Biliary tract cancer: Implicated immune-mediated pathways ...
Biliary tract cancer: Implicated immune-mediated pathways and their associated potential targets. Tariq N1, 2, Vogel A3, McNamara MG1, 2 and Valle JW1, 21Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, United Kingdom2Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom.3Clinic of Gastroenterology, Hepatology and Endocrinology, Hannover Medical High School, Carl Neuberg Str. 1, 30625 Hannover, GermanyCorresponding author:Prof Juan W Valle,Division of Cancer Sciences, University of Manchester, The Christie NHS Foundation Trust,Wilmslow Road, Manchester M20 4BX, United Kingdom.Telephone: +44 (0)161 446 8106Fax: +44 (0)161 446 3468Email: Juan.Valle@christie.nhs.ukKeywords: biliary tract cancer, immunotherapy, immune check-point inhibitorsSummaryThere is a well-established link between biliary tract cancers (BTC) and chronic inflammatory conditions such as primary sclerosing cholangitis, chronic cholecystitis, chronic cholelithiasis, liver-fluke-associated infestations and chronic viral hepatic infections. These associated risk factors highlight the potential for development of immune-modulatory agents in this poor-prognostic disease group with limited treatment options. Clinical trials have evaluated the role of immune cells, inflammatory biomarkers, vaccines, cytokines, adoptive cell therapy and immune check point inhibitors in patients with BTC. Although these have demonstrated the importance of the immune environment in BTC, currently none of these immune-based therapies have been approved for use in this disease group. The role of immune-modulatory agents is a developing field and has yet to find its way “from bench-to-bedside” in BTC.IntroductionBiliary tract cancers (BTCs) are relatively poorly understood rare malignancies with an increasing prevalence reported in the last few decades ADDIN EN.CITE <EndNote><Cite><Author>Khan</Author><Year>2002</Year><RecNum>1074</RecNum><DisplayText><style face="superscript">1, 2</style></DisplayText><record><rec-number>1074</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1074</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Khan, Shahid A</author><author>Davidson, Brian R</author><author>Goldin, Robert</author><author>Pereira, SP</author><author>Rosenberg, William MC</author><author>Taylor-Robinson, Simon D</author><author>Thillainayagam, Andrew V</author><author>Thomas, Howard C</author><author>Thursz, Mark R</author><author>Wasan, Harpreet</author></authors></contributors><titles><title>Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>vi1-vi9</pages><volume>51</volume><number>suppl 6</number><dates><year>2002</year></dates><isbn>0017-5749</isbn><urls></urls></record></Cite><Cite><Author>Saha</Author><Year>2016</Year><RecNum>1075</RecNum><record><rec-number>1075</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1075</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saha, Supriya K</author><author>Zhu, Andrew X</author><author>Fuchs, Charles S</author><author>Brooks, Gabriel A</author></authors></contributors><titles><title>Forty-year trends in cholangiocarcinoma incidence in the US: intrahepatic disease on the rise</title><secondary-title>The oncologist</secondary-title></titles><periodical><full-title>The oncologist</full-title></periodical><pages>594-599</pages><volume>21</volume><number>5</number><dates><year>2016</year></dates><isbn>1083-7159</isbn><urls></urls></record></Cite></EndNote>1, 2. The incidence varies hugely with age-standardised rate (ASR) of 3.46/100,000 in males and 2.99/100,000 in females in England & Wales ADDIN EN.CITE <EndNote><Cite><Author>West</Author><Year>2006</Year><RecNum>1097</RecNum><DisplayText><style face="superscript">3</style></DisplayText><record><rec-number>1097</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1097</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>West, J</author><author>Wood, H</author><author>Logan, RFA</author><author>Quinn, M</author><author>Aithal, GP</author></authors></contributors><titles><title>Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001</title><secondary-title>British journal of cancer</secondary-title></titles><periodical><full-title>British journal of cancer</full-title></periodical><pages>1751-1758</pages><volume>94</volume><number>11</number><dates><year>2006</year></dates><isbn>0007-0920</isbn><urls></urls></record></Cite></EndNote>3, whereas in Thailand, the ASR is 33.4/100,000 in males and 12.3/100,000 in females ADDIN EN.CITE <EndNote><Cite><Author>Sripa</Author><Year>2008</Year><RecNum>1098</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>1098</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1098</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sripa, Banchob</author><author>Pairojkul, Chawalit</author></authors></contributors><titles><title>Cholangiocarcinoma: Lessons from Thailand</title><secondary-title>Current opinion in gastroenterology</secondary-title></titles><periodical><full-title>Current opinion in gastroenterology</full-title></periodical><pages>349-356</pages><volume>24</volume><number>3</number><dates><year>2008</year></dates><isbn>0267-1379
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ADDIN EN.CITE.DATA 10-13. In contrast, in the West, the prevalence of BTC is much lower and primary sclerosing cholangitis is one of the major risk factors ADDIN EN.CITE <EndNote><Cite><Author>Khan</Author><Year>1999</Year><RecNum>248</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>248</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">248</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Khan, Zareen R</author><author>Neugut, Alfred I</author><author>Ahsan, Habibul</author><author>Chabot, John A</author></authors></contributors><titles><title>Risk factors for biliary tract cancers</title><secondary-title>The American journal of gastroenterology</secondary-title></titles><periodical><full-title>The American journal of gastroenterology</full-title></periodical><pages>149-152</pages><volume>94</volume><number>1</number><dates><year>1999</year></dates><isbn>0002-9270</isbn><urls></urls></record></Cite></EndNote>11.Treatment options for early-stage disease includes surgery followed by adjuvant chemotherapy with an improvement in median overall survival (OS) from 36 to 53 months ADDIN EN.CITE <EndNote><Cite><Author>Primrose</Author><Year>2017</Year><RecNum>1112</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>1112</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1112</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Primrose, John Neil</author><author>Fox, Richard</author><author>Palmer, Daniel H</author><author>Prasad, Raj</author><author>Mirza, Darius</author><author>Anthoney, David Alan</author><author>Corrie, Philippa</author><author>Falk, Stephen</author><author>Wasan, Harpreet Singh</author><author>Ross, Paul J</author></authors></contributors><titles><title>Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study</title></titles><dates><year>2017</year></dates><publisher>American Society of Clinical Oncology</publisher><isbn>0732-183X</isbn><urls></urls></record></Cite></EndNote>14. For patients with locally-advanced disease, loco-regional therapies ADDIN EN.CITE <EndNote><Cite><Author>Rizvi</Author><Year>2017</Year><RecNum>1100</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>1100</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1100</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rizvi, Sumera</author><author>Khan, Shahid A</author><author>Hallemeier, Christopher L</author><author>Kelley, Robin K</author><author>Gores, Gregory J</author></authors></contributors><titles><title>Cholangiocarcinoma—evolving concepts and therapeutic strategies</title><secondary-title>Nature Reviews Clinical Oncology</secondary-title></titles><periodical><full-title>Nature Reviews Clinical Oncology</full-title></periodical><dates><year>2017</year></dates><isbn>1759-4782</isbn><urls></urls></record></Cite></EndNote>15 [e.g. trans-arterial chemoembolisation (TACE) and external beam radiation therapy (EBRT)] may be considered. However, these have not yet been validated in prospective randomised-controlled trials ADDIN EN.CITE <EndNote><Cite><Author>Rizvi</Author><Year>2017</Year><RecNum>1100</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>1100</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1100</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rizvi, Sumera</author><author>Khan, Shahid A</author><author>Hallemeier, Christopher L</author><author>Kelley, Robin K</author><author>Gores, Gregory J</author></authors></contributors><titles><title>Cholangiocarcinoma—evolving concepts and therapeutic strategies</title><secondary-title>Nature Reviews Clinical Oncology</secondary-title></titles><periodical><full-title>Nature Reviews Clinical Oncology</full-title></periodical><dates><year>2017</year></dates><isbn>1759-4782</isbn><urls></urls></record></Cite></EndNote>15 and therefore their use is very variable. For patients with locally-advanced and metastatic disease, the combination of gemcitabine and cisplatin has been shown to improve median OS from 8 months (with gemcitabine alone) to 11.7 months (with the combination) ADDIN EN.CITE <EndNote><Cite><Author>Valle</Author><Year>2010</Year><RecNum>1114</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>1114</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1114</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Valle, Juan</author><author>Wasan, Harpreet</author><author>Palmer, Daniel H</author><author>Cunningham, David</author><author>Anthoney, Alan</author><author>Maraveyas, Anthony</author><author>Madhusudan, Srinivasan</author><author>Iveson, Tim</author><author>Hughes, Sharon</author><author>Pereira, Stephen P</author></authors></contributors><titles><title>Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer</title><secondary-title>New England Journal of Medicine</secondary-title></titles><periodical><full-title>New England Journal of Medicine</full-title></periodical><pages>1273-1281</pages><volume>362</volume><number>14</number><dates><year>2010</year></dates><isbn>0028-4793</isbn><urls></urls></record></Cite></EndNote>16. 