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1
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Baharom F, Hermans D, Delamarre L, Seder RA. Vax-Innate: improving therapeutic cancer vaccines by modulating T cells and the tumour microenvironment. Nat Rev Immunol 2025; 25:195-211. [PMID: 39433884 DOI: 10.1038/s41577-024-01091-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2024] [Indexed: 10/23/2024]
Abstract
T cells have a critical role in mediating antitumour immunity. The success of immune checkpoint inhibitors (ICIs) for cancer treatment highlights how enhancing endogenous T cell responses can mediate tumour regression. However, mortality remains high for many cancers, especially in the metastatic setting. Based on advances in the genetic characterization of tumours and identification of tumour-specific antigens, individualized therapeutic cancer vaccines targeting mutated tumour antigens (neoantigens) are being developed to generate tumour-specific T cells for improved therapeutic responses. Early clinical trials using individualized neoantigen vaccines for patients with advanced disease had limited clinical efficacy despite demonstrated induction of T cell responses. Therefore, enhancing T cell activity by improving the magnitude, quality and breadth of T cell responses following vaccination is one current goal for improving outcome against metastatic tumours. Another major consideration is how T cells can be further optimized to function within the tumour microenvironment (TME). In this Perspective, we focus on neoantigen vaccines and propose a new approach, termed Vax-Innate, in which vaccination through intravenous delivery or in combination with tumour-targeting immune modulators may improve antitumour efficacy by simultaneously increasing the magnitude, quality and breadth of T cells while transforming the TME into a largely immunostimulatory environment for T cells.
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Affiliation(s)
| | - Dalton Hermans
- Vaccine Research Center, National Institutes of Health, Bethesda, MD, USA
| | | | - Robert A Seder
- Vaccine Research Center, National Institutes of Health, Bethesda, MD, USA.
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Lu J, Zhang X, Liu H, Liu Y. Exploring the Multifaceted Role of WT1 in Kidney Development and Disease. Kidney Blood Press Res 2025; 50:176-188. [PMID: 39929160 DOI: 10.1159/000544025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 01/31/2025] [Indexed: 03/12/2025] Open
Abstract
BACKGROUND The Wilms' tumor suppressor gene (WT1) is a critical regulator in kidney development and disease pathogenesis. With the identification of at least 36 isoforms in mammals, each potentially playing distinct roles, WT1's complexity is becoming increasingly apparent. The -KTS and +KTS isoforms, in particular, have been implicated in DNA and RNA regulation, respectively. This review consolidates recent insights into WT1's multifaceted role in renal morphogenesis and its implications in kidney diseases. SUMMARY Our review highlights WT1's expression during embryonic kidney development and its maintenance in postnatal kidney function. We discuss the association of WT1 mutations with genetic nephropathies like Denys-Drash and Frasier syndromes, emphasizing its genetic significance. Additionally, we explore the implications of WT1 expression alterations in glomerular diseases, such as IgA nephropathy and lupus nephritis, where its role extends beyond a mere biomarker to a potential therapeutic target. KEY MESSAGES The WT1 gene and its protein products are central to understanding kidney morphogenesis and the molecular basis of renal disorders. As our understanding of WT1's regulatory mechanisms expands, so does the potential for developing targeted therapies for kidney diseases. This review calls for further research to elucidate the precise functions of WT1 isoforms and to explore the upstream regulators of WT1 that could offer novel treatment strategies for kidney pathologies. The significance of WT1 in intricate signaling pathways governing kidney health and disease is underscored, highlighting the need for continued investigation into this pivotal gene.
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Affiliation(s)
- Jing Lu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Xiaohu Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
- Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Hanmin Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yang Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China
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Dadgar N, Arunachalam AK, Hong H, Phoon YP, Arpi-Palacios JE, Uysal M, Wehrle CJ, Aucejo F, Ma WW, Melenhorst JJ. Advancing Cholangiocarcinoma Care: Insights and Innovations in T Cell Therapy. Cancers (Basel) 2024; 16:3232. [PMID: 39335203 PMCID: PMC11429565 DOI: 10.3390/cancers16183232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/16/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, with poor prognosis and limited treatment options. Traditional therapies, such as surgery, chemotherapy, and radiation, have shown limited efficacy, especially in advanced cases. Recent advancements in immunotherapy, particularly T cell-based therapies like chimeric antigen receptor T (CAR T) cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-based therapies, have opened new avenues for improving outcomes in CCA. This review provides a comprehensive overview of the current state of T cell therapies for CCA, focusing on CAR T cell therapy. It highlights key challenges, including the complex tumor microenvironment and immune evasion mechanisms, and the progress made in preclinical and clinical trials. The review also discusses ongoing clinical trials targeting specific CCA antigens, such as MUC1, EGFR, and CD133, and the evolving role of precision immunotherapy in enhancing treatment outcomes. Despite significant progress, further research is needed to optimize these therapies for solid tumors like CCA. By summarizing the most recent clinical results and future directions, this review underscores the promising potential of T cell therapies in revolutionizing CCA treatment.
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Affiliation(s)
- Neda Dadgar
- Cleveland Clinic Foundation, Enterprise Cancer Institute, Translational Hematology & Oncology Research, Cleveland, OH 44114, USA;
| | - Arun K. Arunachalam
- Cleveland Clinic Foundation, Lerner Research Institute, Center for Immunotherapy and Precision Immuno-Oncology, Cleveland, OH 44195, USA; (A.K.A.); (H.H.); (Y.P.P.); (J.E.A.-P.); (M.U.)
| | - Hanna Hong
- Cleveland Clinic Foundation, Lerner Research Institute, Center for Immunotherapy and Precision Immuno-Oncology, Cleveland, OH 44195, USA; (A.K.A.); (H.H.); (Y.P.P.); (J.E.A.-P.); (M.U.)
| | - Yee Peng Phoon
- Cleveland Clinic Foundation, Lerner Research Institute, Center for Immunotherapy and Precision Immuno-Oncology, Cleveland, OH 44195, USA; (A.K.A.); (H.H.); (Y.P.P.); (J.E.A.-P.); (M.U.)
| | - Jorge E. Arpi-Palacios
- Cleveland Clinic Foundation, Lerner Research Institute, Center for Immunotherapy and Precision Immuno-Oncology, Cleveland, OH 44195, USA; (A.K.A.); (H.H.); (Y.P.P.); (J.E.A.-P.); (M.U.)
| | - Melis Uysal
- Cleveland Clinic Foundation, Lerner Research Institute, Center for Immunotherapy and Precision Immuno-Oncology, Cleveland, OH 44195, USA; (A.K.A.); (H.H.); (Y.P.P.); (J.E.A.-P.); (M.U.)
| | - Chase J. Wehrle
- Cleveland Clinic Foundation, Digestive Diseases & Surgery Institute, Cleveland, OH 44195, USA; (C.J.W.); (F.A.)
| | - Federico Aucejo
- Cleveland Clinic Foundation, Digestive Diseases & Surgery Institute, Cleveland, OH 44195, USA; (C.J.W.); (F.A.)
| | - Wen Wee Ma
- Cleveland Clinic Foundation, Taussig Cancer Institute, Cleveland, OH 44106, USA;
| | - Jan Joseph Melenhorst
- Cleveland Clinic Foundation, Lerner Research Institute, Center for Immunotherapy and Precision Immuno-Oncology, Cleveland, OH 44195, USA; (A.K.A.); (H.H.); (Y.P.P.); (J.E.A.-P.); (M.U.)
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Amhis N, Carignan J, Tai LH. Transforming pancreaticobiliary cancer treatment: Exploring the frontiers of adoptive cell therapy and cancer vaccines. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200825. [PMID: 39006944 PMCID: PMC11246060 DOI: 10.1016/j.omton.2024.200825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Pancreaticobiliary cancer, encompassing malignancies of both the pancreatic and biliary tract, presents a formidable clinical challenge marked by a uniformly bleak prognosis. The asymptomatic nature of its early stages often leads to delayed detection, contributing to an unfavorable 5-year overall survival rate. Conventional treatment modalities have shown limited efficacy, underscoring the urgent need for alternative therapeutic approaches. In recent years, immunotherapy has emerged as a promising avenue in the fight against pancreaticobiliary cancer. Strategies such as therapeutic vaccines and the use of tumor-infiltrating lymphocytes have garnered attention for their potential to elicit more robust and durable responses. This review seeks to illuminate the landscape of emerging immunotherapeutic interventions, offering insights from both clinical and research perspectives. By deepening our understanding of pancreaticobiliary cancer and exploring innovative treatment modalities, we aim to catalyze improvements in patient outcomes and quality of life.
