for advanced biliary tract cancer. J. Gastrointest. Surg. 17(9), 1609–1617 (2013).
    • 79. 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 36(6), 559–562 (2006).
    • 80. Tran E, Turcotte S, Gros A et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344(6184), 641–645 (2014).
    • 81. Boileve A, Hilmi M, Gougis P et al. Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: safety run-in results of the randomized IMMUNOBIL PRODIGE 57 Phase II trial. Eur. J. Cancer 143, 55–63 (2021).
    • 82. Klein O, Kee D, Nagrial A et al. Evaluation of combination nivolumab and ipilimumab immunotherapy in patients with advanced biliary tract cancers: subgroup analysis of a Phase II nonrandomized clinical trial. JAMA Oncol. 6(9), 1405–1409 (2020).
    • 83. Hong TS, Goyal L, Parikh AR et al. A pilot study of durvalumab/tremelimumab (durva/treme) and radiation (XRT) for metastatic biliary tract cancer (mBTC): preliminary safety and efficacy. J. Clin. Oncol. 38(Suppl. 4), 547–547 (2020).
    • 84. Zhou J, Gong J, Cao Y et al. Anlotinib plus TQB2450 in patients with advanced refractory biliary tract cancer (BTC): an open-label, dose-escalating, and dose-expansion cohort of Phase Ib trial. J. Clin. Oncol. 39(Suppl. 3), 292–292 (2021).
    • 85. Kelley RK, Mitchell E, Behr S et al. Phase II trial of pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC). J. Clin. Oncol. 36(Suppl. 4), 386–386 (2018).
    • 86. Sharabi AB, Lim M, Deweese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 16(13), e498–e509 (2015).
    • 87. Asna N, Livoff A, Batash R et al. Radiation therapy and immunotherapy-a potential combination in cancer treatment. Curr. Oncol. 25(5), e454–e460 (2018).
    • 88. Van Bussel MTJ, Awada A, De Jonge MJA et al. A first-in-man Phase I study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours. Br. J. Cancer 124(4), 728–735 (2021).
    • 89. Sahai V, Buckley TH, Griffith KA, Zalupski M. A multi-center Phase Ib/II study of nal-irinotecan, 5-fluouracil and leucovorin in combination with nivolumab as second-line therapy for patients with advanced unresectable biliary tract cancer. J. Clin. Oncol. 37(Suppl. 15), TPS4154–TPS4154 (2019).
    • 90. Lv M, Chen M, Zhang R et al. Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res. 30(11), 966–979 (2020).
    • 91. Papadopoulos KP, Harb W, Lu N et al. Phase I study of KN035, a novel fusion anti-PD-L1 antibody administered subcutaneously in patients with advanced solid tumors in the USA. Ann. Oncol. 29, viii405 (2018).
    • 92. Hu Y, Lin H, Hao M, Zhou Y, Chen Q, Chen Z. Efficacy and safety of apatinib in treatment of unresectable intrahepatic cholangiocarcinoma: an observational study. Cancer Manag. Res. 12, 5345–5351 (2020).
    • 93. Ma HS, Poudel B, Torres ER et al. A CD40 agonist and PD-1 antagonist antibody reprogram the microenvironment of nonimmunogenic tumors to allow T-cell-mediated anticancer activity. Cancer Immunol. Res. 7(3), 428–442 (2019).
    • 94. Guo J, Sheng X, Si L et al. A Phase Ib study of JS001, a humanized IgG4 mAb against programmed death-1 (PD-1) combination with axitinib in patients with metastatic mucosal melanoma. J. Clin. Oncol. 36(Suppl. 15), 9528–9528 (2018).
    • 95. Sulkowski PL, Corso CD, Robinson ND et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci. Transl. Med. 9(375), eaal2463 (2017).
    • 96. Shen L, Ciesielski M, Ramakrishnan S et al. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS ONE 7(1), e30815 (2012).
    • 97. Zheng H, Zhao W, Yan C et al. HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin. Cancer Res. 22(16), 4119–4132 (2016).
    • 98. Goyal L, Sirard C, Schrag M et al. Phase I and biomarker study of the Wnt pathway modulator DKN-01 in combination with gemcitabine/cisplatin in advanced biliary tract cancer. Clin. Cancer Res. 26(23), 6158–6167 (2020).
    • 99. Zhu Y, Yang J, Xu D et al. Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade. Gut 68(9), 1653–1666 (2019).
    • 100. Leblond MM, Tille L, Nassiri S et al. CD40 agonist restores the antitumor efficacy of anti-PD1 therapy in muscle-invasive bladder cancer in an IFN I/II-mediated manner. Cancer Immunol. Res. 8(9), 1180–1192 (2020).
    • 101. Ma Z, Li H, Liu L. Combining PD-1 inhibitor with VEGF/VEGFR2 inhibitor in chemotherapy: report of a patient with end-stage cholangiocarcinoma and review of literature. Recent Pat. Anticancer Drug Discov. 16(1), 101–107 (2021).