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ADDIN EN.CITE.DATA 17, 18. Given the modest survival benefit and limited treatment options available ADDIN EN.CITE <EndNote><Cite><Author>Valle</Author><Year>2010</Year><RecNum>1114</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>1114</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1114</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Valle, Juan</author><author>Wasan, Harpreet</author><author>Palmer, Daniel H</author><author>Cunningham, David</author><author>Anthoney, Alan</author><author>Maraveyas, Anthony</author><author>Madhusudan, Srinivasan</author><author>Iveson, Tim</author><author>Hughes, Sharon</author><author>Pereira, Stephen P</author></authors></contributors><titles><title>Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer</title><secondary-title>New England Journal of Medicine</secondary-title></titles><periodical><full-title>New England Journal of Medicine</full-title></periodical><pages>1273-1281</pages><volume>362</volume><number>14</number><dates><year>2010</year></dates><isbn>0028-4793</isbn><urls></urls></record></Cite></EndNote>16, there is a need to explore innovative treatment modalities for patients with advanced BTC. As BTC is associated with immune-mediated risk factors, understanding the underlying immune environment and how this can be harnessed, may lead to the development of novel immune-mediated treatments in this disease group.Methodology:Biomedical electronic databases, including EMBASE, MEDLINE, PUBMED and were interrogated for all full manuscripts and conference abstracts, written in the English language (at least the abstract), and published up to January 2018, using the following keywords; “biliary tract cancer”, “immunotherapy”, and “immune-checkpoint inhibitors”. The role of immune cells and their function in the tumour microenvironment of patients with BTCThe role of the immune environment in the carcinogenesis process has been studied in depth, and a number of hypotheses have been proposed. One of these is “cancer immune-editing”, encompassing three steps leading to carcinogenesis: elimination, whereby immune surveillance abolishes nascent transmuted cells; equilibrium, whereby cancer cells which have the capacity to overcome the immune surveillance co-exist in harmony with the immune system; and lastly escape, whereby tumour cells multiply and expand exponentially in an immune-competent host ADDIN EN.CITE <EndNote><Cite><Author>Dunn</Author><Year>2002</Year><RecNum>1076</RecNum><DisplayText><style face="superscript">19</style></DisplayText><record><rec-number>1076</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1076</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dunn, Gavin P</author><author>Bruce, Allen T</author><author>Ikeda, Hiroaki</author><author>Old, Lloyd J</author><author>Schreiber, Robert D</author></authors></contributors><titles><title>Cancer immunoediting: from immunosurveillance to tumor escape</title><secondary-title>Nature immunology</secondary-title></titles><periodical><full-title>Nature immunology</full-title></periodical><pages>991-998</pages><volume>3</volume><number>11</number><dates><year>2002</year></dates><urls></urls></record></Cite></EndNote>19. The host immunity constitutes a plethora of immune cells and interacts with the cancer through its surroundings, the “tumour microenvironment” (TME) ADDIN EN.CITE <EndNote><Cite><Author>Mellman</Author><Year>2011</Year><RecNum>1117</RecNum><DisplayText><style face="superscript">20</style></DisplayText><record><rec-number>1117</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1117</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mellman, Ira</author><author>Coukos, George</author><author>Dranoff, Glenn</author></authors></contributors><titles><title>Cancer immunotherapy comes of age</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><pages>480</pages><volume>480</volume><number>7378</number><dates><year>2011</year></dates><isbn>1476-4687</isbn><urls></urls></record></Cite></EndNote>20; a complex structure that constitutes the immune infiltrate, stromal cells, extracellular matrix and tumour vasculature ADDIN EN.CITE <EndNote><Cite><Author>Hanahan</Author><Year>2012</Year><RecNum>1118</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>1118</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1118</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hanahan, Douglas</author><author>Coussens, Lisa M</author></authors></contributors><titles><title>Accessories to the crime: functions of cells recruited to the tumor microenvironment</title><secondary-title>Cancer cell</secondary-title></titles><periodical><full-title>Cancer cell</full-title></periodical><pages>309-322</pages><volume>21</volume><number>3</number><dates><year>2012</year></dates><isbn>1535-6108</isbn><urls></urls></record></Cite></EndNote>21. The immune-infiltrating cells include cluster of differentiation 4+ T-cells (CD4+ T-cells), CD8+ T-cells, tumour infiltrating lymphocytes (TILs), CD66b+ neutrophils and interleukin-17+ T-helper cells (IL17+ TH cells), to name a few. The intensities of these various immune infiltrates within the TME in patients with BTC were evaluated in a meta-analysis. This analysis reported a positive association of OS with high levels of expression of CD4+ T-cells, CD8+ T-cells, TILs, major histocompatibility complex-I (MHC-I) presenting cells and natural-killer group 2, member D cells (NKG2D) (Hazard Ratio [HR] 0.52, p-value(p) <0.00001). In contrast to this, high levels of CD66b+neutrophils, PD-1+/CD8+ TIL cells were negatively associated with OS (HR 1.79, p<0.00001) in the same patient population ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2017</Year><RecNum>1119</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>1119</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1119</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, Ying</author><author>Ding, Min</author><author>Zhang, Qian</author><author>Wang, Jinghan</author><author>Yang, Xijing</author><author>Zhou, Fuping</author><author>Li, Linfang</author><author>Yuan, Zhengang</author><author>Jin, Huajun</author><author>Qian, Qijun</author></authors></contributors><titles><title>Activation or suppression of the immune response mediators in biliary tract cancer (BTC) patients: a systematic review and meta-analysis</title><secondary-title>Journal of Cancer</secondary-title></titles><periodical><full-title>Journal of Cancer</full-title></periodical><pages>74</pages><volume>8</volume><number>1</number><dates><year>2017</year></dates><urls></urls></record></Cite></EndNote>22. Another study of 110 patients with resected stage I-IV GBC reported high CD4+ T cell count in 51% (n=23/45) cases, high CD8+ T-cells in 37.8% (n=17/45), NKC in 33.3% (n=15/45) and high dendritic cells in 48.9 % (n=22/45). A favourable prognosis was seen with high levels of CD4+ T-cells (p=0.0033), CD8+ T-cells (p=0.0081) and dendritic cells (p=0.04) ADDIN EN.CITE <EndNote><Cite><Author>Nakakubo</Author><Year>2003</Year><RecNum>1120</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>1120</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1120</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nakakubo, Y</author><author>Miyamoto, M</author><author>Cho, Y</author><author>Hida, Y</author><author>Oshikiri, T</author><author>Suzuoki, M</author><author>Hiraoka, K</author><author>Itoh, T</author><author>Kondo, S</author><author>Katoh, H</author></authors></contributors><titles><title>Clinical significance of immune cell infiltration within gallbladder cancer</title><secondary-title>British journal of cancer</secondary-title></titles><periodical><full-title>British journal of cancer</full-title></periodical><pages>1736</pages><volume>89</volume><number>9</number><dates><year>2003</year></dates><isbn>1532-1827</isbn><urls></urls></record></Cite></EndNote>23.The above studies highlight the relationship between immune cells and OS. The role of immune cells in the phasic process of carcinogenesis in patients with BTCFurther to the studies on correlation of patients’ clinical outcomes with various components of the immune system, a study evaluated the role of these immune cells in the cascade that leads to carcinogenesis. Levels of immune-infiltrate cells were measured in 375 surgically-resected patients with BTC (stages I-IV), including 157 intrahepatic (IHC), 149 extrahepatic (EHC) and 69 with GBC; differences between these levels as precancerous lesions developed into a tumour were also studied ADDIN EN.CITE <EndNote><Cite><Author>Goeppert</Author><Year>2013</Year><RecNum>1121</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>1121</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goeppert, B</author><author>Frauenschuh, L</author><author>Zucknick, M</author><author>Stenzinger, A</author><author>Andrulis, M</author><author>Klauschen, F</author><author>Joehrens, K</author><author>Warth, A</author><author>Renner, M</author><author>Mehrabi, A</author></authors></contributors><titles><title>Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer</title><secondary-title>British journal of cancer</secondary-title></titles><periodical><full-title>British journal of cancer</full-title></periodical><pages>2665</pages><volume>109</volume><number>10</number><dates><year>2013</year></dates><isbn>1532-1827</isbn><urls></urls></record></Cite></EndNote>24. CD8+ T-cells (48.4%) were more common than CD4+ T-cells (36.3%), B-lymphocytes were low (1.4%), macrophages were high (77.6%) and NKC were low (19.1%). Interestingly, CD4+ T-cells, CD8+ T-cells, B-lymphocytes, regulatory T-cells, NKC and mast cells were higher in precancerous lesions (e.g. Bil-IN III) and their numbers gradually decreased as the cells transformed into cancerous lesions and then metastasised ADDIN EN.CITE <EndNote><Cite><Author>Goeppert</Author><Year>2013</Year><RecNum>1121</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>1121</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goeppert, B</author><author>Frauenschuh, L</author><author>Zucknick, M</author><author>Stenzinger, A</author><author>Andrulis, M</author><author>Klauschen, F</author><author>Joehrens, K</author><author>Warth, A</author><author>Renner, M</author><author>Mehrabi, A</author></authors></contributors><titles><title>Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer</title><secondary-title>British