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Affiliation(s)
- Nawal Amhis
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
- Department of Surgery, Division of General Surgery, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Julie Carignan
- Centre de Recherche du CHUS, Sherbrooke, QC J1H 5N4, Canada
| | - Lee-Hwa Tai
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC J1H 5N4, Canada
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Zanuso V, Tesini G, Valenzi E, Rimassa L. New systemic treatment options for advanced cholangiocarcinoma. JOURNAL OF LIVER CANCER 2024; 24:155-170. [PMID: 39113642 PMCID: PMC11449581 DOI: 10.17998/jlc.2024.08.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 08/04/2024] [Accepted: 08/07/2024] [Indexed: 10/05/2024]
Abstract
Cholangiocarcinoma (CCA) is a rare and aggressive cancer, mostly diagnosed at advanced or metastatic stage, at which point systemic treatment represents the only therapeutic option. Chemotherapy has been the backbone of advanced CCA treatment. More recently, immunotherapy has changed the therapeutic landscape, as immune checkpoint inhibitors have yielded the first improvement in survival and currently, the addition of either durvalumab or pembrolizumab to standard of care cisplatin plus gemcitabine represents the new first-line treatment option. However, the use of immunotherapy in subsequent lines has not demonstrated its efficacy and therefore, it is not approved, except for pembrolizumab in the selected microsatellite instability-high population. In addition, advances in comprehensive genomic profiling have led to the identification of targetable genetic alterations, such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2), human epidermal growth factor receptor 2 (HER2), proto-oncogene B-Raf (BRAF), neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), and mouse double minute 2 homolog (MDM2), thus favoring the development of a precision medicine approach in previously treated patients. Despite these advances, the use of molecularly driven agents is limited to a subgroup of patients. This review aims to provide an overview of the newly approved systemic therapies, the ongoing studies, and future research challenges in advanced CCA management.
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Affiliation(s)
- Valentina Zanuso
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Giulia Tesini
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Elena Valenzi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy
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Zhang G, Li J, Li G, Zhang J, Yang Z, Yang L, Jiang S, Wang J. Strategies for treating the cold tumors of cholangiocarcinoma: core concepts and future directions. Clin Exp Med 2024; 24:193. [PMID: 39141161 PMCID: PMC11324771 DOI: 10.1007/s10238-024-01460-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 07/31/2024] [Indexed: 08/15/2024]
Abstract
Cholangiocarcinoma (CCA) is a rare type of digestive tract cancer originating from the epithelial cells of the liver and biliary tract. Current treatment modalities for CCA, such as chemotherapy and radiation therapy, have demonstrated limited efficacy in enhancing survival rates. Despite the revolutionary potential of immunotherapy in cancer management, its application in CCA remains restricted due to the minimal infiltration of immune cells in these tumors, rendering them cold and unresponsive to immune checkpoint inhibitors (ICIs). Cancer cells within cold tumors deploy various mechanisms for evading immune attack, thus impeding clinical management. Recently, combination immunotherapy has become increasingly essential to comprehend the mechanisms underlying cold tumors to enhance a deficient antitumor immune response. Therefore, a thorough understanding of the knowledge on the combination immunotherapy of cold CCA is imperative to leverage the benefits of immunotherapy in treating patients. Moreover, gut microbiota plays an essential role in the immunotherapeutic responses in CCA. In this review, we summarize the current concepts of immunotherapy in CCA and clarify the intricate dynamics within the tumor immune microenvironment (TIME) of CCA. We also delve into the evasion mechanisms employed by CCA tumors against the anti-tumor immune responses. The context of combination immunotherapies in igniting cold tumors of CCA and the critical function of gut microbiota in prompting immune responses have also been annotated. Furthermore, we have proposed future directions in the realm of CCA immunotherapy, aiming to improve the clinical prognosis of CCA patients.
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Affiliation(s)
- GuanBo Zhang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - JinSong Li
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Gang Li
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Jie Zhang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Zhi Yang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - Lin Yang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - ShiJie Jiang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China
| | - JiaXing Wang
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital, Chengdu, 610041, Sichuan, China.
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Yue S, Zhang Y, Zhang W. Recent Advances in Immunotherapy for Advanced Biliary Tract Cancer. Curr Treat Options Oncol 2024; 25:1089-1111. [PMID: 39066855 PMCID: PMC11329538 DOI: 10.1007/s11864-024-01243-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2024] [Indexed: 07/30/2024]
Abstract
OPINION STATEMENT Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies that arise from the epithelium of the biliary tract. Most patients present with locally advanced or metastatic disease at the time of diagnosis. For patients with unresectable BTC, the survival advantage provided by systemic chemotherapy was limited. Over the last decade, immunotherapy has significantly improved the therapeutic landscape of solid tumors. There is an increasing number of studies evaluating the application of immunotherapy in BTC, including immune checkpoint inhibitors (ICIs), cancer vaccines and adoptive cell therapy. The limited response to ICIs monotherapy in unselected patients prompted investigators to explore different combination therapy strategies. Early clinical trials of therapeutic cancer vaccination and adoptive cell therapy have shown encouraging clinical results. However, there still has been a long way to go via validation of therapeutic efficacy and exploration of strategies to increase the efficacy. Identifying biomarkers that predict the response to immunotherapy will allow a more accurate selection of candidates. This review will provide an up-to-date overview of the current clinical data on the role of immunotherapy, summarize the promising biomarkers predictive of the response to ICIs and discuss the perspective for future research direction of immunotherapy in advanced BTC.
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Affiliation(s)
- Shiwei Yue
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China
| | - Yunpu Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China
| | - Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China.
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China.
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Heumann P, Albert A, Gülow K, Tümen D, Müller M, Kandulski A. Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma. Cancers (Basel) 2024; 16:1690. [PMID: 38730642 PMCID: PMC11083102 DOI: 10.3390/cancers16091690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/17/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor.
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Affiliation(s)
- Philipp Heumann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
| | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
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Sun Y, Gong J, Li Z, Han L, Sun D. Gallbladder cancer: surgical treatment, immunotherapy, and targeted therapy. Postgrad Med 2024; 136:278-291. [PMID: 38635593 DOI: 10.1080/00325481.2024.2345585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 04/12/2024] [Indexed: 04/20/2024]
Abstract
Gallbladder cancer is a common type of biliary tract tumor. Optimal management for early stage cases typically involves radical excision as the primary treatment modality. Various surgical techniques, including laparoscopic, robotic, and navigational surgery, have demonstrated favorable clinical outcomes in radical gallbladder excision. Unfortunately, most patients are ineligible for surgical intervention because of the advanced stage of the disease upon diagnosis. Consequently, non-surgical interventions, such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy, have become the mainstay of treatment for patients in advanced stages. This review focuses on elucidating various surgical techniques as well as advancements in immunotherapy and targeted therapy in the context of recent advancements in gallbladder cancer research.
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Affiliation(s)
- Yanjun Sun
- Department of General Surgery, The Armed Police Corps Hospital of Anhui, Hefei, China
| | - Junfeng Gong
- Department of General Surgery, The Armed Police Corps Hospital of Anhui, Hefei, China
| | | | - Lin Han
- Department of General Surgery, The Armed Police Corps Hospital of Anhui, Hefei, China
| | - Dengqun Sun
- Department of General Surgery, The Armed Police Corps Hospital of Anhui, Hefei, China
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Zhao Y, Yang M, Feng J, Wang X, Liu Y. Advances in immunotherapy for biliary tract cancers. Chin Med J (Engl) 2024; 137:524-532. [PMID: 37646139 DOI: 10.1097/cm9.0000000000002759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Indexed: 09/01/2023] Open
Abstract
ABSTRACT Biliary tract cancers (BTC), a heterogeneous disease with poor prognosis, including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC). Although surgery is currently the primary regimen to treat BTC, most BTC patients are diagnosed at an advanced stage and miss the opportunity of surgical eradication. As a result, non-surgical therapy serves as the main intervention for advanced BTC. In recent years, immunotherapy has emerged as one of the most promising therapies in a number of solid cancers, and it includes immune checkpoint inhibitors (ICIs) monotherapy or combined therapy, tumor vaccines, oncolytic virus immunotherapy, adoptive cell therapy (ACT), and cytokine therapy. However, these therapies have been practiced in limited clinical settings in patients with BTC. In this review, we focus on the discussion of latest advances of immunotherapy in BTC and update the progress of multiple current clinical trials with different immunotherapies.
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Affiliation(s)
- Yuhao Zhao
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease, Shanghai 200082, China
| | - Mao Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease, Shanghai 200082, China
| | - Jiayi Feng
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease, Shanghai 200082, China
| | - Xu'an Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease, Shanghai 200082, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease, Shanghai 200082, China
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11
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Wilbur HC, Azad NS. Immunotherapy for the treatment of biliary tract cancer: an evolving landscape. Ther Adv Med Oncol 2024; 16:17588359241235799. [PMID: 38449562 PMCID: PMC10916472 DOI: 10.1177/17588359241235799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 02/12/2024] [Indexed: 03/08/2024] Open
Abstract
Biliary tract cancers (BTCs), consisting of intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, are an aggressive, heterogeneous malignancy. They are most often diagnosed in the locally advanced or metastatic setting, at which point treatment consists of systemic therapy or best supportive care. Our understanding of the tumor microenvironment and the molecular classification has led to the identification of targetable mutations, such as isocitrate dehydrogenase 1 and fibroblast growth factor receptor 2. Despite the identification of these genomic alterations, until recently, little advancement had been made in the first-line setting for advanced BTC. While immunotherapy (IO) has revolutionized the treatment of many malignancies, the use of IO in BTC had yielded limited results prior to TOPAZ-1. In this review, we discuss the systemic therapeutic advances for BTC over the past decade, the rationale for immunotherapy in BTC, prior trials utilizing IO in BTC, and current and emerging immune-based therapeutic options. We further analyze the culmination of these advances, which resulted in the approval of durvalumab with gemcitabine and cisplatin for the first-line treatment of BTC per TOPAZ-1. We also discuss the results of KEYNOTE-966, which similarly reported improved clinical outcomes with the use of pembrolizumab in combination with gemcitabine and cisplatin.
