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Update on immunotherapy in the management of gallbladder cancer

    Joseph Kassab‡

    *Author for correspondence:

    E-mail Address: joseph.r.kassab@gmail.com

    Department of Hematology & Oncology, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1104 2020, Lebanon

    ‡Authors contributed equally

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    ,
    Ludovic Saba‡

    Department of Hematology & Oncology, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1104 2020, Lebanon

    ‡Authors contributed equally

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    ,
    Georges Gebrael‡

    Department of Hematology & Oncology, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1104 2020, Lebanon

    ‡Authors contributed equally

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    ,
    Sami Kais

    Department of Hematology & Oncology, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1104 2020, Lebanon

    ,
    Rebecca Kassab

    Department of Hematology & Oncology, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1104 2020, Lebanon

    &
    Hampig R Kourie

    Department of Hematology & Oncology, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1104 2020, Lebanon

    Published Online:https://doi.org/10.2217/imt-2022-0191

    Gallbladder cancer (GBC) is a relatively infrequent but highly lethal cancer with a poor prognosis. Management remains challenging and controversial, and most patients are diagnosed at an advanced stage. However, with the progressive advances in the use of immunotherapies, new treatment modalities are being implemented. In September 2022, the US FDA approved durvalumab (a PD-L1 inhibitor) in combination with chemotherapy for adult patients with locally advanced or metastatic GBC. This groundbreaking news is the first FDA approval for the use of immunotherapy in biliary tract cancers. This article reviews the newest advances and trials regarding immunotherapy for GBC.

    Plain language summary

    Gallbladder cancer (GBC) is a malignant tumor that affects the cells of the gallbladder. Management of this condition is challenging and continuously evolving. Surgery, radiotherapy and chemotherapy are the current standards of care. However, recently, immunotherapy, a treatment that stimulates the host's immune system to target cancerous cells, has proven to be effective as a line of treatment. Promising results are continuously published. This article reviews the major advances in immunotherapy regarding the management of GBC.