journal of cancer</secondary-title></titles><periodical><full-title>British journal of cancer</full-title></periodical><pages>2665</pages><volume>109</volume><number>10</number><dates><year>2013</year></dates><isbn>1532-1827</isbn><urls></urls></record></Cite></EndNote>24. In contrast, macrophage numbers gradually increased as the precancerous lesion transformed into cancer and then spread into metastases. This study also reported a positive correlation of OS with presence of CD4+ T-cells (p=0.002), CD8+ T-cells (p=0.015), total regulatory T-lymphocytes (p=0.018) and total B-lymphocytes (p=0.032) ADDIN EN.CITE <EndNote><Cite><Author>Goeppert</Author><Year>2013</Year><RecNum>1121</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>1121</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goeppert, B</author><author>Frauenschuh, L</author><author>Zucknick, M</author><author>Stenzinger, A</author><author>Andrulis, M</author><author>Klauschen, F</author><author>Joehrens, K</author><author>Warth, A</author><author>Renner, M</author><author>Mehrabi, A</author></authors></contributors><titles><title>Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer</title><secondary-title>British journal of cancer</secondary-title></titles><periodical><full-title>British journal of cancer</full-title></periodical><pages>2665</pages><volume>109</volume><number>10</number><dates><year>2013</year></dates><isbn>1532-1827</isbn><urls></urls></record></Cite></EndNote>24. The above work highlights the stepwise change in the immune microenvironment in various stages of carcinogenesis of BTC. The role of macrophages and fibroblasts in carcinogenesis in patients with BTCIn an animal model, the role of tissue associated macrophages(TAMs) and cancer-associated fibroblasts(CAFs) in the carcinogenesis of CCA was evaluated ADDIN EN.CITE <EndNote><Cite><Author>Thanee</Author><Year>2015</Year><RecNum>1122</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>1122</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1122</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thanee, Malinee</author><author>Loilome, Watcharin</author><author>Techasen, Anchalee</author><author>Namwat, Nisana</author><author>Boonmars, Thidarut</author><author>Pairojkul, Chawalit</author><author>Yongvanit, Puangrat</author></authors></contributors><titles><title>Quantitative changes in tumor-associated M2 macrophages characterize cholangiocarcinoma and their association with metastasis</title><secondary-title>Asian Pac J Cancer Prev</secondary-title></titles><periodical><full-title>Asian Pac J Cancer Prev</full-title></periodical><pages>3043-3050</pages><volume>16</volume><number>7</number><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>25. This study reported increasing intensity of TAMs, as the lesions changed from hyperplastic to dysplastic, and eventually, to CCA. Whereas in human cell lines, markers of TAMs (CD68 and CD163) were seen in 53% and 51% of cases, respectively ADDIN EN.CITE <EndNote><Cite><Author>Thanee</Author><Year>2015</Year><RecNum>1122</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>1122</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1122</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thanee, Malinee</author><author>Loilome, Watcharin</author><author>Techasen, Anchalee</author><author>Namwat, Nisana</author><author>Boonmars, Thidarut</author><author>Pairojkul, Chawalit</author><author>Yongvanit, Puangrat</author></authors></contributors><titles><title>Quantitative changes in tumor-associated M2 macrophages characterize cholangiocarcinoma and their association with metastasis</title><secondary-title>Asian Pac J Cancer Prev</secondary-title></titles><periodical><full-title>Asian Pac J Cancer Prev</full-title></periodical><pages>3043-3050</pages><volume>16</volume><number>7</number><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>25. Thus, fibroblasts and macrophages appear to be numerically prevalent, and may have an important functional role in carcinogenesis. The role of inflammatory biomarkers in patients with BTCInterleukin-6 (IL-6) has been implicated as a facilitator towards neoplastic growth due to its ability to block apoptosis of cells during inflammation ADDIN EN.CITE <EndNote><Cite><Author>Hodge</Author><Year>2005</Year><RecNum>1053</RecNum><DisplayText><style face="superscript">26</style></DisplayText><record><rec-number>1053</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1053</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hodge, David R</author><author>Hurt, Elaine M</author><author>Farrar, William L</author></authors></contributors><titles><title>The role of IL-6 and STAT3 in inflammation and cancer</title><secondary-title>European journal of cancer</secondary-title></titles><periodical><full-title>European Journal of Cancer</full-title></periodical><pages>2502-2512</pages><volume>41</volume><number>16</number><dates><year>2005</year></dates><isbn>0959-8049</isbn><urls></urls></record></Cite></EndNote>26. A study evaluating the role of IL-6 and its association with epithelial mesenchymal transition (EMT) associated proteins (twist, vimentin and e-cadherin) in 20 cholecystectomy samples from patients with GBC ADDIN EN.CITE <EndNote><Cite><Author>Zhang</Author><Year>2015</Year><RecNum>1078</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>1078</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1078</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhang, Mingdi</author><author>Gong, Wei</author><author>Zhang, Yong</author><author>Yang, Yong</author><author>Zhou, Di</author><author>Weng, Mingzhe</author><author>Qin, Yiyu</author><author>Jiang, Alex</author><author>Ma, Fei</author><author>Quan, Zhiwei</author></authors></contributors><titles><title>Expression of interleukin-6 is associated with epithelial-mesenchymal transition and survival rates in gallbladder cancer</title><secondary-title>Molecular medicine reports</secondary-title></titles><periodical><full-title>Molecular medicine reports</full-title></periodical><pages>3539-3546</pages><volume>11</volume><number>5</number><dates><year>2015</year></dates><isbn>1791-2997</isbn><urls></urls></record></Cite></EndNote>27, reported a high frequency of IL-6 in 40% (n=8/20; 40%), twist in 20% (4/20) and vimentin in 70% (14/20). Patients whose tumours had increased levels of IL-6 and twist, and low levels of e-cadherin had a worse OS.Blood IL-6 levels were assessed in another study where 60 patients with hepatic disease were included [CCA (n=15), hepatocellular carcinoma (HCC) (n=14), colorectal cancer (CRC) hepatic metastasis (n=26) and benign biliary tract disease (n=5)] were studied. All 15 patients (100%) with CCA had elevated levels of IL-6. Moreover, levels were higher in these patients with CCA when compared to patients with other cancer types ADDIN EN.CITE <EndNote><Cite><Author>Goydos</Author><Year>1998</Year><RecNum>1123</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>1123</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1123</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goydos, James S</author><author>Brumfield, Anne M</author><author>Frezza, Eldo</author><author>Booth, Alexandra</author><author>Lotze, Michael T</author><author>Carty, Sally E</author></authors></contributors><titles><title>Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker</title><secondary-title>Annals of surgery</secondary-title></titles><periodical><full-title>Annals of surgery</full-title></periodical><pages>398</pages><volume>227</volume><number>3</number><dates><year>1998</year></dates><urls></urls></record></Cite></EndNote>28. There was also a correlation between tumour burden and IL-6 levels (the higher the tumour burden, the greater the levels of IL-6) in CCA (p=0.04) and 2 weeks after curative resection the levels of IL-6 dropped to undetectable range in these patients ADDIN EN.CITE <EndNote><Cite><Author>Goydos</Author><Year>1998</Year><RecNum>1123</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>1123</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1123</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goydos, James S</author><author>Brumfield, Anne M</author><author>Frezza, Eldo</author><author>Booth, Alexandra</author><author>Lotze, Michael T</author><author>Carty, Sally E</author></authors></contributors><titles><title>Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker</title><secondary-title>Annals of surgery</secondary-title></titles><periodical><full-title>Annals of surgery</full-title></periodical><pages>398</pages><volume>227</volume><number>3</number><dates><year>1998</year></dates><urls></urls></record></Cite></EndNote>28. Further studies are needed to evaluate the role of IL-6 as a biomarker in BTC.Another marker, the neutrophil lymphocyte ratio (NLR) was analysed retrospectively in 864 patients with all stages of BTC to evaluate its prognostic value. In patients with NLR ≥ 3.0, median OS was 12.0 months versus 21.6 months in patients with NLR <3.0 (adjusted HR=1.26, p=0.01) ADDIN EN.CITE <EndNote><Cite><Author>McNamara</Author><Year>2014</Year><RecNum>1073</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>1073</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1073</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McNamara, M. G.</author><author>Templeton, A. J.</author><author>Maganti, M.</author><author>Walter, T.</author><author>Horgan, A. M.</author><author>McKeever, L.</author><author>Min, T.</author><author>Amir, E.</author><author>Knox, J. J.