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Affiliation(s)
- Helen Catherine Wilbur
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Nilofer S. Azad
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 401 N. Broadway, Baltimore, MD 21287, USA
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Gugulothu KN, Anvesh Sai P, Suraparaju S, Karuturi SP, Pendli G, Kamma RB, Nimmagadda K, Modepalli A, Mamilla M, Vashist S. WT1 Cancer Vaccine in Advanced Pancreatic Cancer: A Systematic Review. Cureus 2024; 16:e56934. [PMID: 38665761 PMCID: PMC11043900 DOI: 10.7759/cureus.56934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Advanced pancreatic cancer is one of the prominent contributors to cancer-related mortality globally. Chemotherapy, especially gemcitabine, is generally used for the treatment of advanced pancreatic cancer. Despite the treatment, the fatality rate for advanced pancreatic cancer is alarmingly high. Thus, the dire need for better treatment alternatives has drawn focus to cancer vaccinations. The Wilms tumor gene (WT1), typically associated with Wilms tumor, is found to be excessively expressed in some cancers, such as pancreatic cancer. This characteristic feature is harvested to develop cancer vaccines against WT1. This review aims to systematically summarize the clinical trials investigating the efficacy and safety of WT1 vaccines in patients with advanced pancreatic cancer. An extensive literature search was conducted on databases Medline, Web of Science, ScienceDirect, and Google Scholar using the keywords "Advanced pancreatic cancer," "Cancer vaccines," "WT1 vaccines," and "Pulsed DC vaccines," and the results were exclusively studied to construct this review. WT1 vaccines work by introducing peptides from the WT1 protein to trigger an immune response involving cytotoxic T lymphocytes via antigen-presenting cells. Upon activation, these lymphocytes induce apoptosis in cancer cells by specifically targeting those with increased WT1 levels. WT1 vaccinations, which are usually given in addition to chemotherapy, have demonstrated clinically positive results and minimal side effects. However, there are several challenges to their widespread use, such as the immunosuppressive nature of tumors and heterogeneity in expression. Despite these limitations, the risk-benefit profile of cancer vaccines is encouraging, especially for the WT1 vaccine in the treatment of advanced pancreatic cancer. Considering the fledgling status of their development, large multicentric, variables-matched, extensive analysis across diverse demographics is considered essential.
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Affiliation(s)
| | | | - Sonika Suraparaju
- Internal Medicine, Sri Padmavathi Medical College for Women, Tirupati, IND
| | | | - Ganesh Pendli
- Internal Medicine, PES Institute of Medical Sciences and Research, Kuppam, IND
| | - Ravi Babu Kamma
- Internal Medicine, Sri Venkata Sai (SVS) Medical College, Mahabubnagar, IND
| | | | - Alekhya Modepalli
- Internal Medicine, Sri Padmavathi Medical College for Women, Tirupati, IND
| | - Mahesh Mamilla
- Internal Medicine, Sri Venkateswara Medical College, Tirupati, IND
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13
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Herpels M, Ishihara J, Sadanandam A. The clinical terrain of immunotherapies in heterogeneous pancreatic cancer: unravelling challenges and opportunities. J Pathol 2023; 260:533-550. [PMID: 37550956 DOI: 10.1002/path.6171] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 08/09/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer and has abysmal survival rates. In the past two decades, immunotherapeutic agents with success in other cancer types have gradually been trialled against PDACs at different stages of cancer progression, either as a monotherapy or in combination with chemotherapy. Unfortunately, to this day, chemotherapy still prolongs the survival rates the most and is prescribed in clinics despite the severe side effects in other cancer types. The low success rates of immunotherapy against PDAC have been attributed most frequently to its complex and multi-faceted tumour microenvironment (TME) and low mutational burden. In this review, we give a comprehensive overview of the immunotherapies tested in PDAC clinical trials thus far, their limitations, and potential explanations for their failure. We also discuss the existing classification of heterogenous PDACs into cancer, cancer-associated fibroblast, and immune subtypes and their potential opportunity in patient selection as a form of personalisation of PDAC immunotherapy. © 2023 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Melanie Herpels
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Department of Bioengineering, Imperial College London, London, UK
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, UK
| | - Anguraj Sadanandam
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Centre for Global Oncology, Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Centre for Translational Immunotherapy, Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
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14
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Lo JH, Agarwal R, Goff LW, Heumann TR. Immunotherapy in Biliary Tract Cancers: Current Standard-of-Care and Emerging Strategies. Cancers (Basel) 2023; 15:3312. [PMID: 37444422 PMCID: PMC10340362 DOI: 10.3390/cancers15133312] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade, immunotherapy has had a profound impact on the management of many solid tumor types, particularly in using immune checkpoint inhibition to enable a tumor-directed T cell response. Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of biomarker-based tumor-agnostic indications for immunotherapy. However, immunotherapy in conjunction with chemotherapy, molecularly targeted therapies, and/or anti-angiogenic therapies has gained traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific immunotherapy approval, establishing the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of pembrolizumab with gemcitabine and cisplatin in the same setting, adding further evidence for the addition of immune checkpoint inhibition to the standard chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted therapeutics for the subset of BTCs harboring alterations in IDH1, FGFR2, MAP kinase signaling, HER2, and beyond, and there has been great interest in investigating combinations of these agents with immunotherapy. Emerging immunotherapy strategies beyond immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive cell therapy, and cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of immunotherapy in BTC management in the near future.
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Affiliation(s)
| | | | | | - Thatcher R. Heumann
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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15
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Manthopoulou E, Ramai D, Dhar J, Samanta J, Ioannou A, Lusina E, Sacco R, Facciorusso A. Cholangiocarcinoma in the Era of Immunotherapy. Vaccines (Basel) 2023; 11:1062. [PMID: 37376451 PMCID: PMC10301507 DOI: 10.3390/vaccines11061062] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/27/2023] [Accepted: 06/03/2023] [Indexed: 06/29/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a rare malignancy of the gastrointestinal tract, with aggressive behavior, and portends a poor prognosis. Traditionally, it is classified according to its site of involvement as intrahepatic, perihilar, and distal cholangiocarcinoma. A host of genetic and epigenetic factors have been involved in its pathogenesis. Chemotherapy has remained the standard first-line treatment over the last decade, with a disappointing median overall survival of 11 months for locally advanced and metastatic CCA. The advent of immunotherapy has revolutionized the treatment of many pancreaticobiliary malignancies, offering durable responses with a safe therapeutic profile. To date, there have been no significant advances in the management of CCA. Novel immunotherapeutic methods, such as cancer vaccines, adoptive cell therapy, and combinations of immune checkpoint inhibitors with other agents, are currently under investigation and may improve prognosis with overall survival. Efforts to find robust biomarkers for response to treatment along with multiple clinical trials are also ongoing in this regard. In this review, we present an overview of the current advances and the future perspectives of immunotherapy in the management of CCA.
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Affiliation(s)
- Eleni Manthopoulou
- Department of Gastroenterology, St. Savvas Oncology Hospital of Athens, 11522 Athens, Greece;
| | - Daryl Ramai
- Gastroenterology and Hepatology, University of Utah Health, Salt Lake City, UT 801385, USA;
| | - Jahnvi Dhar
- Department of Gastroenterology, Sohana Multi-Speciality Hospital, Mohali 140308, India;
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India;
| | - Jayanta Samanta
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India;
| | - Alexandros Ioannou
- Department of Gastroenterology, Alexandra General Hospital, Lourou 4-2, 11528 Athens, Greece;
| | - Ekaterina Lusina
- Therapeutic Unit, Gastroenterology Department, Chaika Clinics, Lesnaya Street 9, 125196 Moscow, Russia;
| | - Rodolfo Sacco
- Department Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy;
| | - Antonio Facciorusso
- Department Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy;
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16
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Zeng W, Mao R, Zhang Z, Chen X. Combination Therapies for Advanced Biliary Tract Cancer. J Clin Transl Hepatol 2023; 11:490-501. [PMID: 36643047 PMCID: PMC9817051 DOI: 10.14218/jcth.2022.00277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 08/09/2022] [Accepted: 08/18/2022] [Indexed: 01/18/2023] Open
Abstract
Biliary tract cancers (BTCs) are a group of malignant neoplasms that have recently increased in incidence and have a poor prognosis. Surgery is the only curative therapy. However, most patients are only indicated for palliative therapy because of advanced-stage disease at diagnosis and rapid progression. The current first-line treatment for advanced BTC is gemcitabine and cisplatin chemotherapy. Nonetheless, many patients develop resistance to this regimen. Over the years, few chemotherapy regimens have managed to improve the overall survival of patients. Accordingly, novel therapies such as targeted therapy have been introduced to treat this patient population. Extensive research on tumorigenesis and the genetic profiling of BTC have revealed the heterogenicity and potential target pathways, such as EGFR, VEGF, MEK/ERK, PI3K and mTOR. Moreover, mutational analysis has documented the presence of IDH1, FGFR2, HER2, PRKACA, PRKACB, BRAF, and KRAS gene aberrations. The emergence of immunotherapy in recent years has expanded the treatment landscape for this group of malignancies. Cancer vaccines, adoptive cell transfer, and immune checkpoint inhibitors have been extensively investigated in trials of BTC. Therefore, patient stratification and a combination of various therapies have become a reasonable and important clinical strategy to improve patient outcomes. This review elaborates the literature on combined treatment strategies for advanced BTC from the past few years and ongoing clinical trials to provide new inspiration for the treatment of advanced BTC.
