T-Cell Subsets as Potential Biomarkers for Hepatobiliary Cancers and Selection of Immunotherapy Regimens as a Treatment Strategy

Authors:
Chandan Kumar-Sinha Michigan Center for Translational Pathology,
Department of Pathology,

Search for other papers by Chandan Kumar-Sinha in
Current site
Google Scholar
PubMed
Close
 PhD
and
Vaibhav Sahai Division of Hematology and Oncology, Department of Internal Medicine, and
Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.

Search for other papers by Vaibhav Sahai in
Current site
Google Scholar
PubMed
Close
 MBBS, MS
Restricted access

Patients with advanced hepatocellular or biliary cancers have a dismal prognosis with limited efficacy from standard systemic therapies. The benefit of precision medicine has so far been limited to a subset of biliary cancers, including FGFR rearrangements; hotspot mutations in IDH1/2, BRAF, and BRCA1/2; and other rare alterations. In contrast, hepatocellular carcinoma, an inflammation-driven cancer with an immune-infiltrated microenvironment, provides a promising opportunity for immunotherapy, compared with the highly desmoplastic immune desert or excluded stromal microenvironment in biliary cancers. The immune contexture in hepatobiliary cancers is mostly immunosuppressive, protumorigenic, and exhausted, which together with low tumor mutation burden and decreased neoantigens provides challenges for immunotherapy. A better understanding of the spatiotemporal profile of T cells within the tumor microenvironment and the dynamic interplay of immune modulators in the context of standard or experimental therapies is crucial to define additional markers of response and design evidence-based combinatorial regimens. This review considers recent literature in this area and highlights promising leads and emerging trends.

Submitted February 15, 2021; final revision received July 28, 2021; accepted for publication September 22, 2021.

Disclosures: Dr. Kumar-Sinha has disclosed not receiving any financial consideration from any person or organization to support the preparation analysis, results, or discussion of this article. Dr. Sahai has disclosed serving as a Principal Investigator for Agios, Bristol-Myers Squibb, Celgene, Clovis, Exelixis, Fibrogen, Incyte, Ipsen, MedImmune, Merck, NCI, and Rafael; as a consultant and advisory board member for AstraZeneca, GlaxoSmithKline, Histosonics, Incyte, QED, and Rafael; and on the data safety monitoring board for Incyte.

Correspondence: Vaibhav Sahai, MBBS, MS, Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Rogel Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5948. Email: vsahai@umich.edu
  • Collapse
  • Expand
  • 1.

    Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet 2015;47:10031010.

  • 2.

    Rebouissou S, Nault JC. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J Hepatol 2020;72:215229.

  • 3.

    Dhanasekaran R, Nault JC, Roberts LR, et al. Genomic medicine and implications for hepatocellular carcinoma prevention and therapy. Gastroenterology 2019;156:492509.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018;391:13011314.

  • 5.

    Jusakul A, Cutcutache I, Yong CH, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov 2017;7:11161135.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Lowery MA, Ptashkin R, Jordan E, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin Cancer Res 2018;24:41544161.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Zou S, Li J, Zhou H, et al. Mutational landscape of intrahepatic cholangiocarcinoma. Nat Commun 2014;5:5696.

  • 8.

    Jiao Y, Pawlik TM, Anders RA, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 2013;45:14701473.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Narayan RR, Creasy JM, Goldman DA, et al. Regional differences in gallbladder cancer pathogenesis: insights from a multi-institutional comparison of tumor mutations. Cancer 2019;125:575585.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Li M, Zhang Z, Li X, et al. Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. Nat Genet 2014;46:872876.

  • 11.

    Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol 2018;36:276282.

  • 12.

    Bahleda R, Italiano A, Hierro C, et al. Multicenter phase I study of erdafitinib (JNJ-42756493), oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced or refractory solid tumors. Clin Cancer Res 2019;25:48884897.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol 2020;21:671684.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Lavingia V, Fakih M. Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma—2 case reports and a brief review. J Gastrointest Oncol 2016;7:E98102.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Bogenberger JM, DeLeon TT, Arora M, et al. Emerging role of precision medicine in biliary tract cancers. NPJ Precis Oncol 2018;2:21.