</author></authors></contributors><titles><title>Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer</title><secondary-title>European Journal of Cancer</secondary-title></titles><periodical><full-title>European Journal of Cancer</full-title></periodical><pages>1581-1589</pages><volume>50</volume><number>9</number><keywords><keyword>Biliary tract cancer</keyword><keyword>Neutrophil/lymphocyte ratio</keyword><keyword>Prognosis</keyword></keywords><dates><year>2014</year><pub-dates><date>2014/06/01/</date></pub-dates></dates><isbn>0959-8049</isbn><urls><related-urls><url><style face="underline" font="default" size="100%"> face="underline" font="default" size="100%">. The derived neutrophil-to-lymphocyte ratio (dNLR; used when the absolute lymphocyte count is not available) has been studied as a prognostic marker in 462 patients with advanced BTC from the combined data of two clinical studies (ABC-02 and BT22). Cisplatin-gemcitabine-treated patients with low dNLR had a median OS of 10.6 months versus 6.4 months in the high dNLR group (≥3) (HR= 1.62, p=<0.001). The adjusted HR for progression-free survival (PFS) was 1.4 for the low dNLR group ADDIN EN.CITE <EndNote><Cite><Author>Grenader</Author><Year>2015</Year><RecNum>1124</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>1124</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1124</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grenader, T</author><author>Nash, S</author><author>Plotkin, Y</author><author>Furuse, J</author><author>Mizuno, N</author><author>Okusaka, T</author><author>Wasan, H</author><author>Valle, J</author><author>Bridgewater, J</author></authors></contributors><titles><title>Derived neutrophil lymphocyte ratio may predict benefit from cisplatin in the advanced biliary cancer: the ABC-02 and BT-22 studies</title><secondary-title>Annals of Oncology</secondary-title></titles><periodical><full-title>Annals of Oncology</full-title></periodical><pages>1910-1916</pages><volume>26</volume><number>9</number><dates><year>2015</year></dates><isbn>1569-8041</isbn><urls></urls></record></Cite></EndNote>30. The above work demonstrates an adverse association of clinical outcomes with high NLR, consistent with findings in other solid malignancies ADDIN EN.CITE <EndNote><Cite><Author>Templeton</Author><Year>2014</Year><RecNum>1056</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>1056</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1056</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Templeton, Arnoud J</author><author>McNamara, Mairéad G</author><author>?eruga, Bo?tjan</author><author>Vera-Badillo, Francisco E</author><author>Aneja, Priya</author><author>Oca?a, Alberto</author><author>Leibowitz-Amit, Raya</author><author>Sonpavde, Guru</author><author>Knox, Jennifer J</author><author>Tran, Ben</author></authors></contributors><titles><title>Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis</title><secondary-title>JNCI: Journal of the National Cancer Institute</secondary-title></titles><periodical><full-title>JNCI: Journal of the National Cancer Institute</full-title></periodical><volume>106</volume><number>6</number><dates><year>2014</year></dates><isbn>0027-8874</isbn><urls></urls></record></Cite></EndNote>31. This inexpensive, readily available biomarker may warrant further prospective evaluation and ultimately validation. The role of stimulatory immunotherapies such as vaccines in patients with BTCThe host immune response to cancer is induced by release of cancer-associated antigens by cancer cells, which are presented through antigen presenting cells (APC). Some of these cancer-associated antigens have been evaluated as cancer vaccines in different cancers. In BTC, these include Wilms’ tumour gene-1 antigen (WT1) and Mucin-1 (MUC-1) ADDIN EN.CITE <EndNote><Cite><Author>Criscitiello</Author><Year>2012</Year><RecNum>1125</RecNum><DisplayText><style face="superscript">32, 33</style></DisplayText><record><rec-number>1125</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1125</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Criscitiello, Carmen</author></authors></contributors><titles><title>Tumor-associated antigens in breast cancer</title><secondary-title>Breast Care</secondary-title></titles><periodical><full-title>Breast Care</full-title></periodical><pages>262-266</pages><volume>7</volume><number>4</number><dates><year>2012</year></dates><isbn>1661-3791</isbn><urls></urls></record></Cite><Cite><Author>Oka</Author><Year>2004</Year><RecNum>1077</RecNum><record><rec-number>1077</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1077</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Oka, Yoshihiro</author><author>Tsuboi, Akihiro</author><author>Taguchi, Tetsuya</author><author>Osaki, Tadashi</author><author>Kyo, Taiichi</author><author>Nakajima, Hiroko</author><author>Elisseeva, Olga A</author><author>Oji, Yusuke</author><author>Kawakami, Manabu</author><author>Ikegame, Kazuhiro</author></authors></contributors><titles><title>Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression</title><secondary-title>Proceedings of the National Academy of Sciences of the United States of America</secondary-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title></periodical><pages>13885-13890</pages><volume>101</volume><number>38</number><dates><year>2004</year></dates><isbn>0027-8424</isbn><urls></urls></record></Cite></EndNote>32, 33. Wilms’ tumour-1 antigen was analysed in 494 samples from patients with different tumour types (BTC =23). The authors reported that polyclonal (C-19) WT1 antigen was expressed in 80% (n=15/22) of patients ADDIN EN.CITE <EndNote><Cite><Author>Nakatsuka</Author><Year>2006</Year><RecNum>74</RecNum><DisplayText><style face="superscript">34</style></DisplayText><record><rec-number>74</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">74</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nakatsuka, Shin-ichi</author><author>Oji, Yusuke</author><author>Horiuchi, Tetsuya</author><author>Kanda, Takayoshi</author><author>Kitagawa, Michio</author><author>Takeuchi, Tamotsu</author><author>Kawano, Kiyoshi</author><author>Kuwae, Yuko</author><author>Yamauchi, Akira</author><author>Okumura, Meinoshin</author></authors></contributors><titles><title>Immunohistochemical detection of WT1 protein in a variety of cancer cells</title><secondary-title>Modern pathology</secondary-title></titles><periodical><full-title>Modern pathology</full-title></periodical><pages>804-814</pages><volume>19</volume><number>6</number><dates><year>2006</year></dates><isbn>0893-3952</isbn><urls></urls></record></Cite></EndNote>34. Due to this high frequency, a Japanese phase I study of 16 patients with advanced BTC evaluated toxicity, safety and the optimum dose of the WT1 vaccine, given in combination with gemcitabine. There were no dose limiting-toxicities for the combination and the median OS in BTC was 9.5 months ADDIN EN.CITE <EndNote><Cite><Author>Kaida</Author><Year>2011</Year><RecNum>1126</RecNum><DisplayText><style face="superscript">35</style></DisplayText><record><rec-number>1126</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1126</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kaida, Miho</author><author>Morita-Hoshi, Yuriko</author><author>Soeda, Atsuko</author><author>Wakeda, Takako</author><author>Yamaki, Yuni</author><author>Kojima, Yasushi</author><author>Ueno, Hideki</author><author>Kondo, Shunsuke</author><author>Morizane, Chigusa</author><author>Ikeda, Masafumi</author></authors></contributors><titles><title>Phase 1 trial of Wilms tumor 1 (WT1) peptide vaccine and gemcitabine combination therapy in patients with advanced pancreatic or biliary tract cancer</title><secondary-title>Journal of immunotherapy</secondary-title></titles><periodical><full-title>Journal of Immunotherapy</full-title></periodical><pages>92-99</pages><volume>34</volume><number>1</number><dates><year>2011</year></dates><isbn>1524-9557</isbn><urls></urls></record></Cite></EndNote>35. Mucin-1 antigen, also found to be expressed in BTC, is a glycoprotein associated with cell membranes. A study analysed 32 surgical specimens of IHC and 7 of bile duct cystadenocarcinoma for the presence of MUC1. It was negative in bile duct cystadenocarcinoma (0%, n=0/7), 50% (n=6/12) in perihilar IHC, and 85% (n=17/20) in mass-forming IHC ADDIN EN.CITE <EndNote><Cite><Author>Higashi</Author><Year>1999</Year><RecNum>229</RecNum><DisplayText><style face="superscript">36</style></DisplayText><record><rec-number>229</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">229</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Higashi, Michiyo</author><author>Yonezawa, Suguru</author><author>Ho, Jenny JL</author><author>Tanaka, Sadao</author><author>Irimura, Tatsuro</author><author>Kim, Young S</author><author>Sato, Eiichi</author></authors></contributors><titles><title>Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: its relationship with a new morphological classification of cholangiocarcinoma</title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>1347-1355</pages><volume>30</volume><number>6</number><dates><year>1999</year></dates><isbn>1527-3350</isbn><urls></urls></record></Cite></EndNote>36. A phase I study accrued patients (n=3 BTC, and n=6 pancreatic cancer [PC]) to assess the efficacy of MUC-1 vaccine; of these, 1 patient developed stable disease ADDIN EN.CITE <EndNote><Cite><Author>YAMAMOTO</Author><Year>2005</Year><RecNum>1127</RecNum><DisplayText><style face="superscript">37</style></DisplayText><record><rec-number>1127</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1127</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>YAMAMOTO, KOTARO</author><author>UENO, TOMIO</author><author>KAWAOKA, TORU</author><author>HAZAMA, SHOICHI</author><author>FUKUI, MIKIKO</author><author>SUEHIRO, YUTAKA</author><author>HAMANAKA, YUICHIRO</author><author>IKEMATSU, YOSHITO</author><author>IMAI, KOHZOH</author><author>OKA, MASAAKI</author></authors></contributors><titles><title>MUC1 peptide vaccination in patients with advanced pancreas or biliary tract cancer</title><secondary-title>Anticancer research</secondary-title></titles><periodical><full-title>Anticancer Research</full-title></periodical><pages>3575-3579</pages><volume>25</volume><number>5</number><dates><year>2005</year></dates><isbn>0250-7005</isbn><urls></urls></record></Cite></EndNote>37. A MUC-1 peptide-loaded dendritic cell vaccine was evaluated in the adjuvant setting in a phase I/II study of 12 cases of surgically-resected PC and BTCs. At the end of the study period, 4/12 patients were still alive; the median OS was reported as 26 months ADDIN EN.CITE <EndNote><Cite><Author>Lepisto</Author><Year>2008</Year><RecNum>1128</RecNum><DisplayText><style face="superscript">38</style></DisplayText><record><rec-number>1128</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1128</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lepisto, Andrew