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Affiliation(s)
- Weifeng Zeng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ruiqi Mao
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Correspondence to: Zhanguo Zhang and Xiaoping Chen, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, 1095 Jiefang Avenue, Wuhan, Hubei 430030, China. ORCID: https://orcid.org/0000-0002-4527-4975 (ZZ). Tel: +86-27-83663400, Fax: +86-27-83662851, E-mail: (ZZ) and (XC)
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Correspondence to: Zhanguo Zhang and Xiaoping Chen, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, 1095 Jiefang Avenue, Wuhan, Hubei 430030, China. ORCID: https://orcid.org/0000-0002-4527-4975 (ZZ). Tel: +86-27-83663400, Fax: +86-27-83662851, E-mail: (ZZ) and (XC)
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17
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Zhao LM, Shi AD, Yang Y, Liu ZL, Hu XQ, Shu LZ, Tang YC, Zhang ZL. Advances in molecular and cell therapy for immunotherapy of cholangiocarcinoma. Front Oncol 2023; 13:1140103. [PMID: 37064120 PMCID: PMC10090456 DOI: 10.3389/fonc.2023.1140103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 03/17/2023] [Indexed: 03/31/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly malignant tumor of the hepatobiliary system that has failed to respond to many traditional therapies to a certain extent, including surgery, chemotherapy and radiotherapy. In recent years, the new therapeutic schemes based on immunology have fundamentally changed the systemic treatment of various malignant tumors to a certain extent. In view of the immunogenicity of CCA, during the occurrence and development of CCA, some immunosuppressive substances are released from cells and immunosuppressive microenvironment is formed to promote the escape immune response of its own cells, thus enhancing the malignancy of the tumor and reducing the sensitivity of the tumor to drugs. Some immunotherapy regimens for cholangiocarcinoma have produced good clinical effects. Immunotherapy has more precise characteristics and less adverse reactions compared with traditional treatment approaches. However, due to the unique immune characteristics of CCA, some patients with CCA may not benefit in the long term or not benefit at all after current immunotherapy. At present, the immunotherapy of CCA that have been clinically studied mainly include molecular therapy and cell therapy. In this article, we generalized and summarized the current status of immunotherapy strategies including molecular therapy and cell therapy in CCA in clinical studies, and we outlined our understanding of how to enhance the clinical application of these immunotherapy strategies.
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Affiliation(s)
- Li-ming Zhao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - An-da Shi
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Yan Yang
- Department of General Surgery, Shanxian Central Hospital, Heze, China
| | - Zeng-li Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
- Department of General Surgery, Qilu Hospital (Qingdao), Shandong University, Jinan, China
| | - Xiao-Qiang Hu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Li-Zhuang Shu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Yong-chang Tang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
- *Correspondence: Yong-chang Tang, ; Zong-li Zhang,
| | - Zong-li Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
- *Correspondence: Yong-chang Tang, ; Zong-li Zhang,
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18
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Skouteris N, Papageorgiou G, Fioretzaki R, Charalampakis N, Schizas D, Kykalos S, Tolia M. Immune checkpoint inhibitors and combinations with other agents in cholangiocarcinoma. Immunotherapy 2023; 15:487-502. [PMID: 36876442 DOI: 10.2217/imt-2022-0225] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023] Open
Abstract
Cholangiocarcinoma consists of a heterogeneous group of malignancies with generally poor prognoses. Immunotherapy has emerged in the treatment landscape of many tumors, offering survival benefits, but data regarding the use of immunotherapy for cholangiocarcinoma remain vague. In this review, the authors analyze differences in the tumor microenvironment and various immune escape mechanisms and discuss available immunotherapy combinations with other agents among completed and ongoing clinical trials, such as chemotherapy, targeted agents, antiangiogenic drugs, local ablative therapies, cancer vaccines, adoptive cell therapy and PARP and TGF-β inhibitors. Ongoing research to identify appropriate biomarkers is warranted.
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Affiliation(s)
- Nikolaos Skouteris
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Georgios Papageorgiou
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Rodanthi Fioretzaki
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Nikolaos Charalampakis
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | - Stylianos Kykalos
- Second Propedeutic Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | - Maria Tolia
- Department of Radiation Oncology, University Hospital of Crete, Voutes, Heraklion, Crete, 71110, Greece
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Yu X, Zhu L, Wang T, Chen J. Immune microenvironment of cholangiocarcinoma: Biological concepts and treatment strategies. Front Immunol 2023; 14:1037945. [PMID: 37138880 PMCID: PMC10150070 DOI: 10.3389/fimmu.2023.1037945] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 03/27/2023] [Indexed: 05/05/2023] Open
Abstract
Cholangiocarcinoma is characterized by a poor prognosis with limited treatment and management options. Chemotherapy using gemcitabine with cisplatin is the only available first-line therapy for patients with advanced cholangiocarcinoma, although it offers only palliation and yields a median survival of < 1 year. Recently there has been a resurgence of immunotherapy studies focusing on the ability of immunotherapy to inhibit cancer growth by impacting the tumor microenvironment. Based on the TOPAZ-1 trial, the US Food and Drug Administration has approved the combination of durvalumab and gemcitabine with cisplatin as the first-line treatment of cholangiocarcinoma. However, immunotherapy, like immune checkpoint blockade, is less effective in cholangiocarcinoma than in other types of cancer. Although several factors such as the exuberant desmoplastic reaction are responsible for cholangiocarcinoma treatment resistance, existing literature on cholangiocarcinoma cites the inflammatory and immunosuppressive environment as the most common factor. However, mechanisms activating the immunosuppressive tumor microenvironment contributing to cholangiocarcinoma drug resistance are complicated. Therefore, gaining insight into the interplay between immune cells and cholangiocarcinoma cells, as well as the natural development and evolution of the immune tumor microenvironment, would provide targets for therapeutic intervention and improve therapeutic efficacy by developing multimodal and multiagent immunotherapeutic approaches of cholangiocarcinoma to overcome the immunosuppressive tumor microenvironment. In this review, we discuss the role of the inflammatory microenvironment-cholangiocarcinoma crosstalk and reinforce the importance of inflammatory cells in the tumor microenvironment, thereby highlighting the explanatory and therapeutic shortcomings of immunotherapy monotherapy and proposing potentially promising combinational immunotherapeutic strategies.
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Affiliation(s)
- Xianzhe Yu
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Department of Gastrointestinal Surgery, Chengdu Second People’s Hospital, Chengdu, Sichuan, China
| | - Lingling Zhu
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Ting Wang
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jiang Chen
- Department of General Surgery, Sir Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- *Correspondence: Jiang Chen,
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Abstract
PURPOSE OF REVIEW Biliary tract cancers (BTCs) are a heterogenous group of cancers arising from the biliary tract. The hallmark of these cancers is the advanced stage of presentation and a paucity of durable treatment options. Despite the advances in targeted therapy and immunotherapy in solid tumors, systemic cytotoxic chemotherapy has remained the mainstay for cholangiocarcinomas. RECENT FINDINGS With advances in the understanding of the tumor microenvironment, genetic features, and inflammatory milieu, have led to the identification of tumor-infiltrating immune cells as indicators of prognosis and response to treatment in BTC. Through an improved comprehension of immunology, immuno-oncology is becoming another pillar of treatment along with traditional radiation, surgery, cytotoxic chemotherapy, and targeted therapies. This article reviews the evidence for immunotherapy use in cholangiocarcinoma, which still being in infancy, and offers promising new novel options for the management of biliary tract cancers.
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21
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Ruff SM, Shannon AH, Pawlik TM. Advances in Targeted Immunotherapy for Hepatobiliary Cancers. Int J Mol Sci 2022; 23:13961. [PMID: 36430440 PMCID: PMC9698563 DOI: 10.3390/ijms232213961] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer of the hepatobiliary system can be divided into primary liver cancer and biliary tract cancer (BTC), which includes hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder cancer (GBC). These aggressive cancers often present at an advanced stage or among patients with poorly preserved liver function. The primary treatment for HCC and BTC when diagnosed early is surgical resection, but given the high rate of recurrence and often advanced stage at diagnosis, many patients will require systemic therapy. Unfortunately, even with systemic therapy, long-term survival is poor. The immune system plays an important role in preventing cancer progression. The unique immune environment of the liver and subsequent alterations to the immune microenvironment by tumor cells to create a favorable microenvironment plays a key role in the progression of HCC and BTC. Due to the paucity of effective systemic therapies and distinctive immune environment of the liver, research and clinical trials are investigating the use of immunotherapy in HCC and BTC. This review will focus on current immunotherapies and emerging data for the treatment of HCC and BTC.