  • 16.

    Pellino A, Loupakis F, Cadamuro M, et al. Precision medicine in cholangiocarcinoma. Transl Gastroenterol Hepatol 2018;3:40.

  • 17.

    Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014;515:577581.

  • 18.

    Patel SJ, Sanjana NE, Kishton RJ, et al. Identification of essential genes for cancer immunotherapy. Nature 2017;548:537542.

  • 19.

    Meng X, Huang Z, Teng F, et al. Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy. Cancer Treat Rev 2015;41: 868876.

  • 20.

    Łuksza M, Riaz N, Makarov V, et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 2017;551:517520.

  • 21.

    Cristescu R, Mogg R, Ayers M, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 2018;362:eaar3593.

  • 22.

    Kelley RK, Sangro B, Harris WP, et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC) [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 4508.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol 2020;38:193202.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol 2020;6:e204564.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature 2017;541:321330.

  • 26.

    Bian J, Lin J, Long J, et al. T lymphocytes in hepatocellular carcinoma immune microenvironment: insights into human immunology and immunotherapy. Am J Cancer Res 2020;10:45854606.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Sia D, Jiao Y, Martinez-Quetglas I, et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 2017;153:812826.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Hopkins BD, Pauli C, Du X, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 2018;560:499503.

  • 29.

    Foerster F, Hess M, Gerhold-Ay A, et al. The immune contexture of hepatocellular carcinoma predicts clinical outcome. Sci Rep 2018;8:5351.

  • 30.

    Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021;592:450456.

  • 31.

    Bozward AG, Warricker F, Oo YH, et al. Natural killer cells and regulatory T cells cross talk in hepatocellular carcinoma: exploring therapeutic options for the next decade. Front Immunol 2021;12:643310.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Guan X, Lu Y, Zhu H, et al. The crosstalk between cancer cells and neutrophils enhances hepatocellular carcinoma metastasis via neutrophil extracellular traps-associated cathepsin G component: a potential therapeutic target. J Hepatocell Carcinoma 2021;8:451465.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Osei-Bordom D, Bozward AG, Oo YH. The hepatic microenvironment and regulatory T cells. Cell Immunol 2020;357:104195.

  • 34.

    Ma C, Han M, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 2018;360:eaan5931.

  • 35.

    Rimassa L, Personeni N, Aghemo A, et al. The immune milieu of cholangiocarcinoma: from molecular pathogenesis to precision medicine. J Autoimmun 2019;100:1726.

  • 36.

    Tariq NU, Vogel A, McNamara MG, et al. Biliary tract cancer: implicated immune-mediated pathways and their associated potential targets. Oncol Res Treat 2018;41:298304.

  • 37.

    Banales JM, Cardinale V, Carpino G, et al. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol 2016;13:261280.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    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 2020;72:965981.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Zhao Q, Huang ZL, He M, et al. BTLA identifies dysfunctional PD-1-expressing CD4+ T cells in human hepatocellular carcinoma. OncoImmunology 2016;5:e1254855.

  • 40.

    Toubal A, Nel I, Lotersztajn S, et al. Mucosal-associated invariant T cells and disease. Nat Rev Immunol 2019;19:643657.

  • 41.

    Budhu A, Forgues M, Ye QH, et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 2006;10:99111.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Zhang JP, Yan J, Xu J, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol 2009;50:980989.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Kinoshita M, Kobayashi S, Gotoh K, et al. Heterogeneity of Treg/Th17 according to cancer progression and modification in biliary tract cancers via self-producing cytokines. Dig Dis Sci 2020;65:29372948.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Ikemoto T, Shimada M, Ishikawa D, et al. Peripheral Tr1 and Foxp3+ Treg as markers of recurrent malignancies in patients with hepato-biliary pancreatic cancers. Anticancer Res 2017;37:55415552.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Gabrielson A, Wu Y, Wang H, et al. Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol Res 2016;4:419430.

  • 46.