J</author><author>Moser, Arthur J</author><author>Zeh, Herbert</author><author>Lee, Kenneth</author><author>Bartlett, David</author><author>McKolanis, John R</author><author>Geller, Brian A</author><author>Schmotzer, Amy</author><author>Potter, Douglas P</author><author>Whiteside, Theresa</author></authors></contributors><titles><title>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</title><secondary-title>Cancer therapy</secondary-title></titles><periodical><full-title>Cancer therapy</full-title></periodical><pages>955</pages><volume>6</volume><number>B</number><dates><year>2008</year></dates><urls></urls></record></Cite></EndNote>38. This study is unique as it looked at the use of vaccines in the adjuvant setting rather than in the metastatic disease group. Further to WT1 and MUC-1 vaccines, other cancer vaccines were assessed in a phase I study which accrued 9 patients with advanced IHC, EHC and GBC, refractory to standard chemotherapy, to evaluate the simultaneous administration of three cancer peptide vaccines i.e. cell division cycle associated-1 (CDCA1), Cadherin-3 (CDH3) and kinesin family member 20A (KIF20A). They reported stable disease after the 8th vaccination (1.84 months) in 4 patients, whereas 4 patients developed progressive disease. This study allowed patients to continue treatment despite disease progression, and these patients eventually developed stable disease on long-term vaccines. The median OS was 9.7 months. Whilst modest, an OS of 9.7 months following chemotherapy in refractory disease warrants further evaluation in phase II/III studies ADDIN EN.CITE <EndNote><Cite><Author>Aruga</Author><Year>2014</Year><RecNum>1129</RecNum><DisplayText><style face="superscript">39</style></DisplayText><record><rec-number>1129</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1129</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aruga, Atsushi</author><author>Takeshita, Nobuhiro</author><author>Kotera, Yoshihito</author><author>Okuyama, Ryuji</author><author>Matsushita, Norimasa</author><author>Ohta, Takehiro</author><author>Takeda, Kazuyoshi</author><author>Yamamoto, Masakazu</author></authors></contributors><titles><title>Phase I clinical trial of multiple-peptide vaccination for patients with advanced biliary tract cancer</title><secondary-title>Journal of translational medicine</secondary-title></titles><periodical><full-title>Journal of translational medicine</full-title></periodical><pages>61</pages><volume>12</volume><number>1</number><dates><year>2014</year></dates><isbn>1479-5876</isbn><urls></urls></record></Cite></EndNote>39.The role of cytokines as an immunotherapy in patients with BTCApart from the evaluation of vaccines in BTC, use of IL-2 as immunotherapy was analysed in a study alongside 13-cis-retinoic acid (RA) in 54 patients with a diagnosis of inoperable or locally advanced PC and BTC. All patients were initially treated with 3 cycles of gemcitabine and cisplatin. Then, patients with stable disease (n=38) went on to have consolidation chemo-radiotherapy with capecitabine. Of these, 14 patients (n=7 PC, n=7 BTC) who continued to have stable disease, went on to receive IL-2 and RA. After a median follow up of 27.5 months, 3 patients had achieved complete radiological responses and 11 had partial responses. After 4 years, 2 of 7 patients with PC and 3 of 7 patients with BTC were still alive; the median PFS was 16.2 months and the median OS was not reached at the last follow up (27.5 months) ADDIN EN.CITE <EndNote><Cite><Author>Recchia</Author><Year>2009</Year><RecNum>794</RecNum><DisplayText><style face="superscript">40</style></DisplayText><record><rec-number>794</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">794</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>F. Recchia</author><author>G. Sica</author><author>G. Candeloro</author><author>R. Bisegna</author><author>S. Necozione</author><author>P. Bonfili</author><author>V. Tombolini</author><author>S. Rea</author></authors></contributors><titles><title>Multicenter phase II study of sequential chemotherapy, radiotherapy, and immunotherapy in locally advanced pancreatic (Pa) and biliary tree (Bt) adenocarcinoma (ADK)</title><secondary-title>Journal of Clinical Oncology</secondary-title></titles><periodical><full-title>Journal of clinical oncology</full-title></periodical><pages>3047-3047</pages><volume>27</volume><number>15S</number><dates><year>2009</year></dates><urls><related-urls><url> promising, a major limitation of this study was that the patients with rapidly progressive disease were filtered out in the early steps. Therefore, patients who went on to receive the immunotherapy might be the ones with a more favourable underlying biology. The role of adoptive cell therapy in patients with BTCAdoptive cell therapy (ACT) refers to a process whereby patient’s?T-cells are extracted from a tumour biopsy or peripheral blood. These are then modified, expanded in vitro and re-infused into the patient after host lymphodepletion. In BTC, the evidence for use of ACT is limited to case reports or small case series of patients treated in single arm phase II studies. ?A single case study of a patient with metastatic CCA treated with TILs after progression through multiple lines of chemotherapy was reported. This patient was recruited to a phase II study ADDIN EN.CITE <EndNote><Cite><Author>NCT01174121</Author><RecNum>635</RecNum><DisplayText><style face="superscript">41</style></DisplayText><record><rec-number>635</rec-number><foreign-keys><key app="EN" db-id="rrse55p5brx9eme5szdvewr5x0drpwaf09aw" timestamp="1498659926">635</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>NCT01174121</author></authors></contributors><titles><title>Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer</title><short-title>NCT01174121</short-title></titles><keywords><keyword>Metastatic Colorectal Cancer|Metastatic Gastric Cancer|Metastatic Pancreatic Cancer|Metastatic Hepatocellular Carcinoma|Metastatic Cholangiocarcinoma</keyword></keywords><dates></dates><urls><related-urls><url> where short-term cultured autologous TILs, following a lymphocyte-depleting regimen plus use of pembrolizumab, was tested. The patient was first treated with ACT, consisting of CD4+ erbb2 interacting protein (ERbB2IP) mutation specific T-cells, and this was then followed by IL-2, to enhance T-cell proliferation and function. After the treatment, all metastatic sites started to regress and a 30% partial response was seen at 7 months. The disease remained stable for 13 months. After this, some progression was seen in lung metastases, whereas the liver metastases remained stablePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmFuPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 42. In another case study, a 59 year old patient with a diagnosis of locally advanced IHC received IL-2 activated T-cells and a monoclonal antibody to CD3, two months post resection as an adjuvant therapy. After an immunological reaction was observed (skin reaction and raised peripheral blood lymphocytes), the patient was given the same immunotherapy 3-monthly to maintain the response. At the time the case was reported, the patient was 3.5 years post-surgery without recurrence ADDIN EN.CITE <EndNote><Cite><Author>Higuchi</Author><Year>2006</Year><RecNum>1130</RecNum><DisplayText><style face="superscript">43</style></DisplayText><record><rec-number>1130</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1130</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Higuchi, Ryota</author><author>Yamamoto, Masakazu</author><author>Hatori, Takashi</author><author>Shimizu, Koichi</author><author>Imai, Kenichirou</author><author>Takasaki, Ken</author></authors></contributors><titles><title>Intrahepatic cholangiocarcinoma with lymph node metastasis successfully treated by immunotherapy with CD3-activated T cells and dendritic cells after surgery: report of a case</title><secondary-title>Surgery today</secondary-title></titles><periodical><full-title>Surgery today</full-title></periodical><pages>559-562</pages><volume>36</volume><number>6</number><dates><year>2006</year></dates><isbn>0941-1291</isbn><urls></urls></record></Cite></EndNote>43.Further to this case report, the same authors reported a case-control adjuvant study which investigated the use of autologous dendritic cell vaccine alongside activated T-cell transfer in patients who underwent curative surgery for IHC. Thirty-six patients were treated with adjuvant adoptive transfer of T-cells plus dendritic cell vaccine, and 26 patients were enrolled into the surgery only group. This study reported an improved OS of 31.9 months in the vaccinated group versus 17.4 months in the surgery only group (p=0.022) ADDIN EN.CITE <EndNote><Cite><Author>Shimizu</Author><Year>2012</Year><RecNum>1131</RecNum><DisplayText><style face="superscript">44</style></DisplayText><record><rec-number>1131</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1131</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shimizu, Koichi</author><author>Kotera, Yoshihito</author><author>Aruga, Atsushi</author><author>Takeshita, Nobuhiro</author><author>Takasaki, Ken</author><author>Yamamoto, Masakazu</author></authors></contributors><titles><title>Clinical utilization of postoperative dendritic cell vaccine plus activated T‐cell transfer in patients with intrahepatic cholangiocarcinoma</title><secondary-title>Journal of hepato-biliary-pancreatic sciences</secondary-title></titles><periodical><full-title>Journal of hepato-biliary-pancreatic sciences</full-title></periodical><pages>171-178</pages><volume>19</volume><number>2</number><dates><year>2012</year></dates><isbn>1868-6982</isbn><urls></urls></record></Cite></EndNote>44. These case reports and small series suggest some activity for ACT in patients with advanced BTC. The role of immune checkpoint inhibitors in BTCProgrammed cell death ligand-1 (PD-L1) or B7 homologue 1 (B7-H1) is a ligand that binds to programmed death-1 receptor (PD-1), and their interaction can result in inhibition of T-lymphocyte survival, propagation, cytokine release and cytotoxicity to escape the host cancer immune response ADDIN EN.CITE <EndNote><Cite><Author>Zitvogel</Author><Year>2012</Year><RecNum>1132</RecNum><DisplayText><style