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Affiliation(s)
| | | | - Timothy M. Pawlik
- Department of Surgery, Division of Surgical Oncology, Wexner Medical Center, The James Comprehensive Cancer Center, The Ohio State University, 395 W. 12th Ave., Suite 670, Columbus, OH 43210, USA
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22
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Apport de l'immunothérapie dans le traitement des cancers des voies biliaires avancés. Bull Cancer 2022; 109:11S11-11S20. [DOI: 10.1016/s0007-4551(22)00464-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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23
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Yuan ZG, Zeng TM, Tao CJ. Current and emerging immunotherapeutic approaches for biliary tract cancers. Hepatobiliary Pancreat Dis Int 2022; 21:440-449. [PMID: 36115807 DOI: 10.1016/j.hbpd.2022.08.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/29/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Biliary tract cancers (BTCs) comprise a heterogeneous group of aggressive malignancies with unfavorable prognoses. The benefit of chemotherapy seems to have reached a bottleneck and, therefore, new effective therapeutic strategies for advanced BTCs are needed. Molecularly targeted therapies in selected patients are rapidly changing the situation. However, the low frequency of specific driver alterations in BTCs limits their wide application. Recently, immunotherapeutic approaches are also under active investigation in BTCs, but the role of immunotherapy in BTCs remains controversial. DATA SOURCES PubMed, Web of Science, and meeting resources were searched for relevant articles published from January 2017 to May 2022. The search aimed to identify current and emerging immunotherapeutic approaches for BTCs. Information on clinical trials was obtained from https://clinicaltrials.gov/ and http://www.chictr.org.cn/. RESULTS Immunotherapy in BTC patients is currently under investigation, and most of the investigations focused on the application of immune checkpoint inhibitors (ICIs). However, only a subgroup of BTCs with microsatellite-instability high (MSI-H)/DNA mismatch repair-deficient (dMMR) or tumor mutational burden-high (TMB-H) benefit from monotherapy of ICIs, and limited activity was observed in the second or subsequent settings. Nevertheless, promising results come from studies of ICIs in combination with other therapeutic approaches, including chemotherapy, in advanced BTCs, with a moderate toxicity profile. Recent studies demonstrated that compared to GEMCIS alone, durvalumab plus GEMCIS significantly improved patient survival (TOPAZ-1 trial) and that ICIs-combined chemoimmunotherapy is poised to become a new frontline therapy option, regardless of TMB and MMR/MSI status. Adoptive cell therapy and peptide- or dendritic-based cancer vaccines are other immunotherapeutic options that are being studied in BTCs. Numerous biomarkers have been investigated to define their predictive role in response to ICIs, but no predictive biomarker has been validated, except MSI-H/dMMR. CONCLUSIONS The role of immunotherapy in BTCs is currently under investigation and the results of ongoing studies are eagerly anticipated. Several studies have demonstrated the safety and efficacy of ICIs in combination with chemotherapy in treatment-naive patients, such as the phase III TOPAZ-1 trial, which will change the standard care of first-line chemotherapy for advanced BTCs. However, further research is needed to understand the best combination with immunotherapy and to discover more predictive biomarkers to guide clinical practice.
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Affiliation(s)
- Zhen-Gang Yuan
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai 200438, China.
| | - Tian-Mei Zeng
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai 200438, China
| | - Chen-Jie Tao
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai 200438, China
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Elvevi A, Laffusa A, Scaravaglio M, Rossi RE, Longarini R, Stagno AM, Cristoferi L, Ciaccio A, Cortinovis DL, Invernizzi P, Massironi S. Clinical treatment of cholangiocarcinoma: an updated comprehensive review. Ann Hepatol 2022; 27:100737. [PMID: 35809836 DOI: 10.1016/j.aohep.2022.100737] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 06/25/2022] [Indexed: 02/04/2023]
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA). The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types. When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor. In order to ameliorate patients' survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.
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Affiliation(s)
- Alessandra Elvevi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Alice Laffusa
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Miki Scaravaglio
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Roberta Elisa Rossi
- Gastroenterology and Endoscopy Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy
| | - Raffaella Longarini
- Division of Oncology, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Anna Maria Stagno
- Division of Oncology, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Antonio Ciaccio
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Diego Luigi Cortinovis
- Division of Oncology, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Sara Massironi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
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25
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Yin C, Alqahtani A, Noel MS. The Next Frontier in Pancreatic Cancer: Targeting the Tumor Immune Milieu and Molecular Pathways. Cancers (Basel) 2022; 14:2619. [PMID: 35681599 PMCID: PMC9179513 DOI: 10.3390/cancers14112619] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/13/2022] [Accepted: 05/19/2022] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with abysmal prognosis. It is currently the third most common cause of cancer-related mortality, despite being the 11th most common cancer. Chemotherapy is standard of care in all stages of pancreatic cancer, yet survival, particularly in the advanced stages, often remains under one year. We are turning to immunotherapies and targeted therapies in PDAC in order to directly attack the core features that make PDAC notoriously resistant to chemotherapy. While the initial studies of these agents in PDAC have generally been disappointing, we find optimism in recent preclinical and early clinical research. We find that despite the immunosuppressive effects of the PDAC tumor microenvironment, new strategies, such as combining immune checkpoint inhibitors with vaccine therapy or chemokine receptor antagonists, help elicit strong immune responses. We also expand on principles of DNA homologous recombination repair and highlight opportunities to use agents, such as PARP inhibitors, that exploit deficiencies in DNA repair pathways. Lastly, we describe advances in direct targeting of driver mutations and metabolic pathways and highlight some technological achievements such as novel KRAS inhibitors.
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Affiliation(s)
| | | | - Marcus S. Noel
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA; (C.Y.); (A.A.)
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26
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Giorgione R, Risaliti M, Bartolini I, Rossi G, Pillozzi S, Muiesan P, Taddei A, Antonuzzo L. The emerging role of immunotherapy in biliary tract cancer: a review of new evidence and predictive biomarkers. Immunotherapy 2022; 14:567-576. [PMID: 35382560 DOI: 10.2217/imt-2021-0257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Biliary tract cancers (BTCs) are frequently diagnosed in advanced stages and are highly lethal. Immunotherapy may play a role in the treatment of these patients. Promising results come from monotherapy or combination therapy studies in pretreated patients. In addition, several studies have demonstrated the safety and efficacy of immune checkpoint inhibitors (ICIs) in combination with chemotherapy in treatment-naive patients. Numerous biomarkers have been investigated to define their predictive role in response to ICIs. However, the full extent of the benefit of immunotherapies has not yet been fully established and, except for high microsatellite instability status, no other biomarkers were uniquely predictive of response to ICIs.
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Affiliation(s)
- Roberta Giorgione
- Medical Oncology Unit, Careggi University Hospital, Florence, 50134, Italy
| | - Matteo Risaliti
- Department of Experimental & Clinical Medicine, University of Florence, Florence, 50134, Italy
| | - Ilenia Bartolini
- Department of Experimental & Clinical Medicine, University of Florence, Florence, 50134, Italy
| | - Gemma Rossi
- Medical Oncology Unit, Careggi University Hospital, Florence, 50134, Italy
| | - Serena Pillozzi
- Medical Oncology Unit, Careggi University Hospital, Florence, 50134, Italy
| | - Paolo Muiesan
- Department of Experimental & Clinical Medicine, University of Florence, Florence, 50134, Italy
| | - Antonio Taddei
- Department of Experimental & Clinical Medicine, University of Florence, Florence, 50134, Italy
| | - Lorenzo Antonuzzo
- Medical Oncology Unit, Careggi University Hospital, Florence, 50134, Italy.,Department of Experimental & Clinical Medicine, University of Florence, Florence, 50134, Italy
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27
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Kang S, El-Rayes BF, Akce M. Evolving Role of Immunotherapy in Advanced Biliary Tract Cancers. Cancers (Basel) 2022; 14:1748. [PMID: 35406520 PMCID: PMC8996885 DOI: 10.3390/cancers14071748] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 12/17/2022] Open
Abstract
Biliary tract cancers (BTC) comprise a rare and diverse group of malignancies that involve the gallbladder and biliary tree. These cancers typically present in later stages because they are aggressive in nature and affected patients are often asymptomatic in earlier stages of disease. Moreover, BTCs are generally refractory to cytotoxic chemotherapy, which further contributes to their associated poor survival outcomes. Novel therapy approaches are clearly needed. Molecular targeted agents have been developed based on our expanding knowledge of the genetic mutations underlying BTCs and represent a promising treatment strategy in molecularly selected subgroups of patients. In addition, the advent of immunotherapy over recent years has dramatically changed the bleak outcomes observed in malignancies such as melanoma. Our growing understanding of the complex tumor microenvironment in BTC has identified mechanisms of tumor immune evasion that could potentially be targeted with immunotherapy. As a result, different immunotherapeutic approaches including immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapy, have been investigated. The use of immunotherapeutic agents is currently only approved for a small subset of treatment-refractory BTCs based on microsatellite instability (MSI) status and tumor mutational burden (TMB), but this will likely change with the potential approval of immunotherapy plus chemotherapy as a result of the TOPAZ-1 trial.