    Ma J, Zheng B, Goswami S, et al. PD1Hi CD8+ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma. J Immunother Cancer 2019;7:331.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Wang Y, Ding M, Zhang Q, 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;8:7484.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Tanaka R, Kimura K, Eguchi S, et al. Preoperative neutrophil-to-lymphocyte ratio predicts tumor-infiltrating CD8+ T cells in biliary tract cancer. Anticancer Res 2020;40:28812887.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    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 2016;23:26102617.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Tian L, Ma J, Ma L, et al. PD-1/PD-L1 expression profiles within intrahepatic cholangiocarcinoma predict clinical outcome. World J Surg Oncol 2020;18:303.

  • 51.

    Yu F, Gong L, Mo Z, et al. Programmed death ligand-1, tumor infiltrating lymphocytes and HLA expression in Chinese extrahepatic cholangiocarcinoma patients: possible immunotherapy implications. Biosci Trends 2019;13:5869.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Ghidini M, Cascione L, Carotenuto P, et al. Characterisation of the immune-related transcriptome in resected biliary tract cancers. Eur J Cancer 2017;86:158165.

  • 53.

    DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 2018;378:23862398.

  • 54.

    Umemoto K, Togashi Y, Arai Y, et al. The potential application of PD-1 blockade therapy for early-stage biliary tract cancer. Int Immunol 2020;32:273281.

  • 55.

    Jing CY, Fu YP, Yi Y, et al. HHLA2 in intrahepatic cholangiocarcinoma: an immune checkpoint with prognostic significance and wider expression compared with PD-L1. J Immunother Cancer 2019;7:77.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Lu JC, Zeng HY, Sun QM, et al. Distinct PD-L1/PD1 profiles and clinical implications in intrahepatic cholangiocarcinoma patients with different risk factors. Theranostics 2019;9:46784687.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57.

    Pinato DJ, Guerra N, Fessas P, et al. Immune-based therapies for hepatocellular carcinoma. Oncogene 2020;39:36203637.

  • 58.

    Kim RD, Chung V, Alese OB, et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol 2020;6:888894.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    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 2020;147:21902198.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389:24922502.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61.

    Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018;19:940952.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62.

    Benson AB III, D'Angelica MI, Abbott DE, et al. NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. Version 5.2021. Accessed December 28, 2021. To view the most recent version, visit NCCN.org

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63.

    Yau T, Park JW, Finn RS, et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC) [abstract]. Ann Oncol 2019;30(Suppl 5):Abstract LBA38_PR.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64.

    Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 2020;38:110.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65.

    Ioka T, Ueno M, Oh DY, et al. Evaluation of safety and tolerability of durvalumab (D) with or without tremelimumab (T) in patients (pts) with biliary tract cancer (BTC) [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 387.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66.

    Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005;25:95439553.

  • 67.

    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 2 nonrandomized clinical trial. JAMA Oncol 2020;6:14051409.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 68.

    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) [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 4582.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69.

    Puhr HC, Ilhan-Mutlu A. New emerging targets in cancer immunotherapy: the role of LAG3. ESMO Open 2019;4:e000482.

  • 70.

    Qin SK, Li Q, Ming Xu J, et al. Icaritin-induced immunomodulatory efficacy in advanced hepatitis B virus-related hepatocellular carcinoma: immunodynamic biomarkers and overall survival. Cancer Sci 2020;111:42184231.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71.

    Sato Y, Tanaka S, Kinoshita M, et al. Immunosuppressive tumor microenvironment in occupational cholangiocarcinoma: supportive evidence for the efficacy of immune checkpoint inhibitor therapy. J Hepatobiliary Pancreat Sci 2020;27:860869.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72.

    Xue Y, Gao S, Gou J, et al. Platinum-based chemotherapy in combination with PD-1/PD-L1 inhibitors: preclinical and clinical studies and mechanism of action. Expert Opin Drug Deliv 2021;18:187203.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73.

    Oh DY, Lee KH, Lee DW, 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) [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 4520.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 74.

    Imfinzi plus chemotherapy significantly improved overall survival in 1st-line advanced biliary tract cancer in TOPAZ-1 phase III trial at interim analysis [news release]. Cambridge, UK; October 5, 2021. Available at: https://www.astrazeneca.com/media-centre/press-releases/2021/imfinzi-improved-survival-in-biliary-tract-cancer.html

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75.

    de la Torre-Alaez M, Matilla A, Varela M, et al. Nivolumab after selective internal radiation therapy (SIRT) using SIR-spheres resin microspheres in patients with hepatocellular carcinoma: the NASIR-HCC trial [abstract]. Presented at the 2020 ILCA Virtual Conference; September 11–13, 2020. Abstract 0-27.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76.

