{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T13:54:23Z","timestamp":1777038863807,"version":"3.51.4"},"reference-count":82,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,12]],"date-time":"2022-11-12T00:00:00Z","timestamp":1668211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cancer of the hepatobiliary system can be divided into primary liver cancer and biliary tract cancer (BTC), which includes hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder cancer (GBC). These aggressive cancers often present at an advanced stage or among patients with poorly preserved liver function. The primary treatment for HCC and BTC when diagnosed early is surgical resection, but given the high rate of recurrence and often advanced stage at diagnosis, many patients will require systemic therapy. Unfortunately, even with systemic therapy, long-term survival is poor. The immune system plays an important role in preventing cancer progression. The unique immune environment of the liver and subsequent alterations to the immune microenvironment by tumor cells to create a favorable microenvironment plays a key role in the progression of HCC and BTC. Due to the paucity of effective systemic therapies and distinctive immune environment of the liver, research and clinical trials are investigating the use of immunotherapy in HCC and BTC. This review will focus on current immunotherapies and emerging data for the treatment of HCC and BTC.<\/jats:p>","DOI":"10.3390\/ijms232213961","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T02:29:32Z","timestamp":1668392972000},"page":"13961","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Advances in Targeted Immunotherapy for Hepatobiliary Cancers"],"prefix":"10.3390","volume":"23","author":[{"given":"Samantha M.","family":"Ruff","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, Wexner Medical Center, The James Comprehensive Cancer Center, The Ohio State University, 395 W. 12th Ave., Suite 670, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander H.","family":"Shannon","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, Wexner Medical Center, The James Comprehensive Cancer Center, The Ohio State University, 395 W. 12th Ave., Suite 670, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7994-9870","authenticated-orcid":false,"given":"Timothy M.","family":"Pawlik","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, Wexner Medical Center, The James Comprehensive Cancer Center, The Ohio State University, 395 W. 12th Ave., Suite 670, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","unstructured":"Xu, J. (2022, October 13). Trends in Liver Cancer Mortality Among Adults Aged 25 and Over in the United States, 2000\u20132016, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/30044212\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1053\/j.gastro.2013.10.013","article-title":"Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma","volume":"145","author":"Rizvi","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.jhep.2021.11.018","article-title":"BCLC strategy for prognosis prediction and treatment recommendation Barcelona Clinic Liver Cancer (BCLC) staging system: The 2022 update","volume":"76","author":"Reig","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1007\/s005340200076","article-title":"Biliary tract cancer treatment: Results from the Biliary Tract Cancer Statistics Registry in Japan","volume":"9","author":"Nagakawa","year":"2002","journal-title":"J. Hepato-Biliary-Pancreatic Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/sj.bjc.6605211","article-title":"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\u2014The UK ABC-01 Study","volume":"101","author":"Valle","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1056\/NEJMoa1915745","article-title":"Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1093\/oxfordjournals.annonc.a010676","article-title":"Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer","volume":"7","author":"Glimelius","year":"1996","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Refolo, M.G., Messa, C., Guerra, V., Carr, B.I., and D\u2019Alessandro, R. (2020). Inflammatory Mechanisms of HCC Development. Cancers, 12.","DOI":"10.3390\/cancers12030641"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/cmi.2016.3","article-title":"Liver immunology and its role in inflammation and homeostasis","volume":"13","author":"Robinson","year":"2016","journal-title":"Cell. Mol. Immunol."},{"key":"ref_11","first-page":"651","article-title":"Cholangiocarcinoma","volume":"7","author":"Brindley","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1186\/s40425-019-0749-z","article-title":"Immunotherapy in hepatocellular carcinoma: The complex inter-face between inflammation, fibrosis, and the immune response","volume":"7","author":"Keenan","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/s41422-020-0343-4","article-title":"Immune checkpoint signaling and cancer immunotherapy","volume":"30","author":"He","year":"2020","journal-title":"Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-018-0191-1","article-title":"Immune checkpoint inhibitors: Recent progress and potential biomarkers","volume":"50","author":"Darvin","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13046-019-1259-z","article-title":"Combination of CTLA-4 and PD-1 blockers for treatment of cancer","volume":"38","author":"Rotte","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jhep.2013.02.022","article-title":"A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C","volume":"59","author":"Sangro","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1200\/JCO.20.03555","article-title":"Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients with Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I\/II Study","volume":"39","author":"Kelley","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Abou-Alfa, G.K., Lau, G., Kudo, M., Chan, S.L., Kelley, R.K., Furuse, J., Sukeepaisarnjaroen, W., Kang, Y.