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Affiliation(s)
- Sandra Kang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA;
| | - Bassel F. El-Rayes
- Department of Internal Medicine, Division of Hematology and Oncology, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA;
| | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA;
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28
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Immunotherapy in Gastrointestinal Malignancies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1342:259-272. [PMID: 34972968 DOI: 10.1007/978-3-030-79308-1_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Gastrointestinal (GI) cancers represent a heterogeneous group of malignancies, each with a unique tumor biology that in turn affects response to treatment and subsequent prognosis. The interplay between tumor cells and the local immune microenvironment also varies within each GI malignancy and can portend prognosis and response to therapy. Treatment with immune checkpoint inhibitors has changed the treatment landscape of various solid tumors including (but not limited to) renal cell carcinoma, melanoma, and lung cancer. Advances in the understanding between the interplay between the immune system and tumors cells have led to the integration of immunotherapy as standard of care in various GI malignancies. For example, immunotherapy is now a mainstay of treatment for tumors harboring defects in DNA mismatch repair proteins and tumors harboring a high mutational load, regardless of primary site of origin. Data from recent clinical trials have led to the integration of immunotherapy as standard of care for a subset of gastroesophageal cancers and hepatocellular carcinoma. Here, we outline the current landscape of immunotherapy in GI malignancies and highlight ongoing clinical trials that will likely help to further our understanding of how and when to integrate immunotherapy into the treatment of various GI malignancies.
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29
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Fu S, Piccioni DE, Liu H, Lukas RV, Kesari S, Aregawi D, Hong DS, Yamaguchi K, Whicher K, Zhang Y, Chen YL, Poola N, Eddy J, Blum D. A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies. Sci Rep 2021; 11:22355. [PMID: 34785698 PMCID: PMC8595891 DOI: 10.1038/s41598-021-01707-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 10/19/2021] [Indexed: 11/09/2022] Open
Abstract
WT2725 is a Wilms' tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56-81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309-648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6-19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development.Trial registration: NCT01621542.
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Affiliation(s)
- Siqing Fu
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
| | - David E. Piccioni
- grid.266100.30000 0001 2107 4242UCSD Moores Cancer Center, San Diego, CA USA
| | - Hongtao Liu
- grid.412578.d0000 0000 8736 9513University of Chicago Medical Center, Chicago, IL USA
| | - Rimas V. Lukas
- grid.16753.360000 0001 2299 3507Northwestern University, Chicago, IL USA ,Lou and Jean Malnati Brain Tumor Institute, Chicago, IL USA
| | - Santosh Kesari
- Saint John’s Cancer Institute and Pacific Neuroscience Institute, Santa Monica, CA USA
| | - Dawit Aregawi
- grid.240473.60000 0004 0543 9901Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA USA
| | - David S. Hong
- grid.240145.60000 0001 2291 4776Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA
| | - Kenichiro Yamaguchi
- grid.417741.00000 0004 1797 168XSumitomo Dainippon Pharma Co., Ltd., Tokyo, Japan
| | - Kate Whicher
- grid.419756.8Sunovion Pharmaceuticals Inc., Marlborough, MA USA
| | - Yi Zhang
- grid.419756.8Sunovion Pharmaceuticals Inc., Marlborough, MA USA
| | - Yu-Luan Chen
- grid.419756.8Sunovion Pharmaceuticals Inc., Marlborough, MA USA
| | - Nagaraju Poola
- grid.419756.8Sunovion Pharmaceuticals Inc., Marlborough, MA USA ,Present Address: Otsuka Pharmaceuticals, Princeton, NJ USA
| | - John Eddy
- grid.419756.8Sunovion Pharmaceuticals Inc., Marlborough, MA USA ,Present Address: Morphic Therapeutic, Waltham, MA USA
| | - David Blum
- grid.419756.8Sunovion Pharmaceuticals Inc., Marlborough, MA USA
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30
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Manne A, Woods E, Tsung A, Mittra A. Biliary Tract Cancers: Treatment Updates and Future Directions in the Era of Precision Medicine and Immuno-Oncology. Front Oncol 2021; 11:768009. [PMID: 34868996 PMCID: PMC8634105 DOI: 10.3389/fonc.2021.768009] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/13/2021] [Indexed: 12/12/2022] Open
Abstract
The effective management of biliary tract cancers (BTCs) has been hampered by limited options for systemic therapy. In recent years, the focus on precision medicine has made technologies such as next-generation sequencing (NGS) accessible to clinicians to identify targetable mutations in BTCs in tumor tissue (primarily) as well as blood, and to treat them with targeted therapies when possible. It has also expanded our understanding of functional pathways associated with genetic alterations and opened doors for identifying novel targets for treatment. Recent advances in the precision medicine approach allowed us to identify new molecular markers in BTCs, such as epigenetic changes (methylation and histone modification) and non-DNA markers such as messenger RNA, microRNA, and long non-coding RNA. It also made detecting these markers from non-traditional sources such as blood, urine, bile, and cytology (from fine-needle aspiration and biliary brushings) possible. As these tests become more accessible, we can see the integration of different molecular markers from all available sources to aid physicians in diagnosing, assessing prognosis, predicting tumor response, and screening BTCs. Currently, there are a handful of approved targeted therapies and only one class of immunotherapy agents (immune checkpoint inhibitors or ICIs) to treat BTCs. Early success with new targets, vascular endothelial growth factor receptor (VEGFR), HER2, protein kinase receptor, and Dickkopf-1 (DKK1); new drugs for known targets, fibroblast growth factor receptors (FGFRs) such as futabatinib, derazantinib, and erdafitinib; and ICIs such as durvalumab and tremelimumab is encouraging. Novel immunotherapy agents such as bispecific antibodies (bintrafusp alfa), arginase inhibitors, vaccines, and cellular therapy (chimeric antigen receptor-T cell or CAR-T, natural killer cells, tumor-infiltrating lymphocytes) have the potential to improve outcomes of BTCs in the coming years.
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Affiliation(s)
- Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Edward Woods
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Allan Tsung
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, OH, United States
| | - Arjun Mittra
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
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Pancreatic Cancer and Immunotherapy: A Clinical Overview. Cancers (Basel) 2021; 13:cancers13164138. [PMID: 34439292 PMCID: PMC8393975 DOI: 10.3390/cancers13164138] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC's immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.
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32
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The State of Immunotherapy in Hepatobiliary Cancers. Cells 2021; 10:cells10082096. [PMID: 34440865 PMCID: PMC8393650 DOI: 10.3390/cells10082096] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 08/02/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary cancers, including hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder carcinoma (GBC), are lethal cancers with limited therapeutic options. Curative-intent treatment typically involves surgery, yet recurrence is common and many patients present with advanced disease not amenable to an operation. Immunotherapy represents a promising approach to improve outcomes, but the immunosuppressive tumor microenvironment of the liver characteristic of hepatobiliary cancers has hampered the development and implementation of this therapeutic approach. Current immunotherapies under investigation include immune checkpoint inhibitors (ICI), the adoptive transfer of immune cells, bispecific antibodies, vaccines, and oncolytic viruses. Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two ICIs that have demonstrated utility in HCC, and newer immune checkpoint targets are being tested in clinical trials. In advanced CCA and GBC, PD-1 ICIs have resulted in antitumor responses, but only in a minority of select patients. Other ICIs are being investigated for patients with CCA and GBC. Adoptive transfer may hold promise, with reports of complete durable regression in metastatic CCA, yet this therapeutic approach may not be generalizable. Alternative approaches have been developed and promising results have been observed, but clinical trials are needed to validate their utility. While the treatment of hepatobiliary cancers involves unique challenges that these cancers present, the progress seen with ICIs and adoptive transfer has solidified immunotherapy as an important approach in these challenging patients with few other effective treatment options.
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Charalampakis N, Papageorgiou G, Tsakatikas S, Fioretzaki R, Kole C, Kykalos S, Tolia M, Schizas D. Immunotherapy for cholangiocarcinoma: a 2021 update. Immunotherapy 2021; 13:1113-1134. [PMID: 34190581 DOI: 10.2217/imt-2021-0126] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a rare malignancy with generally dismal prognosis. Immunotherapy has revolutionized the management of cancer patients during the last decade, offering durable responses with an acceptable safety profile, but there are still no significant advances regarding CCA. Novel immunotherapeutic methods, such as cancer vaccines, oncolytic viruses, adoptive cell therapy and combinations of immune checkpoint inhibitors with other agents are currently under investigation and may improve prognosis. Efforts to find robust biomarkers for response are also ongoing. In this review, we discuss the rationale for the use of immunotherapy in CCA and available clinical data. Ongoing trials will also be presented, as well as key findings from each study.