face="superscript">45</style></DisplayText><record><rec-number>1132</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1132</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Zitvogel, Laurence</author><author>Kroemer, Guido</author></authors></contributors><titles><title>Targeting PD-1/PD-L1 interactions for cancer immunotherapy</title></titles><dates><year>2012</year></dates><publisher>Taylor & Francis</publisher><isbn>2162-402X</isbn><urls></urls></record></Cite></EndNote>45. Pembrolizumab, a humanised monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1, has received Food and Drug Administration (FDA) approval for melanoma, advanced and metastatic non-small cell lung cancer, metastatic head and neck squamous cell cancer, classical Hodgkin’s lymphoma and metastatic urothelial cancer. Expression of PD-L1 across various tumour types has been evaluated and correlated with poor, better prognosis, or no effect ADDIN EN.CITE <EndNote><Cite><Author>Thompson</Author><Year>2004</Year><RecNum>1059</RecNum><DisplayText><style face="superscript">46, 47</style></DisplayText><record><rec-number>1059</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1059</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thompson, R Houston</author><author>Gillett, Michael D</author><author>Cheville, John C</author><author>Lohse, Christine M</author><author>Dong, Haidong</author><author>Webster, W Scott</author><author>Krejci, Kent G</author><author>Lobo, John R</author><author>Sengupta, Shomik</author><author>Chen, Lieping</author></authors></contributors><titles><title>Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target</title><secondary-title>Proceedings of the National Academy of Sciences of the United States of America</secondary-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title></periodical><pages>17174-17179</pages><volume>101</volume><number>49</number><dates><year>2004</year></dates><isbn>0027-8424</isbn><urls></urls></record></Cite><Cite><Author>Okazaki</Author><Year>2007</Year><RecNum>1060</RecNum><record><rec-number>1060</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1060</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Okazaki, Taku</author><author>Honjo, Tasuku</author></authors></contributors><titles><title>PD-1 and PD-1 ligands: from discovery to clinical application</title><secondary-title>International immunology</secondary-title></titles><periodical><full-title>International immunology</full-title></periodical><pages>813-824</pages><volume>19</volume><number>7</number><dates><year>2007</year></dates><isbn>1460-2377</isbn><urls></urls></record></Cite></EndNote>46, 47. A basket study which included various solid tumours, established the significance of PD-L1 expression on cancer cells, as well as the tumour immune infiltrate as a predictive biomarker for response to PD-L1 inhibitors ADDIN EN.CITE <EndNote><Cite><Author>Herbst</Author><Year>2014</Year><RecNum>942</RecNum><DisplayText><style face="superscript">48</style></DisplayText><record><rec-number>942</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">942</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Herbst, R. S.</author><author>Soria, J. C.</author><author>Kowanetz, M.</author><author>Fine, G. D.</author><author>Hamid, O.</author><author>Gordon, M. S.</author><author>Sosman, J. A.</author><author>McDermott, D. F.</author><author>Powderly, J. D.</author><author>Gettinger, S. N.</author><author>Kohrt, H. E.</author><author>Horn, L.</author><author>Lawrence, D. P.</author><author>Rost, S.</author><author>Leabman, M.</author><author>Xiao, Y.</author><author>Mokatrin, A.</author><author>Koeppen, H.</author><author>Hegde, P. S.</author><author>Mellman, I.</author><author>Chen, D. S.</author><author>Hodi, F. S.</author></authors></contributors><titles><title>Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><volume>515</volume><dates><year>2014</year></dates><label>Herbst2014</label><urls><related-urls><url>. Table 1 summarises the clinical studies reporting expression of PD-L1 in BTC. Most studies have been done on IHC where up to 100% of cancer cells or immune cells show PD-L1 expression, although ranges are wide (as low as 29%). In patients with EHC, the ranges are much lower; whether this is a true difference or reflects the limitations of sample size and methodology is uncertain. Moreover, PD-L1 expression alone only provides a limited glimpse into immune-competency. The interim results from the KEYNOTE-028 phase Ib clinical study for patients with BTC and PD-L1 expression (≥1%) treated with pembrolizumab, reported an overall response rate (ORR) of 17%, reasonable toxicity and durable response (duration of treatment 40+ to 42+ weeks, when reported) ADDIN EN.CITE <EndNote><Cite><Author>Bang</Author><Year>2015</Year><RecNum>1134</RecNum><DisplayText><style face="superscript">49</style></DisplayText><record><rec-number>1134</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1134</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bang, YJ</author><author>Doi, T</author><author>De Braud, F</author><author>Piha-Paul, S</author><author>Hollebecque, A</author><author>Razak, AR Abdul</author><author>Lin, CC</author><author>Ott, PA</author><author>He, AR</author><author>Yuan, SS</author></authors></contributors><titles><title>525 Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: Interim results of KEYNOTE-028</title><secondary-title>European Journal of Cancer</secondary-title></titles><periodical><full-title>European Journal of Cancer</full-title></periodical><pages>S112</pages><volume>51</volume><dates><year>2015</year></dates><isbn>0959-8049</isbn><urls></urls></record></Cite></EndNote>49. The mature analysis and results of this study, expected to complete accrual in July 2018, are awaited. Pembrolizumab was also approved in May 2017 by the FDA for the treatment of patients with metastatic or inoperable solid tumours with high microsatellite instability (MSI) or mismatch repair deficiency (MMR) ADDIN EN.CITE <EndNote><Cite><RecNum>901</RecNum><DisplayText><style face="superscript">50</style></DisplayText><record><rec-number>901</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">901</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors></contributors><titles></titles><pages>FDA approval of cancer treatment for solid tumour with specific genetic feature</pages><dates></dates><urls><related-urls><url>. One of the genetic risk factors for BTC includes Lynch syndrome, characterised by MSI and MMR-deficiency ADDIN EN.CITE <EndNote><Cite><Author>Shigeyasu</Author><Year>2014</Year><RecNum>1135</RecNum><DisplayText><style face="superscript">51</style></DisplayText><record><rec-number>1135</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1135</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shigeyasu, Kunitoshi</author><author>Tanakaya, Kohji</author><author>Nagasaka, Takeshi</author><author>Aoki, Hideki</author><author>Fujiwara, Toshiyoshi</author><author>Sugano, Kokichi</author><author>Ishikawa, Hideki</author><author>Yoshida, Teruhiko</author><author>Moriya, Yoshihiro</author><author>Furukawa, Yoichi</author></authors></contributors><titles><title>Early detection of metachronous bile duct cancer in Lynch syndrome: report of a case</title><secondary-title>Surgery today</secondary-title></titles><periodical><full-title>Surgery today</full-title></periodical><pages>1975-1981</pages><volume>44</volume><number>10</number><dates><year>2014</year></dates><isbn>0941-1291</isbn><urls></urls></record></Cite></EndNote>51. 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ADDIN EN.CITE.DATA 53 . Thus, pembrolizumab may have clinical efficacy in patients with BTC with high MSI or MMR.Table 2 summarises the current immune-mediated trials in BTC registered on clinical (last accessed 01/01/2018).DiscussionAs immunotherapy is incorporated into the list of conventional anti-cancer treatments alongside surgery, chemotherapy, radiotherapy and targeted treatments, there has been a trend for development of strategies to help clinicians with tools to assess the efficacy of these treatments. Such models include the use of an immunoscore, cancer immunogram, PD-L1 expression, host microbiota and tumour mutation burden (TMB), to name a few. Of these, the immunoscore (combined analysis of presence of CD8+ and CD45RO+ in certain areas in a cancer) ADDIN EN.CITE <EndNote><Cite><Author>Galon</Author><Year>2014</Year><RecNum>1136</RecNum><DisplayText><style face="superscript">54</style></DisplayText><record><rec-number>1136</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1136</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Galon, Jér?me</author><author>Mlecnik, Bernhard</author><author>Bindea, Gabriela</author><author>Angell, Helen K</author><author>Berger, Anne</author><author>Lagorce, Christine</author><author>Lugli, Alessandro</author><author>Zlobec, Inti</author><author>Hartmann, Arndt</author><author>Bifulco, Carlo</author></authors></contributors><titles><title>Towards the introduction of the ‘Immunoscore’in the classification of malignant tumours</title><secondary-title>The Journal of pathology</secondary-title></titles><periodical><full-title>The Journal of pathology</full-title></periodical><pages>199-209</pages><volume>232</volume><number>2</number><dates><year>2014</year></dates><isbn>1096-9896</isbn><urls></urls></record></Cite></EndNote>54 has been validated as a prognostic tool for patient outcomes in resected CRC, but its application across other tumour types neds to be confirmeded. Unlike immunoscore, the cancer immunogram, which consists of seven key elements, is not yet a validated tool, but it acts as an initial framework for studying the interface between cancer and the immune system, and may predict the likelihood of response to checkpoint inhibitors ADDIN EN.CITE <EndNote><Cite><Author>Blank</Author><Year>2016</Year><RecNum>1137</RecNum><DisplayText><style face="superscript">55</style></DisplayText><record><rec-number>1137</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1137</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Blank, Christian U</author><author>Haanen, John B</author><author>Ribas, Antoni</author><author>Schumacher, Ton N</author></authors></contributors><titles><title>The “cancer immunogram”</title><secondary-title>Science</secondary-title></titles><periodical><full-title>Science</full-title><abbr-1>Science (New York, N.Y.)