-K., Van Dao, T., and De Toni, E.N. (2022). Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM \u00c9vid., 1.","DOI":"10.1056\/EVIDoa2100070"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/S2468-1253(22)00043-7","article-title":"Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: An open-label, single-centre, phase 2 study","volume":"7","author":"Oh","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Oh, D.-Y., He, A.R., Qin, S., Chen, L.-T., Okusaka, T., Vogel, A., Kim, J.W., Suksombooncharoen, T., Lee, M.A., and Kitano, M. (2022). Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM \u00c9vid., 1.","DOI":"10.1056\/EVIDoa2200015"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1016\/S0140-6736(17)31046-2","article-title":"Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1\/2 dose escalation and expansion trial","volume":"389","author":"Sangro","year":"2017","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S1470-2045(21)00604-5","article-title":"Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): A randomised, multicentre, open-label, phase 3 trial","volume":"23","author":"Yau","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3727\/105221620X15880179864121","article-title":"Immune Checkpoint Inhibitors in Hepatocellular Cancer: Current Understanding on Mechanisms of Resistance and Biomarkers of Response to Treatment","volume":"20","author":"Onuma","year":"2020","journal-title":"Gene Expr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1002\/hep.23173","article-title":"Chronically inflamed livers up-regulate expression of inhibitory B7 family members","volume":"50","author":"Kassel","year":"2009","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.3748\/wjg.v17.i28.3322","article-title":"Immunostaining of PD-1\/PD-Ls in liver tissues of patients with hepatitis and hepatocellular carcinoma","volume":"17","author":"Wang","year":"2011","journal-title":"World J. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1038\/s43018-021-00234-4","article-title":"Neoadjuvant cabozantinib and nivolumab convert locally advanced hepatocellular carcinoma into resectable disease with enhanced antitumor immunity","volume":"2","author":"Ho","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/S2468-1253(21)00427-1","article-title":"Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: A randomised, open-label, phase 2 trial","volume":"7","author":"Kaseb","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1001\/jamaoncol.2020.0930","article-title":"A Phase 2 Multi-institutional Study of Nivolumab for Patients with Advanced Refractory Biliary Tract Cancer","volume":"6","author":"Kim","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/S2468-1253(19)30086-X","article-title":"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 1 study","volume":"4","author":"Ueno","year":"2019","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4248","DOI":"10.1158\/1078-0432.CCR-22-1152","article-title":"Impaired Chromatin Remodeling Predicts Better Survival to Modified Gemcitabine and S-1 plus Nivolumab in Advanced Biliary Tract Cancer: A Phase II T1219 Study","volume":"28","author":"Chiang","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1001\/jamaoncol.2020.2814","article-title":"Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients with Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial","volume":"6","author":"Klein","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3523","DOI":"10.1002\/cncr.34394","article-title":"A randomized phase 2 trial of nivolumab, gemcitabine, and cisplatin or nivolumab and ipilimumab in previously untreated advanced biliary cancer: BilT-01","volume":"128","author":"Sahai","year":"2022","journal-title":"Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/S1470-2045(18)30351-6","article-title":"Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial","volume":"19","author":"Zhu","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1200\/JCO.19.01307","article-title":"Pembrolizumab As Second-Line Therapy in Patients with Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial","volume":"38","author":"Finn","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.annonc.2021.02.014","article-title":"Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines","volume":"32","author":"Vogel","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"648068","DOI":"10.3389\/fonc.2021.648068","article-title":"PD-1 Inhibitors Could Improve the Efficacy of Chemotherapy as First-Line Treatment in Biliary Tract Cancers: A Propensity Score Matching Based Analysis","volume":"11","author":"Gou","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/JCO.19.02105","article-title":"Efficacy of Pembrolizumab in Patients with Noncolorectal High Microsatellite Instability\/Mismatch Repair\u2013Deficient Cancer: Results from the Phase II KEYNOTE-158 Study","volume":"38","author":"Marabelle","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.aan6733","article-title":"Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade","volume":"357","author":"Le","year":"2017","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e273","DOI":"10.1093\/oncolo\/oyab073","article-title":"A Phase II Study of Pembrolizumab in Combination with Capecitabine and Oxaliplatin with Molecular Profiling in Patients with Advanced Biliary Tract Carcinoma","volume":"27","author":"Monge","year":"2022","journal-title":"Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1200\/JCO.2022.40.4_suppl.452","article-title":"Phase II study of combination pembrolizumab and olaparib in patients with advanced cholangiocarcinoma: Interim results","volume":"40","author":"Yin","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.jhep.2021.11.030","article-title":"Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma","volume":"76","author":"Cheng","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4317","DOI":"10.1200\/JCO.20.02672","article-title":"Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline","volume":"38","author":"Gordan","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Yarchoan, M., Cope, L., Ruggieri, A.N., Anders, R.A., Noonan, A.M., Goff, L.W., Goyal, L., Lacy, J., Li, D., and Patel, A.K. (2021). Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. J. Clin. Investig., 131.","DOI":"10.1172\/JCI152670"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1136\/gutjnl-2014-307671","article-title":"Tim-3 fosters HCC development by enhancing TGF-\u03b2-mediated alternative activation of macrophages","volume":"64","author":"Yan","year":"2015","journal-title":"Gut"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1158\/0008-5472.CAN-19-2332","article-title":"Tim-3 hampers tumor surveillance of liver resident and conventional NK cells by disrupting PI3K signaling","volume":"80","author":"Tan","year":"2020","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Guo, M., Qi, F., Rao, Q., Sun, J., Du, X., Qi, Z., Yang, B., and Xia, J. (2021). Serum LAG-3 Predicts Outcome and Treatment Response in Hepatocellular Carcinoma Patients with Transarterial Chemoembolization. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.754961"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"810269","DOI":"10.3389\/fonc.2022.810269","article-title":"Immune Checkpoint FGL1 Expression of Circulating Tumor Cells Is Associated with Poor Survival in Curatively Resected Hepatocellular Carcinoma","volume":"12","author":"Yan","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e1254855","DOI":"10.1080\/2162402X.2016.1254855","article-title":"BTLA identifies dysfunctional PD-1-expressing CD4+ T cells in human hepatocellular carcinoma","volume":"5","author":"Zhao","year":"2016","journal-title":"OncoImmunology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1186\/s12967-020-02469-8","article-title":"Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using multiplex quantitative analysis","volume":"18","author":"Guo","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"A97","DOI":"10.1136\/jitc-2021-SITC2021.089","article-title":"89 The immune marker LAG-3 increases the predictive value of CD38+ immune cells for survival outcome in immunotherapy-treated hepatocellular carcinoma","volume":"9","author":"Cheung","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"41339","DOI":"10.18632\/oncotarget.5463","article-title":"A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinoma","volume":"6","author":"Jiang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13046-022-02340-2","article-title":"The role of tumor-infiltrating lymphocytes in cholangiocarcinoma","volume":"41","author":"Liu","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/j.1600-0560.2010.01506.x","article-title":"The biologic importance of tumor-infiltrating lymphocytes","volume":"37","author":"Hodi","year":"2010","journal-title":"J. Cutan. Pathol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.it.2015.02.003","article-title":"The STING pathway and the T cell-inflamed tumor microenvironment","volume":"36","author":"Woo","year":"2015","journal-title":"Trends Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.jhep.2020.11.037","article-title":"CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma","volume":"74","author":"Diggs","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Pan, Y.-R., Wu, C.-E., Chen, M.-H., Huang, W.-K., Shih, H.-J., Lan, K.-L., and Yeh, C.-N. (2020). Comprehensive Evaluation of Immune-Checkpoint DNA Cancer Vaccines in a Rat Cholangiocarcinoma Model. Vaccines, 8.","DOI":"10.3390\/vaccines8040703"},{"key":"ref_57","first-page":"2249","article-title":"Combining cetuximab with killer lymphocytes synergistically inhibits human cholangiocarcinoma cells in vitro","volume":"32","author":"Morisaki","year":"2012","journal-title":"Anticancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"106006","DOI":"10.1016\/j.intimp.2019.106006","article-title":"Gemcitabine enhances cytotoxic activity of effector T-lymphocytes against chemo-resistant cholangiocarcinoma cells","volume":"78","author":"Sawasdee","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Rochigneux, P., Chanez, B., De Rauglaudre, B., Mitry, E., Chabannon, C., and Gilabert, M. (2021). Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials. Cancers, 13.","DOI":"10.3390\/cancers13020271"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.1158\/1078-0432.CCR-19-3259","article-title":"Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials","volume":"26","author":"Shi","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"469","DOI":"10.3390\/gidisord2040042","article-title":"Assessment of Current Gene Therapy Practices in Hepatocellular Carcinoma","volume":"2","author":"McKiver","year":"2020","journal-title":"Gastrointest. Disord."