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Affiliation(s)
- Nikolaos Charalampakis
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Georgios Papageorgiou
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Sergios Tsakatikas
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Rodanthi Fioretzaki
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Christo Kole
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | - Stylianos Kykalos
- Second Propedeutic Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | - Maria Tolia
- Department of Radiation Oncology, University Hospital of Crete, Voutes, 71110, Heraklion, Crete, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
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The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma. Vaccines (Basel) 2021; 9:vaccines9050422. [PMID: 33922362 PMCID: PMC8146949 DOI: 10.3390/vaccines9050422] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 12/17/2022] Open
Abstract
Biliary tract cancer, and intrahepatic cholangiocarcinoma (iCC) in particular, represents a rather uncommon, highly aggressive malignancy with unfavorable prognosis. Therapeutic options remain scarce, with platinum-based chemotherapy is being considered as the gold standard for the management of advanced disease. Comprehensive molecular profiling of tumor tissue biopsies, utilizing multi-omics approaches, enabled the identification of iCC’s intratumor heterogeneity and paved the way for the introduction of novel targeted therapies under the scope of precision medicine. Yet, the unmet need for optimal care of patients with chemo-refractory disease or without targetable mutations still exists. Immunotherapy has provided a paradigm shift in cancer care over the past decade. Currently, immunotherapeutic strategies for the management of iCC are under intense research. Intrinsic factors of the tumor, including programmed death-ligand 1 (PD-L1) expression and mismatch repair (MMR) status, are simply the tip of the proverbial iceberg with regard to resistance to immunotherapy. Acknowledging the significance of the tumor microenvironment (TME) in both cancer growth and drug response, we broadly discuss about its diverse immune components. We further review the emerging role of immunotherapy in this rare disease, summarizing the results of completed and ongoing phase I–III clinical trials, expounding current challenges and future directions.
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35
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Boilève A, Hilmi M, Smolenschi C, Ducreux M, Hollebecque A, Malka D. Immunotherapy in Advanced Biliary Tract Cancers. Cancers (Basel) 2021; 13:1569. [PMID: 33805461 PMCID: PMC8036747 DOI: 10.3390/cancers13071569] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/20/2021] [Accepted: 03/25/2021] [Indexed: 12/11/2022] Open
Abstract
Biliary tract cancers are rare tumors with a poor prognosis. Two-thirds of these primary liver malignancies are diagnosed at advanced stages where therapeutic options are limited. Whereas several molecular targeted therapies emerge in biliary tract cancers, immunotherapy is still investigational, the only approved immunotherapy to date being the immune checkpoint inhibitor pembrolizumab for the small fraction of patients with microsatellite-instable tumors. In microsatellite-stable, pre-treated biliary tract cancers, single-agent immune checkpoint blockade has a limited albeit often long-lasting clinical activity in a still ill-defined subgroup of patients. The identification of predictive biomarkers will allow a better selection of patients that may benefit from immunotherapy. Combinations of immunotherapies with each other, with chemotherapy or targeted molecular therapies are being investigated in early lines of therapy, including first-line.
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Affiliation(s)
- Alice Boilève
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France; (A.B.); (C.S.); (M.D.); (A.H.)
- Université Paris-Saclay, F-91190 Saint-Aubin, France
| | - Marc Hilmi
- Département D’Innovations Thérapeutiques et D’Essais Précoces, Gustave Roussy, F-94805 Villejuif, France;
| | - Cristina Smolenschi
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France; (A.B.); (C.S.); (M.D.); (A.H.)
- Département D’Innovations Thérapeutiques et D’Essais Précoces, Gustave Roussy, F-94805 Villejuif, France;
| | - Michel Ducreux
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France; (A.B.); (C.S.); (M.D.); (A.H.)
- Université Paris-Saclay, F-91190 Saint-Aubin, France
| | - Antoine Hollebecque
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France; (A.B.); (C.S.); (M.D.); (A.H.)
- Département D’Innovations Thérapeutiques et D’Essais Précoces, Gustave Roussy, F-94805 Villejuif, France;
| | - David Malka
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France; (A.B.); (C.S.); (M.D.); (A.H.)
- Université Paris-Saclay, F-91190 Saint-Aubin, France
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Leone V, Ali A, Weber A, Tschaharganeh DF, Heikenwalder M. Liver Inflammation and Hepatobiliary Cancers. Trends Cancer 2021; 7:606-623. [PMID: 33674229 DOI: 10.1016/j.trecan.2021.01.012] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 12/17/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023]
Abstract
Immune regulation has an important role in cancer development, particularly in organs with continuous exposure to environmental pathogens, such as the liver and gastrointestinal tract. Chronic liver inflammation can lead to the development of hepatobiliary cancers, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or combined HCC (cHCC)-CCA. In this review, we discuss the link between oxidative stress and the hepatic immune compartments, as well as how these factors trigger hepatocyte damage, proliferation, and eventually cancer initiation and its sustainment. We further give an overview of new anticancer therapies based on immunomodulation.
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Affiliation(s)
- Valentina Leone
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Research Unit Radiation Cytogenetics, Helmholtz Zentrum München Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany
| | - Adnan Ali
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Achim Weber
- Department of Pathology and Molecular Pathology, Institute of Molecular Cancer Research (IMCR), University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland
| | - Darjus Felix Tschaharganeh
- Helmholtz-University Group Cell Plasticity and Epigenetic Remodeling, German Cancer Research Center (DKFZ) and Institute of Pathology University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
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Abstract
PURPOSE OF REVIEW Cholangiocarcinoma is an aggressive heterogeneous group of cancers of the biliary epithelium and most patients are detected with advanced metastatic disease with poor prognosis. The therapeutic options are limited, and the current standard care as systemic therapy is still cytotoxic chemotherapy. With the understanding of the complex immune microenvironment in the liver and these cancers arising in the milieu of chronic inflammation, recent advances in immune oncology have transformed the landscape of cancer management with breakthroughs in the treatment of several solid tumors. RECENT FINDINGS With the advances of genome sequencing, subgroups of cholangiocarcinoma with hyper mutated status and rich in cancer neoantigen production may be susceptible to immunotherapies like cancer vaccines and immune checkpoint inhibitors by eliciting a host immune response resulting in tumor rejection or overcoming the immunosuppressive local tumor microenvironment. SUMMARY In this review, we look at the most recent evidence behind immunotherapy and its application in the treatment of cholangiocarcinoma. Though its utility is still in early development it shows great promise in improving response rates that may translate to durable disease control and improve clinical outcomes in this aggressive disease.
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Wang M, Chen Z, Guo P, Wang Y, Chen G. Therapy for advanced cholangiocarcinoma: Current knowledge and future potential. J Cell Mol Med 2020; 25:618-628. [PMID: 33277810 PMCID: PMC7812297 DOI: 10.1111/jcmm.16151] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/21/2020] [Accepted: 11/22/2020] [Indexed: 01/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a biliary epithelial tumour that can emerge at any point in the biliary tree. It is commonly classified based on its anatomical site of development into intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PCC) and distal cholangiocarcinoma (DCC), each of which is associated with varying patient demographics, molecular characteristics and treatment options. CCA patients have poor overall prognoses and 5‐year survival rates. Additionally, CCA is often diagnosed at an advanced stage, with surgical treatment restricted to early‐stage disease. Owing to an increase in the incidence of ICC, that of CCA is also on the rise, with a corresponding increase in the associated mortality, particularly in South America and Asia. Therefore, the development of an effective treatment is crucial to improve the survival of CCA patients. We aimed to systematically review the current understanding of advanced CCA treatment and discuss potential effective strategies.
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Affiliation(s)
- Mingxun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Ziyan Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Pengyi Guo
- Department of Cardiothoracic Surgery, Ningbo Yinzhou NO.2 Hospital, Ningbo, China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, Public Health and Management School, Wenzhou Medical University, Wenzhou, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
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Han S, Lee SY, Wang WW, Tan YB, Sim RHZ, Cheong R, Tan C, Hopkins R, Connolly J, Shuen WH, Toh HC. A Perspective on Cell Therapy and Cancer Vaccine in Biliary Tract Cancers (BTCs). Cancers (Basel) 2020; 12:E3404. [PMID: 33212880 PMCID: PMC7698436 DOI: 10.3390/cancers12113404] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/04/2020] [Accepted: 11/10/2020] [Indexed: 02/07/2023] Open
Abstract
Biliary tract cancer (BTC) is a rare, but aggressive, disease that comprises of gallbladder carcinoma, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, with heterogeneous molecular profiles. Advanced disease has limited therapeutic options beyond first-line platinum-based chemotherapy. Immunotherapy has emerged as a viable option for many cancers with a similar unmet need. Therefore, we reviewed current understanding of the tumor immune microenvironment and recent advances in cellular immunotherapy and therapeutic cancer vaccines against BTC. We illustrated the efficacy of dendritic cell vaccination in one patient with advanced, chemorefractory, melanoma-associated antigen (MAGE)-positive gallbladder carcinoma, who was given multiple injections of an allogenic MAGE antigen-positive melanoma cell lysate (MCL)-based autologous dendritic cell vaccine combined with sequential anti-angiogenic therapy. This resulted in good radiological and tumor marker response and an overall survival of 3 years from diagnosis. We postulate the potential synergism of adding anti-angiogenic therapy, such as bevacizumab, to immunotherapy in BTC, as a rational scientific principle to positively modulate the tumor microenvironment to augment antitumor immunity.