    Xie C, Duffy AG, Mabry-Hrones D, et al. Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer. Hepatology 2019;69:20482060.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 77.

    Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 2017;16:25982608.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 78.

    Li J, Wei Q, Wu X, et al. Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response. Clin Transl Med 2020;10:e118.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 79.

    Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun 2016;7:12624.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 80.

    Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:18941905.

  • 81.

    Lin J, Yang X, Long J, et al. Pembrolizumab combined with lenvatinib as non-first-line therapy in patients with refractory biliary tract carcinoma. Hepatobiliary Surg Nutr 2020;9:414424.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 82.

    Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res 2019;25:54495457.

  • 83.

    Yoo C, Oh DY, Choi HJ, et al. Phase I study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with pretreated biliary tract cancer. J Immunother Cancer 2020;8:e000564.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 84.

    Merck KGaA, Darmstadt, Germany, reports Topline data for bintrafusp alfa as second-line monotherapy treatment in biliary tract cancer. Accessed July 1, 2021. Available at: https://www.emdgroup.com/en/news/bintrafusp-topline-data-biliary-tract-cancer-16-03-2021.html

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 85.

    Doi T, Fujiwara Y, Koyama T, et al. Phase I study of the bifunctional fusion protein bintrafusp alfa in Asian patients with advanced solid tumors, including a hepatocellular carcinoma safety-assessment cohort. Oncologist 2020;25:e1292e1302.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 86.

    Boulter L, Guest RV, Kendall TJ, et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest 2015;125:12691285.

  • 87.

    Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov 2019;9:11241141.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 88.

    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 2020;26:61586167.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 89.

    Ebert PJR, Cheung J, Yang Y, et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 2016;44:609621.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 90.

    Bekaii-Saab T, Phelps MA, Li X, et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol 2011;29:23572363.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 91.

    Yarchoan M, Cope L, Anders RA, et al. A multicenter randomized phase 2 trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): a NCI Experimental Therapeutics Clinical Trials Network (ETCTN) study [abstract]. Cancer Res 2020;80 (26 Suppl):Abstract CT043.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 92.

    Jiao S, Xia W, Yamaguchi H, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res 2017;23:37113720.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 93.

    Konstantinopoulos PA, Waggoner S, Vidal GA, et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol 2019;5:11411149.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 94.

    Higuchi T, Flies DB, Marjon NA, et al. CTLA-4 blockade synergizes therapeutically with PARP inhibition in BRCA1-deficient ovarian cancer. Cancer Immunol Res 2015;3:12571268.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 95.

    Karzai F, VanderWeele D, Madan RA, et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J Immunother Cancer 2018;6:141.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 96.

    Zhou G, Sprengers D, Mancham S, et al. Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules. J Hepatol 2019;71:753762.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 97.

    Shimizu K, Kotera Y, Aruga A, et al. Clinical utilization of postoperative dendritic cell vaccine plus activated T-cell transfer in patients with intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci 2012;19:171178.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 98.

    Shi D, Shi Y, Kaseb AO, et al. Chimeric antigen receptor-glypican-3 T-cell therapy for advanced hepatocellular carcinoma: results of phase I trials. Clin Cancer Res 2020;26:39793989.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 99.

    Anwar MY, Williams GR, Paluri RK. CAR T cell therapy in pancreaticobiliary cancers: a focused review of clinical data. J Gastrointest Cancer 2021;52:110.

  • 100.

    Bagaev A, Kotlov N, Nomie K, et al. Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell 2021;39:845865.e7.

  • 101.

    Gohil SH, Iorgulescu JB, Braun DA, et al. Applying high-dimensional single-cell technologies to the analysis of cancer immunotherapy. Nat Rev Clin Oncol 2020;18:244256.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 4163 552 19
PDF Downloads 2790 905 161
EPUB Downloads 0 0 0