    • 102. Schuller A, Doshi A, Cantin S et al. Abstract 4523: inhibition of arginase in combination with anti-PDL1 leads to increased infiltration and activation of CD8+ T cells, NK cells, and CD103+ dendritic cells in mouse syngeneic tumor models. Cancer Res. 80(Suppl. 16), 4523–4523 (2020).
    • 103. Javle MM, Bridgewater JA, Gbolahan OB et al. A Phase I/II study of safety and efficacy of the arginase inhibitor INCB001158 plus chemotherapy in patients (Pts) with advanced biliary tract cancers. J. Clin. Oncol. 39(Suppl. 3), 311–311 (2021).
    • 104. Huang RY, Francois A, Mcgray AR, Miliotto A, Odunsi K. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer. Oncoimmunology 6(1), e1249561 (2017).
    • 105. Leary R, Gardner RB, Mockbee C, Roychowdhury DF. Boosting abscopal response to radiotherapy with sargramostim: a review of data and ongoing studies. Cureus 11(3), e4276 (2019).
    • 106. Tian H, Shi G, Wang Q et al. Erratum: Author Correction: A novel cancer vaccine with the ability to simultaneously produce anti-PD-1 antibody and GM-CSF in cancer cells and enhance Th1-biased antitumor immunity. Signal Transduct. Target Ther. 4, 31 (2019).
    • 107. Bloom AC, Bender LH, Tiwary S et al. Intratumorally delivered formulation, INT230-6, containing potent anticancer agents induces protective T cell immunity and memory. Oncoimmunology 8(10), e1625687 (2019).
    • 108. Chu H, Du F, Jiang L et al. The efficacy of CIK-based immunotherapies for advanced solid tumors. Technol. Cancer Res. Treat. 16(5), 577–585 (2017).
    • 109. Pesce S, Greppi M, Tabellini G et al. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J. Allergy Clin. Immunol. 139(1), 335–346 e333 (2017).
    • 110. Nath S, Mukherjee P. MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol. Med. 20(6), 332–342 (2014).
    • 111. Eriksson E, Milenova I, Wenthe J et al. Shaping the tumor stroma and sparking immune activation by CD40 and 4-1BB signaling induced by an armed oncolytic virus. Clin. Cancer Res. 23(19), 5846–5857 (2017).
    • 112. Musher BL, Smaglo BG, Abidi W et al. A Phase I/II study combining a TMZ-CD40L/4-1BBL-armed oncolytic adenovirus and nab-paclitaxel/gemcitabine chemotherapy in advanced pancreatic cancer: an interim report. J. Clin. Oncol. 38(Suppl. 4), 716–716 (2020).
    • 113. Wu HJ, Chu PY. Role of cancer stem cells in cholangiocarcinoma and therapeutic implications. Int. J. Mol. Sci. 20(17), 4154 (2019).
    • 114. Krebs MG, Lopez J, El-Khoueiry A et al. Abstract CT026: Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers. Cancer Res. 78(Suppl. 13), CT026–CT026 (2018).
    • 115. Mertens JC, Fingas CD, Christensen JD et al. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res. 73(2), 897–907 (2013).
    • 116. Kawamoto M, Umebayashi M, Tanaka H et al. Combined gemcitabine and metronidazole is a promising therapeutic strategy for cancer stem-like cholangiocarcinoma. Anticancer Res. 38(5), 2739–2748 (2018).
    • 117. Xie Y, Wang Y, Li J et al. Cholangiocarcinoma therapy with nanoparticles that combine downregulation of MicroRNA-210 with inhibition of cancer cell invasiveness. Theranostics 8(16), 4305–4320 (2018).
    • 118. Zhou G, Sprengers D, Mancham S et al. Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules. J. Hepatol. 71(4), 753–762 (2019).
    • 119. Li W, Deng Y, Chu Q, Zhang P. Gut microbiome and cancer immunotherapy. Cancer Lett. 447, 41–47 (2019).
    • 120. Bahrambeigi S, Molaparast M, Sohrabi F et al. Targeting PPAR ligands as possible approaches for metabolic reprogramming of T cells in cancer immunotherapy. Immunol. Lett. 220, 32–37 (2020).
    • 121. Pandey A, Stawiski EW, Durinck S et al. Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate. Nat. Commun. 11(1), 4225 (2020).
    • 122. Sadeghlar F, Vogt A, Mohr RU et al. Induction of cytotoxic effector cells towards cholangiocellular, pancreatic, and colorectal tumor cells by activation of the immune checkpoint CD40/CD40L on dendritic cells. Cancer Immunol. Immunother. 70(5), 1451–1464 (2021).
    • 123. Kwilas AR, Ardiani A, Donahue RN, Aftab DT, Hodge JW. Dual effects of a targeted small-molecule inhibitor (cabozantinib) on immune-mediated killing of tumor cells and immune tumor microenvironment permissiveness when combined with a cancer vaccine. J. Transl. Med. 12, 294 (2014).
    • 124. Marshall JL, Gulley JL, Arlen PM et al. Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas. J. Clin. Oncol. 23(4), 720–731 (2005).