</abbr-1></periodical><pages>658-660</pages><volume>352</volume><number>6286</number><dates><year>2016</year></dates><isbn>0036-8075</isbn><urls></urls></record></Cite></EndNote>55. Thus far, the expression of PD-L1 as reported by the KEYNOTE 001 study for non-small cell lung cancer (NSCLC) has been associated with clinical efficacy of agents that block the PD-L1 pathway. Nonetheless, its detection is not without limitations (differences in assays, intra-tumoural heterogeneity, variation in expression post treatments, and dynamic expression in space and time) ADDIN EN.CITE <EndNote><Cite><Author>Grigg</Author><Year>2016</Year><RecNum>1102</RecNum><DisplayText><style face="superscript">56</style></DisplayText><record><rec-number>1102</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1102</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grigg, Claud</author><author>Rizvi, Naiyer A</author></authors></contributors><titles><title>PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction?</title><secondary-title>Journal for immunotherapy of cancer</secondary-title></titles><periodical><full-title>Journal for immunotherapy of cancer</full-title></periodical><pages>48</pages><volume>4</volume><number>1</number><dates><year>2016</year></dates><isbn>2051-1426</isbn><urls></urls></record></Cite></EndNote>56. The recent FDA approval for use of checkpoint inhibitors in other gastrointestinal (GI) malignancies includes HCC and CRC, where they are effective irrespective of PD-L1 status, whereas in gastric or gastro-oesophageal junction cancer the approval is exclusively for patients with PD-L1 positive malignancies. This indicates that PD-1 expression is of limited predictive value for efficacy of checkpoint inhibitors in other GI cancers and leads clinicians and scientists to explore other possibilities to assess clinical efficacy for these newer agents. More recently, further to PD-L1 expression, symbiotic microbial cells that constitute the human microbiome have emerged as components that may influence the clinical efficacy of PD-1 blockade. A study inspected the composition of baseline stool samples from 42 patients with metastatic melanoma, divided into two groups: responders and non-responders (similar characteristics). An association between certain bacterial species in the host gut flora and clinical response was seen in this study ADDIN EN.CITE <EndNote><Cite><Author>Matson</Author><Year>2018</Year><RecNum>1103</RecNum><DisplayText><style face="superscript">57</style></DisplayText><record><rec-number>1103</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1103</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Matson, Vyara</author><author>Fessler, Jessica</author><author>Bao, Riyue</author><author>Chongsuwat, Tara</author><author>Zha, Yuanyuan</author><author>Alegre, Maria-Luisa</author><author>Luke, Jason J</author><author>Gajewski, Thomas F</author></authors></contributors><titles><title>The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients</title><secondary-title>Science</secondary-title></titles><periodical><full-title>Science</full-title><abbr-1>Science (New York, N.Y.)</abbr-1></periodical><pages>104-108</pages><volume>359</volume><number>6371</number><dates><year>2018</year></dates><isbn>0036-8075</isbn><urls></urls></record></Cite></EndNote>57. Apart from PD-L1 expression and host microbiome, TMB is another host factor that has been investigated in relation to response to immune checkpoint inhibitors. A study evaluated 240 patients with advanced NSCLC to review differences between patients who had durable clinical benefit versus no benefit with immune checkpoint inhibitors by performing targeted next generation sequencing as well as whole exome sequencing. It was noted that TMB was higher in patients who had a durable clinical benefit (p=0.006), suggesting its significance as a potential predictive marker ADDIN EN.CITE <EndNote><Cite><Author>Rizvi</Author><Year>2018</Year><RecNum>1104</RecNum><DisplayText><style face="superscript">58</style></DisplayText><record><rec-number>1104</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1104</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rizvi, Hira</author><author>Sanchez-Vega, Francisco</author><author>La, Konnor</author><author>Chatila, Walid</author><author>Jonsson, Philip</author><author>Halpenny, Darragh</author><author>Plodkowski, Andrew</author><author>Long, Niamh</author><author>Sauter, Jennifer L</author><author>Rekhtman, Natasha</author></authors></contributors><titles><title>Molecular Determinants of Response to Anti–Programmed Cell Death (PD)-1 and Anti–Programmed Death-Ligand (PD-L)-Ligand 1 Blockade in Patients With Non–Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing</title><secondary-title>Journal of Clinical Oncology</secondary-title></titles><periodical><full-title>Journal of clinical oncology</full-title></periodical><pages>JCO. 2017.75. 3384</pages><dates><year>2018</year></dates><isbn>0732-183X</isbn><urls></urls></record></Cite></EndNote>58. Data for TMB in BTC is limited. Recent work from MD Anderson, which reviewed 309 patients with BTC, identified TMB of ≥6 mutations/Mb in 19.4% of cases ADDIN EN.CITE <EndNote><Cite><Author>Jain</Author><Year>2017</Year><RecNum>1105</RecNum><DisplayText><style face="superscript">59</style></DisplayText><record><rec-number>1105</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1105</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Apurva Jain</author><author>Rachna T. Shroff</author><author>Mingxin Zuo</author><author>Jacqueline Weatherly</author><author>Funda Meric-Bernstam</author><author>Randi Isaacs</author><author>Siraj Mahamed Ali</author><author>Tanios S. Bekaii-Saab</author><author>Milind M. Javle</author></authors></contributors><titles><title>Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC)</title><secondary-title>Journal of Clinical Oncology</secondary-title></titles><periodical><full-title>Journal of clinical oncology</full-title></periodical><pages>4086-4086</pages><volume>35</volume><number>15_suppl</number><dates><year>2017</year></dates><urls><related-urls><url>. They also reported that PIK3CA and DNA repair pathways might be associated with high TMB (defined at ≥20 mut/Mb), whereas high TMB was only found in 2.9% of cases, rendering BTC at the lower end of spectrum for mutational load ADDIN EN.CITE <EndNote><Cite><Author>Jain</Author><Year>2017</Year><RecNum>1105</RecNum><DisplayText><style face="superscript">59</style></DisplayText><record><rec-number>1105</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1105</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Apurva Jain</author><author>Rachna T. Shroff</author><author>Mingxin Zuo</author><author>Jacqueline Weatherly</author><author>Funda Meric-Bernstam</author><author>Randi Isaacs</author><author>Siraj Mahamed Ali</author><author>Tanios S. Bekaii-Saab</author><author>Milind M. Javle</author></authors></contributors><titles><title>Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC)</title><secondary-title>Journal of Clinical Oncology</secondary-title></titles><periodical><full-title>Journal of clinical oncology</full-title></periodical><pages>4086-4086</pages><volume>35</volume><number>15_suppl</number><dates><year>2017</year></dates><urls><related-urls><url>. However, as response to immunotherapy is a complex, multifaceted phenomenon, this doesn’t necessarily mean that BTC is precluded from the fast growing list of cancers that may benefit from immune-mediated treatments. Apart from the above discussed predictors of response, there are other avenues to consider. Conventionally, most of the patients recruited on to phase I trials are patients with metastatic disease and exhibit a high tumour burden. This high burden suggests an active mechanism for host immune response evasion by the cancer cells. The role of high tumour burden and response to anti-PD-1 therapy was studied in patients with melanoma, particularly in stage IV disease. This trial highlighted an important issue that failure to induce an immune response in some patients was not due to the lack of ability of immune activity, but the imbalance between the high tumour burden and T-cell invigoration ADDIN EN.CITE <EndNote><Cite><Author>Huang</Author><Year>2017</Year><RecNum>1138</RecNum><DisplayText><style face="superscript">60</style></DisplayText><record><rec-number>1138</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1138</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Huang, Alexander C</author><author>Postow, Michael A</author><author>Orlowski, Robert J</author><author>Mick, Rosemarie</author><author>Bengsch, Bertram</author><author>Manne, Sasikanth</author><author>Xu, Wei</author><author>Harmon, Shannon</author><author>Giles, Josephine R</author><author>Wenz, Brandon</author></authors></contributors><titles><title>T-cell invigoration to tumour burden ratio associated with anti-PD-1 response</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><pages>60</pages><volume>545</volume><number>7652</number><dates><year>2017</year></dates><isbn>1476-4687</isbn><urls></urls></record></Cite></EndNote>60. Whilst conducting trials in a metastatic setting in BTC, this issue might be hindering progression towards a positive signal of efficacy from immune-mediated therapies.Immune-mediated treatments are now main-stream in a number of solid tumours. Understanding durability of responses, toxicity management, and use in early stages (e.g. adjuvant) and mechanisms of resistance remain areas of investigation. There is no approved immunotherapy treatment for BTC yet, but the past few years have been enlightening and the list of cancers which are being treated with these agents is fast-growing and future research may eventually lead to development of immunotherapy for poor prognostic tumour types. Nonetheless, the multiple complex autonomous and extrinsic mechanisms that govern de-novo and acquired resistance ADDIN EN.CITE <EndNote><Cite><Author>Syn</Author><Year>2017</Year><RecNum>1092</RecNum><DisplayText><style face="superscript">61</style></DisplayText><record><rec-number>1092</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1092</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Syn, Nicholas L.