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e1440169","DOI":"10.1080\/2162402X.2018.1440169","article-title":"CD133-directed CAR T cells for advanced metastasis malignancies: A phase I trial","volume":"7","author":"Wang","year":"2018","journal-title":"OncoImmunology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1846926","DOI":"10.1080\/2162402X.2020.1846926","article-title":"Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: A single-arm, open-label, phase II trial","volume":"9","author":"Dai","year":"2020","journal-title":"OncoImmunology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-021-85747-9","article-title":"Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma","volume":"11","author":"Supimon","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Phanthaphol, N., Somboonpatarakun, C., Suwanchiwasiri, K., Chieochansin, T., Sujjitjoon, J., Wongkham, S., Maher, J., Junking, M., and Yenchitsomanus, P.-T. (2021). Chimeric Antigen Receptor T Cells Targeting Integrin \u03b1v\u03b26 Expressed on Cholangiocarcinoma Cells. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.657868"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1158\/1078-0432.CCR-17-0432","article-title":"Phase I Study of Chimeric Antigen Receptor\u2013Modified T Cells in Patients with EGFR-Positive Advanced Biliary Tract Cancers","volume":"24","author":"Guo","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/S2468-1253(21)00171-0","article-title":"Current and emerging therapies for advanced biliary tract cancers","volume":"6","author":"Masood","year":"2021","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1007\/s13238-017-0440-4","article-title":"Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers","volume":"9","author":"Feng","year":"2017","journal-title":"Protein Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12029-020-00457-1","article-title":"CAR T Cell Therapy in Pancreaticobiliary Cancers: A Focused Review of Clinical Data","volume":"52","author":"Anwar","year":"2020","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Rep\u00e1raz, D., Aparicio, B., Llopiz, D., Herv\u00e1s-Stubbs, S., and Sarobe, P. (2022). Therapeutic Vaccines against Hepatocellular Carcinoma in the Immune Checkpoint Inhibitor Era: Time for Neoantigens?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042022"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.3892\/ijo.2012.1626","article-title":"Phase I\/II study of immunotherapy using tumor antigen-pulsed dendritic cells in patients with hepatocellular carcinoma","volume":"41","author":"Tada","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.1158\/1078-0432.CCR-21-4424","article-title":"Phase I\/II Multicenter Trial of a Novel Therapeutic Cancer Vaccine, HepaVac-101, for Hepatocellular Carcinoma","volume":"28","author":"Gori","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_73","first-page":"1","article-title":"Identification of tumor antigens and immune subtypes of cholangiocarcinoma for mRNA vaccine development","volume":"20","author":"Huang","year":"2021","journal-title":"Mol. Cancer"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1097\/CJI.0b013e3181fb65b9","article-title":"Phase 1 Trial of Wilms Tumor 1 (WT1) Peptide Vaccine and Gemcitabine Combination Therapy in Patients with Advanced Pancreatic or Biliary Tract Cancer","volume":"34","author":"Kaida","year":"2011","journal-title":"J. Immunother."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1007\/s00534-011-0495-1","article-title":"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 bili-ary tract cancer (WT-BT trial)","volume":"19","author":"Okusaka","year":"2012","journal-title":"J. Hepato-Biliary-Pancreatic Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/1479-5876-12-61","article-title":"Phase I clinical trial of multiple-peptide vaccination for patients with advanced biliary tract cancer","volume":"12","author":"Aruga","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.21873\/anticanres.14907","article-title":"Clinical Trial of a Cancer Vaccine Targeting VEGF and KIF20A in Advanced Biliary Tract Cancer","volume":"41","author":"Murahashi","year":"2021","journal-title":"Anticancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Chen, R., Zheng, D., Li, Q., Xu, S., Ye, C., Jiang, Q., Yan, F., Jia, Y., Zhang, X., and Ruan, J. (2022). Immunotherapy of cholangiocarcinoma: Therapeutic strategies and predictive biomarkers. Cancer Lett.","DOI":"10.1016\/j.canlet.2022.215853"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/s41417-020-00259-4","article-title":"Recent updates on chimeric antigen receptor T cell therapy for hepatocellular carci-noma","volume":"28","author":"Guo","year":"2021","journal-title":"Cancer Gene Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1002\/cam4.1459","article-title":"MRI-guided interventional natural killer cell delivery for liver tumor treatment","volume":"7","author":"Su","year":"2018","journal-title":"Cancer Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"879452","DOI":"10.3389\/fimmu.2022.879452","article-title":"A Phase I Study of Lo-coregional High-Dose Autologous Natural Killer Cell Therapy with Hepatic Arterial Infusion Chemo-therapy in Patients with Locally Advanced Hepatocellular Carcinoma","volume":"13","author":"Bae","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e1919","DOI":"10.1002\/onco.13899","article-title":"Adoptive Transfer of Autologous Invariant Natural Killer T Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial","volume":"26","author":"Gao","year":"2021","journal-title":"Oncologist"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13961\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:16:55Z","timestamp":1760145415000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13961"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,12]]},"references-count":82,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232213961"],"URL":"https:\/\/doi.org\/10.3390\/ijms232213961","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,12]]}}}