    Papers of special note have been highlighted as: • of interest

    References

    • 1. Strom BL, Soloway RD, Rios-Dalenz JL et al. Risk factors for gallbladder cancer. An international collaborative case–control study. Cancer 76(10), 1747–1756 (1995).
    • 2. Lazcano-Ponce EC, Miquel JF, Muñoz N et al. Epidemiology and molecular pathology of gallbladder cancer. CA. Cancer J. Clin. 51(6), 349–364 (2001).
    • 3. Chijiiwa K, Sumiyoshi K, Nakayama F. Impact of recent advances in hepatobiliary imaging techniques on the preoperative diagnosis of carcinoma of the gallbladder. World J. Surg. 15(3), 322–327 (1991).
    • 4. Duffy A, Capanu M, Abou-Alfa GK et al. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J. Surg. Oncol. 98(7), 485–489 (2008).
    • 5. Oertli D, Herzog U, Tondelli P. Primary carcinoma of the gallbladder: operative experience during a 16 year period. Eur. J. Surg. Acta Chir. 159(8), 415–420 (1993).
    • 6. Cheng H, Zhou D, Wang S, Ding J, Ma F. The immunological characteristics of gallbladder carcinoma and advances in immunotherapy practices. Biosci. Trends. 15(1), 9–15 (2021).
    • 7. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann. Surg. 232(4), 557–569 (2000).
    • 8. Aloia TA, Járufe N, Javle M et al. Gallbladder cancer: expert consensus statement. HPB. 17(8), 681–690 (2015).
    • 9. Yamaguchi K, Chijiiwa K, Ichimiya H et al. Gallbladder carcinoma in the era of laparoscopic cholecystectomy. Arch. Surg. Chic. Ill 1960. 131(9), 981–984; discussion 985 (1996).
    • 10. Abramson MA, Pandharipande P, Ruan D et al. Radical resection for T1b gallbladder cancer: a decision analysis. HPB. 11(8), 656–663 (2009).
    • 11. Kwon W, Kim H, Han Y et al. Role of tumour location and surgical extent on prognosis in T2 gallbladder cancer: an international multicentre study. Br. J. Surg. 107(10), 1334–1343 (2020).
    • 12. Primrose JN, Fox R, Palmer DH et al. Adjuvant capecitabine for biliary tract cancer: the BILCAP randomized study. J. Clin. Oncol. 35(Suppl. 15), 4006 (2017).
    • 13. Edeline J, Bonnetain F, Phelip JM et al. Gemox versus surveillance following surgery of localized biliary tract cancer: results of the PRODIGE 12-ACCORD 18 (UNICANCER GI) phase III trial. J. Clin. Oncol. 35(Suppl. 4), 225 (2017).
    • 14. Shroff RT, Kennedy EB, Bachini M et al. Adjuvant therapy for resected biliary tract cancer: ASCO Clinical Practice Guideline. J. Clin. Oncol. 37(12), 1015–1027 (2019).
    • 15. Ben-Josef E, Guthrie KA, El-Khoueiry AB et al. SWOG S0809: a phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J. Clin. Oncol. 33(24), 2617–2622 (2015).
    • 16. Hakeem AR, Papoulas M, Menon KV. The role of neoadjuvant chemotherapy or chemoradiotherapy for advanced gallbladder cancer – a systematic review. Eur. J. Surg. Oncol. 45(2), 83–91 (2019).
    • 17. Valle J, Wasan H, Palmer DH et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 362(14), 1273–1281 (2010).
    • 18. Sharma A, Kalyan Mohanti B, Pal Chaudhary S et al. Modified gemcitabine and oxaliplatin or gemcitabine + cisplatin in unresectable gallbladder cancer: results of a phase III randomised controlled trial. Eur. J. Cancer 123, 162–170 (2019).
    • 19. Kim ST, Kang JH, Lee J et al. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial. Ann. Oncol. 30(5), 788–795 (2019).
    • 20. Tsavaris N, Kosmas C, Gouveris P et al. Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer. Invest. New Drugs 22(2), 193–198 (2004).
    • 21. Patt YZ, Hassan MM, Aguayo A et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer 101(3), 578–586 (2004).
    • 22. Lamarca A, Palmer DH, Wasan HS et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 22(5), 690–701 (2021).
    • 23. Yoo C, Kim K-P, Jeong JH et al. Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study. Lancet Oncol. 22(11), 1560–1572 (2021).
    • 24. Takeda K, Kojima Y, Uno T et al. Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules. J. Immunol. Baltimore. 184(10), 5493–5501 (2010).
    • 25. Mao W, Deng F, Wang D, Gao L, Shi X. Treatment of advanced gallbladder cancer: a SEER-based study. Cancer Med. 9(1), 141–150 (2020).
    • 26. Malik IA, Aziz Z, Zaidi SHM, Sethuraman G. Gemcitabine and Cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder. Am. J. Clin. Oncol. 26(2), 174–177 (2003).
    • 27. Meyerhardt JA, Zhu AX, Stuart K et al. Phase-II study of gemcitabine and cisplatin in patients with metastatic biliary and gallbladder cancer. Dig. Dis. Sci. 53(2), 564–570 (2008).
    • 28. Oh D-Y, He AR, Qin S et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. J. Clin. Oncol. 40(Suppl. 4), 378 (2022).
    • 29. Oh D-Y, Ruth HA, Qin S et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 1(8), EVIDoa2200015 (2022).
    • 30. US FDA. FDA approves durvalumab for locally advanced or metastatic biliary tract cancer (2022). www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-locally-advanced-or-metastatic-biliary-tract-cancer • The preceding two references are of considerable interest because they showcase the TOPAZ-1 clinical trial and its results, which led to US FDA approval in September 2022 of durvalumab in combination with gemcitabine and cisplatin in patients with advanced billiary tract cancer (BTC), including patients with gallbladder cancer
    • 31. Lamarca A, Palmer DH, Wasan HS et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 22(5), 690–701 (2021).
    • 32. Le DT, Durham JN, Smith KN et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357(6349), 409–413 (2017).
    • 33. US FDA. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication (2019). www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication
    • 34. Silva VWK, Askan G, Daniel TD et al. Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency. Chin. Clin. Oncol. 5(5), 62 (2016).
    • 35. 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. 6(6), 888–894 (2020).
    • 36. 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. 6(9), 1405–1409 (2020).
    • 37. Haslauer T, Greil R, Zaborsky N, Geisberger R. CAR T-cell therapy in hematological malignancies. Int. J. Mol. Sci. 22(16), 8996 (2021).
    • 38. Guo Y, Feng K, Liu Y et al. Phase I study of chimeric antigen receptor–modified T cells in patients with EGFR-positive advanced biliary tract cancers. Clin. Cancer Res. 24(6), 1277–1286 (2018).
    • 39. Kobayashi M, Sakabe T, Abe H et al. Dendritic cell-based immunotherapy targeting synthesized peptides for advanced biliary tract cancer. J. Gastrointest. Surg. 17(9), 1609–1617 (2013).
    • 40. Yashima Y, Sato S, Kawai T et al. Intraarterial 5-fluorouracil and interferon therapy is safe and effective for nonresectable biliary tract adenocarcinoma. Hepatol. Int. 9(1), 142–148 (2015).
    • 41. Merck Sharp, Dohme LLC. A phase 3 randomized, double blind study of pembrolizumab plus gemcitabine/cisplatin versus placebo plus gemcitabine/cisplatin as first-line therapy in participants with advanced and/or unresectable biliary tract carcinoma. (2019). https://clinicaltrials.gov/ct2/show/NCT04003636
    • 42. European Organisation for Research and Treatment of Cancer. Open-label first line, single-arm phase II study of cisgem combined with pembrolizumab in patients with advanced or metastatic biliary tract cancer (2017). https://clinicaltrials.gov/ct2/show/NCT03260712 • This reference introduces the ongoing clinical trial of pembrolizumab and gemcitabine/cisplatin versus placebo plus gemcitabine/cisplatin as first-line therapy in participants with advanced and/or unresectable BTC including GBC.
    • 43. Knudson KM, Hicks KC, Luo X et al. M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. Oncoimmunology 7(5), e1426519 (2018).
    • 44. EMD Serono Research & Development Institute, Inc. A phase II/III, multicenter, randomized, placebo-controlled study of gemcitabine plus cisplatin with or without bintrafusp alfa (M7824) as first-line treatment of biliary tract. https://clinicaltrials.gov/ct2/show/NCT04066491
    • 45. AIO-Studien-gGmbH. A randomized phase II trial of durvalumab and tremelimumab with gemcitabine or gemcitabine and cisplatin compared to gemcitabine and cisplatin in treatment-naïve patients with cholangio- and gallbladder carcinoma (IMMUCHEC) (2018). https://clinicaltrials.gov/ct2/show/NCT03473574
    • 46. Chen X, Wu X, Wu H et al. Camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary tract cancer: a single-arm, open-label, phase II trial. J. Immunother. Cancer 8(2), (2020). https://pubmed.ncbi.nlm.nih.gov/33172881/ • This reference is of interest because it introduces the ongoing clinical trial of durvalumab and tremelimumab with gemcitabine and cisplatin compared to gemcitabine and cisplatin in treatment-naive patients with cholangio- and gallbladder carcinoma.
    • 47. Chen X, Qin S, Gu S et al. Camrelizumab plus oxaliplatin-based chemotherapy as first-line therapy for advanced biliary tract cancer: a multicenter, phase 2 trial. Int. J. Cancer 149(11), 1944–1954 (2021).
    • 48. Li W, Yu Y, Xu X et al. Toripalimab with chemotherapy as first-line treatment for advanced biliary tract tumors: update analytic results of an open-label phase II clinical study (JS001-ZS-BC001). J. Clin. Oncol. 39(Suppl. 15), e16170 (2021).
    • 49. Jingjing L, Qi X, Wei Q et al. A phase 2, randomized, open-label, multicenter study of sintilimab and anlotinib in combination with gemcitabine plus cisplatin (GemCis) as first-line therapy in patients (pts) with advanced biliary tract cancer (BTC): SAGC. J. Clin. Oncol. 40(Suppl. 16), 4100 (2022).
    • 50. Kuang M. Adjuvant immunotherapy combined with chemoradiation for patients with high-risk reseCtable Extrahepatic chOlangiocaRcinoma and gallblaDder Cancer: a phase II, multicenter, randomized controlled trial (2020). https://clinicaltrials.gov/ct2/show/NCT04333927
    • 51. AIO-Studien-gGmbH. A randomized phase II trial of durvalumab and tremelimumab with gemcitabine or gemcitabine and cisplatin compared to gemcitabine and cisplatin in treatment-naïve patients with cholangio- and gallbladder carcinoma (IMMUCHEC) (2018). https://clinicaltrials.gov/ct2/show/NCT03473574
    • 52. Liu T. A single-arm, single-center, prospective clinical study of the efficacy and safety of chemotherapy combined with toripalimab in the treatment of advanced biliary tract cancer (2019). https://clinicaltrials.gov/ct2/show/NCT03796429
    • 53. Kuang M. Adjuvant immunotherapy combined with chemoradiation for patients with high-risk resectable extrahepatic cholangiocarcinoma and gallbladder cancer: a phase II, multicenter, randomized controlled trial (2020). https://clinicaltrials.gov/ct2/show/NCT04333927
    • 54. Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest. A phase II study of immunotherapy with durvalumab and tremelimumab in combination with capecitabine or without capecitabine in adjuvant situation for biliary tract cancer (2022). https://clinicaltrials.gov/ct2/show/NCT05239169
    • 55. Yoo C. Randomized phase 2 study of preoperative gemcitabine plus cisplatin with or without durvalumab (MEDI4736) followed by postoperative durvalumab (MEDI4736) in patients with localized biliary tract cancer (2020). https://clinicaltrials.gov/ct2/show/NCT04308174