    • 125. Duggan MC, Jochems C, Donahue RN et al. A Phase I study of recombinant (r) vaccinia-CEA(6D)-TRICOM and rFowlpox-CEA(6D)-TRICOM vaccines with GM-CSF and IFN-alpha-2b in patients with CEA-expressing carcinomas. Cancer Immunol. Immunother. 65(11), 1353–1364 (2016).
    • 126. Bota DA, Chung J, Dandekar M et al. Phase II study of ERC1671 plus bevacizumab versus bevacizumab plus placebo in recurrent glioblastoma: interim results and correlations with CD4(+) T-lymphocyte counts. CNS Oncol. 7(3), CNS22 (2018).
    • 127. Sarivalasis A, Boudousquie C, Balint K et al. A Phase I/II trial comparing autologous dendritic cell vaccine pulsed either with personalized peptides (PEP-DC) or with tumor lysate (OC-DC) in patients with advanced high-grade ovarian serous carcinoma. J. Transl. Med. 17(1), 391 (2019).
    • 128. Han S, Lee SY, Wang WW et al. A perspective on cell therapy and cancer vaccine in biliary tract cancers (BTCs). Cancers (Basel) 12(11), 3404 (2020).
    • 129. Sangsuwannukul T, Supimon K, Sujjitjoon J et al. Anti-tumour effect of the fourth-generation chimeric antigen receptor T cells targeting CD133 against cholangiocarcinoma cells. Int. Immunopharmacol. 89(Pt B), 107069 (2020).
    • 130. Leelawat K, Thongtawee T, Narong S, Subwongcharoen S, Treepongkaruna SA. Strong expression of CD133 is associated with increased cholangiocarcinoma progression. World J. Gastroenterol. 17(9), 1192–1198 (2011).
    • 131. Huemer F, Leisch M, Geisberger R et al. Combination strategies for immune-checkpoint blockade and response prediction by artificial intelligence. Int. J. Mol. Sci. 21(8), 2856 (2020).
    • 132. Rafiq S, Yeku OO, Jackson HJ et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 36(9), 847–856 (2018).
    • 133. Thakur A, Scholler J, Schalk DL, June CH, Lum LG. Enhanced cytotoxicity against solid tumors by bispecific antibody-armed CD19 CAR T cells: a proof-of-concept study. J. Cancer Res. Clin. Oncol. 146(8), 2007–2016 (2020).
    • 134. Miyazato K, Hayakawa Y. Pharmacological targeting of natural killer cells for cancer immunotherapy. Cancer Sci. 111(6), 1869–1875 (2020).
    • 135. Lange S, Lampe J, Bossow S et al. A novel armed oncolytic measles vaccine virus for the treatment of cholangiocarcinoma. Hum. Gene Ther. 24(5), 554–564 (2013).
    • 136. Zhu ZB, Chen Y, Makhija SK et al. Survivin promoter-based conditionally replicative adenoviruses target cholangiocarcinoma. Int. J. Oncol. 29(5), 1319–1329 (2006).
    • 137. Ahmed J, Chard LS, Yuan M et al. A new oncolytic V accinia virus augments antitumor immune responses to prevent tumor recurrence and metastasis after surgery. J. Immunother. Cancer 8(1), e000415 (2020).
    • 138. Cervera-Carrascon V, Quixabeira DCA, Havunen R et al. Comparison of clinically relevant oncolytic virus platforms for enhancing t cell therapy of solid tumors. Mol. Ther. Oncolytics 17, 47–60 (2020).
    • 139. Shi G, Yang Q, Zhang Y et al. Modulating the tumor microenvironment via oncolytic viruses and CSF-1R inhibition synergistically enhances anti-PD-1 immunotherapy. Mol. Ther. 27(1), 244–260 (2019).
    • 140. Groeneveldt C, Van Hall T, Van Der Burg SH, Ten Dijke P, Van Montfoort N. Immunotherapeutic potential of TGF-beta inhibition and oncolytic viruses. Trends Immunol. 41(5), 406–420 (2020).
    • 141. Jarnagin WR, Zager JS, Hezel M et al. Treatment of cholangiocarcinoma with oncolytic herpes simplex virus combined with external beam radiation therapy. Cancer Gene Ther. 13(3), 326–334 (2006).
    • 142. Yoshida H, Katayose Y, Unno M et al. A novel adenovirus expressing human 4-1BB ligand enhances antitumor immunity. Cancer Immunol. Immunother. 52(2), 97–106 (2003).
    • 143. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 414(6859), 105–111 (2001).
    • 144. Wagner J, Wickman E, Derenzo C, Gottschalk S. CAR T Cell therapy for solid tumors: bright future or dark reality? Mol. Ther. 28(11), 2320–2339 (2020).
    • 145. Ribas A, Dummer R, Puzanov I et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170(6), 1109–1119 e1110 (2017).
    • 146. Patel A, Kaufman HL, Disis ML. Next generation approaches for tumor vaccination. Chin. Clin. Oncol. 6(2), 19 (2017).
    • 147. Korpics MC, Polley MY, Bhave SR et al. A validated T cell radiomics score is associated with clinical outcomes following multisite SBRT and pembrolizumab. Int. J. Radiat. Oncol. Biol. Phys. 108(1), 189–195 (2020).