</author><author>Teng, Michele W. L.</author><author>Mok, Tony S. K.</author><author>Soo, Ross A.</author></authors></contributors><titles><title>De-novo and acquired resistance to immune checkpoint targeting</title><secondary-title>The Lancet Oncology</secondary-title></titles><periodical><full-title>The Lancet Oncology</full-title></periodical><pages>e731-e741</pages><volume>18</volume><number>12</number><dates><year>2017</year><pub-dates><date>12//</date></pub-dates></dates><isbn>1470-2045</isbn><urls><related-urls><url>(17)30607-1</electronic-resource-num></record></Cite></EndNote>61 to immune-modulatory agents remains an avenue for future scientific exploration. Moreover, the value of these agents in conjunction with chemotherapy or radiotherapy which may alter the immunogenicity of solid tumours warrants further study. Currently in BTC, studies of immunotherapeutic agents are ongoing and none of the current investigational drugs have been approved for this disease group. In order to achieve this, the basic immunology of BTC, the TME and the role of immunosuppressive elements on immune cell function needs to be better understood. Conflicts of interest:No conflicts of interest to declare for Dr. Noor-ul-Ain Tariq.Dr. Mairéad G McNamara has served on advisory boards for Ipsen, SHIRE and Celgene.Professor Arndt Vogel has received honoraria from AstraZeneca, Amgen, BMS, MSD, Roche and Lilly.?Professor Juan W Valle is on the Consultancy/Advisory boards for Ipsen, Novartis, AstraZeneca, Lilly, Merck, Baxalta, Delcath Systems, Agios and Pfizer.Funding:Dr. Noor-ul-Ain Tariq is funded by the Timpsons PhD fellowship.References: ADDIN EN.REFLIST 1Khan SA, Davidson BR, Goldin R, Pereira S, Rosenberg WM, Taylor-Robinson SD, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002; 51: vi1-vi9.2Saha SK, Zhu AX, Fuchs CS, Brooks GA. 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Oncotarget. 2017; 8: 24644.66Walter D, Herrmann E, Schnitzbauer A, Zeuzem S, Hansmann ML, Peveling‐Oberhag J, et al. PD‐L1 expression in extrahepatic cholangiocarcinoma. Histopathology. 2017.Table 1. Summary of clinical studies reporting expression of PD-L1 in BTC:StudyNumber of patientsType of CancerPD-L1 expression on cancer cells n (%)PD-L1 expression on immune cellsn (%)Comments ADDIN EN.CITE <EndNote><Cite><Author>Ye</Author><Year>2009</Year><RecNum>1087</RecNum><DisplayText><style face="superscript">62</style></DisplayText><record><rec-number>1087</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1087</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ye, Yufu</author><author>Zhou, Lin</author><author>Xie, Xiaojun</author><author>Jiang, Guoping</author><author>Xie, Haiyang</author><author>Zheng, Shusen</author></authors></contributors><titles><title>Interaction of B7‐H1 on intrahepatic cholangiocarcinoma cells with PD‐1 on tumor‐infiltrating T cells as a mechanism of immune evasion</title><secondary-title>Journal of surgical oncology</secondary-title></titles><periodical><full-title>Journal of surgical oncology</full-title></periodical><pages>500-504</pages><volume>100</volume><number>6</number><dates><year>2009</year></dates><isbn>1096-9098</isbn><urls></urls></record></Cite></EndNote>6231IHC31 (100%)SID 3.41±2.6131 (100%)SID 67.91±29.55SID p<0.001 ADDIN EN.CITE <EndNote><Cite><Author>Sabbatino</Author><Year>2016</Year><RecNum>1088</RecNum><DisplayText><style face="superscript">63</style></DisplayText><record><rec-number>1088</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1088</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sabbatino, Francesco</author><author>Villani, Vincenzo</author><author>Yearley, Jennifer H</author><author>Deshpande, Vikram</author><author>Cai, Lei</author><author>Konstantinidis, Ioannis T</author><author>Moon, Christina</author><author>Nota, Sjoerd</author><author>Wang, Yangyang</author><author>Al-Sukaini, Ahmad</author></authors></contributors><titles><title>PD-L1 and HLA class I antigen expression and clinical course of the disease in intrahepatic cholangiocarcinoma</title><secondary-title>Clinical Cancer Research</secondary-title></titles><periodical><full-title>Clinical Cancer Research</full-title></periodical><pages>470-478</pages><volume>22</volume><number>2</number><dates><year>2016</year></dates><isbn>1078-0432</isbn><urls></urls></record></Cite></EndNote>6327IHC8 (29.6%)27 (100%) ADDIN EN.CITE <EndNote><Cite><Author>Gani</Author><Year>2016</Year><RecNum>1089</RecNum><DisplayText><style face="superscript">64</style></DisplayText><record><rec-number>1089</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1089</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gani, Faiz</author><author>Nagarajan, Neeraja</author><author>Kim, Yuhree</author><author>Zhu, Qingfeng</author><author>Luan, Lan</author><author>Bhaijjee, Feriyl</author><author>Anders, Robert A</author><author>Pawlik, Timothy M</author></authors></contributors><titles><title>Program death 1 immune checkpoint and tumor microenvironment: implications for patients with intrahepatic cholangiocarcinoma</title><secondary-title>Annals of surgical oncology</secondary-title></titles><periodical><full-title>Annals of surgical oncology</full-title></periodical><pages>2610-2617</pages><volume>23</volume><number>8</number><dates><year>2016</year></dates><isbn>1068-9265</isbn><urls></urls></record></Cite></EndNote>6454IHC39 (72.2%)34 (62.9%) ADDIN EN.CITE <EndNote><Cite><Author>Fontugne</Author><Year>2017</Year><RecNum>1090</RecNum><DisplayText><style face="superscript">65</style></DisplayText><record><rec-number>1090</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1090</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fontugne, Jacqueline</author><author>Augustin, Jérémy</author><author>Pujals, Ana?s</author><author>Compagnon, Philippe</author><author>Rousseau, Benoit</author><author>Luciani, Alain</author><author>Tournigand, Christophe</author><author>Cherqui, Daniel</author><author>Azoulay, Daniel</author><author>Pawlotsky, Jean-Michel</author></authors></contributors><titles><title>PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma</title><secondary-title>Oncotarget</secondary-title></titles><periodical><full-title>Oncotarget</full-title></periodical><pages>24644</pages><volume>8</volume><number>15</number><dates><year>2017</year></dates><urls></urls></record></Cite></EndNote>6599IHC, EHC9 (9%)46 (46%) ADDIN EN.CITE <EndNote><Cite><Author>Walter</Author><Year>2017</Year><RecNum>1091</RecNum><DisplayText><style face="superscript">66</style></DisplayText><record><rec-number>1091</rec-number><foreign-keys><key app="EN" db-id="p90wppwr0tdasretp095wtzadvp9se0d2w0f" timestamp="0">1091</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Walter, Dirk</author><author>Herrmann, Eva</author><author>Schnitzbauer, Andreas</author><author>Zeuzem, Stefan</author><author>Hansmann, Martin Leo</author><author>Peveling‐Oberhag, Jan</author><author>Hartmann, Sylvia</author></authors></contributors><titles><title>PD‐L1 expression in extrahepatic cholangiocarcinoma</title><secondary-title>Histopathology</secondary-title></titles><periodical><full-title>Histopathology</full-title></periodical><dates><year>2017</year></dates><isbn>1365-2559</isbn><urls></urls></record></Cite></EndNote>6669EHC8 (11.6%)21 (30.4%)Biliary tract cancer (BTC), Extra-hepatic cholangiocarcinoma (EHC), Intra-hepatic cholangiocarcinoma (IHC), Staining intensity density (SID), Programmed cell death ligand protein 1 (PD-L1)Table 2. Current immune-mediated trials in BTC registered on clinical trials. gov. (last accessed 01/01/2018):NCTStudyPhaseStatusRecruiting CountriesCommentNCT03111732Pembrolizumab with CapeOx in aBTCIIRecruitingUSPD-1 antibodyNCT03358849Allogeneic NK Cell therapy in aBTCIRecruitingKoreaAllogenic natural killer cellNCT03260712Pembrolizumab in BTCIINot yetPD-1 antibodyNCT 02829918Nivolumab in patients with aBTC which is refractoryIIRecruitingUS PD-1 antibody NCT03110328Pembrolizumab in mBTC as 2nd line treatment after failing one cytotoxic chemotherapyIINot yet openKoreaPD-1 antibodyNCT03046862Durvalumab/Tremelimumab in combination with GemCis in chemotherapy-na?ve patients with BTCIIRecruitingKoreaDurvalumab= PD-L1 antibodyTremelimumab= CTLA-4 antibodyNCT03101566Nivolumab in combination with GemCis or Ipilimumab in aBTCIINot yet openUSNivolumab=PD-1 antibodyIpilimumab=CTLA4 antibodyNCT02632019Immunotherapy using precision T-cells specific to neo-antigens for treatment of advanced BTCI/IIRecruitingChinaDendritic cell precision T-cells against neoantigen NCT02586987Study to assess safety and tolerability of ascending doses of selumetinib with MEDI4736 and selumetinib, MEDI4736, tremelimumab in advanced solid tumoursIRecruitingMultinationalSelumetinib= MEK inhibitorMEDI4736= PD=L1 antibodyTremelimumab=CTLA4 antibodyNCT01938612Phase I, open label, multicentre study to evaluate MEDI4736 in advanced solid tumoursIRecruitingMultinationalPD-L1 antibodyNCT02628067Pembrolizumab in patients with advanced solid tumours KEYNOTE-158IIRecruitingMultinationalPD-1 antibodyNCT02821754Pilot study of combined immune checkpoint inhibitors with ablative therapy in HCC and BTC I/IIRecruitingUSDurvalumab=PD-L1 antibodyTremelimumab=CTLA4 antibodyNCT01853618Tremelimumab with chemoembolisation or ablation for liver cancerIActive not recruitingUSCTLA4 antibodyNCT02662348T cell mediated adaptive therapy for Her2 +ve digestive system cancerIEnrolling by invitationChinaHER2 Bi-armed T-cellsAdvanced biliary tract cancer (aBTC), Advanced cholangiocarcinoma (aCCA), Biliary tract cancer (BTC), Capecitabine and Oxaliplatin (CapeOx), carcinoma (ca), Chemotherapy (chemo) Cholangiocarcinoma (CCA), Cytotoxic T lymphocyte-associated antigen 4 (CTLA4), Gallbladder cancer (GBC), Gemcitabine and Cisplatin (GemCis), Human epidermal growth factor receptor (HER), metastatic biliary tract cancer (mBTC), Mitogen activated protein kinase (MEK), Natural Killer cell (NK), Programmed death 1 (PD-1), Programmed cell death protein ligand-1 (PD L-1), Tyrosine kinase inhibitor (TKI), United Kingdom (UK), United States (US). ................
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