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Affiliation(s)
- Shuting Han
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Suat Ying Lee
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Who-Whong Wang
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Yu Bin Tan
- Singapore Health Services, 31 Third Hospital Ave, #03-03 Bowyer Block C, Singapore 168753, Singapore; (Y.B.T.); (R.H.Z.S.)
| | - Rachel Hui Zhen Sim
- Singapore Health Services, 31 Third Hospital Ave, #03-03 Bowyer Block C, Singapore 168753, Singapore; (Y.B.T.); (R.H.Z.S.)
| | - Rachael Cheong
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Cherlyn Tan
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Richard Hopkins
- Institute of Molecular and Cell Biology (IMCB), A*STAR, 61 Biopolis Drive, Singapore 138673, Singapore; (R.H.); (J.C.)
| | - John Connolly
- Institute of Molecular and Cell Biology (IMCB), A*STAR, 61 Biopolis Drive, Singapore 138673, Singapore; (R.H.); (J.C.)
| | - Wai Ho Shuen
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
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Hein KZ, Yao S, Fu S. Wilms' Tumor 1 (WT1): The Vaccine for Cancer. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2020; 3:165-171. [PMID: 35665371 PMCID: PMC9165440 DOI: 10.36401/jipo-20-12] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/26/2020] [Indexed: 06/15/2023]
Abstract
Vaccines have been used to fight and protect against infectious diseases for centuries. With the emergence of immunotherapy in cancer treatment, researchers began investigating vaccines that could be used against cancer, especially against tumors that are resistant to conservative chemotherapy, surgery, and radiotherapy. The Wilms' tumor 1 (WT1) protein is immunogenic, has been detected in almost all types of malignancies, and has played a significant role in prognosis and disease monitoring. In this article, we review recent developments in the treatment of various types of cancers with the WT1 cancer vaccine; we also discuss theoretic considerations of various therapeutic approaches, which were based on preclinical and clinical data.
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Affiliation(s)
- Kyaw Zaw Hein
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shuyang Yao
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Thoracic Surgery, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Siqing Fu
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Mizrahi JD, Shroff RT. New Treatment Options for Advanced Biliary Tract Cancer. Curr Treat Options Oncol 2020; 21:63. [DOI: 10.1007/s11864-020-00767-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Mizrahi J, Pant S. Immunotherapy in Gastrointestinal Malignancies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1244:93-106. [DOI: 10.1007/978-3-030-41008-7_5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Loeuillard E, Conboy CB, Gores GJ, Ilyas SI. Immunobiology of cholangiocarcinoma. JHEP Rep 2019; 1:297-311. [PMID: 32039381 PMCID: PMC7001542 DOI: 10.1016/j.jhepr.2019.06.003] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 06/21/2019] [Accepted: 06/22/2019] [Indexed: 02/08/2023] Open
Abstract
Cholangiocarcinoma (CCA) represents a heterogeneous group of epithelial tumours that are classified according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Although surgical resection and liver transplantation following neoadjuvant therapy are potentially curative options for a subset of patients with early-stage disease, the currently available medical therapies for CCA have limited efficacy. Immunotherapeutic strategies such as immune checkpoint blockade (ICB) harness the host immune system to unleash an effective and durable antitumour response in a subset of patients with a variety of malignancies. However, response to ICB monotherapy has been relatively disappointing in CCA. CCAs are desmoplastic tumours with an abundant tumour immune microenvironment (TIME) that contains immunosuppressive innate immune cells such as tumour-associated macrophages and myeloid-derived suppressor cells. A subset of CCAs may be classified as immune 'hot' tumours with a high density of CD8+ T cells and enhanced expression of immune checkpoint molecules. Immune 'hot' tumour types are associated with higher response rates to ICB. However, the suboptimal response rates to ICB monotherapy in human clinical trials of CCA imply that the preponderance of CCAs are immune 'cold' tumours with a non-T cell infiltrated TIME. An enhanced comprehension of the immunobiology of CCA, particularly the innate immune response to CCA, is essential in the effort to develop effective combination immunotherapeutic strategies that can target a larger subset of CCAs.
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Affiliation(s)
- Emilien Loeuillard
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Sumera I. Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Saeed A, Park R, Al-Jumayli M, Al-Rajabi R, Sun W. Biologics, Immunotherapy, and Future Directions in the Treatment of Advanced Cholangiocarcinoma. Clin Colorectal Cancer 2019; 18:81-90. [DOI: 10.1016/j.clcc.2019.02.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/15/2019] [Accepted: 02/18/2019] [Indexed: 02/07/2023]
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Rimassa L, Personeni N, Aghemo A, Lleo A. The immune milieu of cholangiocarcinoma: From molecular pathogenesis to precision medicine. J Autoimmun 2019; 100:17-26. [PMID: 30862450 DOI: 10.1016/j.jaut.2019.03.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 03/05/2019] [Indexed: 12/11/2022]
Abstract
Cholangiocarcinoma (CCA) is a deadly cancer of the biliary epithelium with limited therapeutic options. It is a heterogeneous group of cancer that could develop at any level from the biliary tree and is currently classified into intrahepatic, perihilar and distal based on its anatomical location. With incidence and mortality rates currently increasing, it is now the second most common type of primary liver cancer and represents up to 3% of all gastrointestinal malignancies. High-throughput genomics and epigenomics have greatly increased our understanding of CCA underlying biology, however its pathogenesis remains largely unknown. CCA is characterized by a highly desmoplastic microenvironment containing stromal cells, mainly cancer-associated fibroblasts, infiltrating tumor epithelium. Tumor microenvironment in CCA is a highly dynamic environment that, besides stromal and endothelial cells, encompass also an abundance of immune cells, of both the innate and adaptive immune system (including tumor-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes) and abundant proliferative factors. It is orchestrated by multiple soluble factors and signals, that eventually define a tumor growth-permissive microenvironment. Through complicate interactions with CCA cells, tumor microenvironment profoundly affects the proliferative and invasive abilities of epithelial cancer cells and plays an important role in accelerating neovascularization and preventing apoptosis of neoplastic cells. In this review, we discuss recent developments regarding the characteristics of the tumor microenvironment, the role of each cellular population, and their multiarticulate interaction with the malignant population. Further we discuss innovative treatment approaches, including immunotherapy, and how identification of CCA secreted factors by both the stromal component and immune cell subsets are leading towards a precision medicine in CCA.
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Affiliation(s)
- Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy
| | - Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy.
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Zhou Q, Andersson R, Hu D, Bauden M, Kristl T, Sasor A, Pawłowski K, Pla I, Hilmersson KS, Zhou M, Lu F, Marko-Varga G, Ansari D. Quantitative proteomics identifies brain acid soluble protein 1 (BASP1) as a prognostic biomarker candidate in pancreatic cancer tissue. EBioMedicine 2019; 43:282-294. [PMID: 30982764 PMCID: PMC6557784 DOI: 10.1016/j.ebiom.2019.04.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 03/27/2019] [Accepted: 04/03/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Pancreatic cancer is a heterogenous disease with a poor prognosis. This study aimed to discover and validate prognostic tissue biomarkers in pancreatic cancer using a mass spectrometry (MS) based proteomics approach. METHODS Global protein sequencing of fresh frozen pancreatic cancer and healthy pancreas tissue samples was conducted by MS to discover potential protein biomarkers. Selected candidate proteins were further verified by targeted proteomics using parallel reaction monitoring (PRM). The expression of biomarker candidates was validated by immunohistochemistry in a large tissue microarray (TMA) cohort of 141 patients with resectable pancreatic cancer. Kaplan-Meier and Cox proportional hazard modelling was used to investigate the prognostic utility of candidate protein markers. FINDINGS In the initial MS-discovery phase, 165 proteins were identified as potential biomarkers. In the subsequent MS-verification phase, a panel of 45 candidate proteins was verified by the development of a PRM assay. Brain acid soluble protein 1 (BASP1) was identified as a new biomarker candidate for pancreatic cancer possessing largely unknown biological and clinical functions and was selected for further analysis. Importantly, bioinformatic analysis indicated that BASP1 interacts with Wilms tumour protein (WT1) in pancreatic cancer. TMA-based immunohistochemistry analysis showed that BASP1 was an independent predictor of prolonged survival (HR 0.468, 95% CI 0.257-0.852, p = .013) and predicted favourable response to adjuvant chemotherapy, whereas WT1 indicated a worsened survival (HR 1.636, 95% CI 1.083-2.473, p = .019) and resistance to chemotherapy. Interaction analysis showed that patients with negative BASP1 and high WT1 expression had the poorest outcome (HR 3.536, 95% CI 1.336-9.362, p = .011). INTERPRETATION We here describe an MS-based proteomics platform for developing biomarkers for pancreatic cancer. Bioinformatic analysis and clinical data from our study suggest that BASP1 and its putative interaction partner WT1 can be used as biomarkers for predicting outcomes in pancreatic cancer patients.
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Affiliation(s)
- Qimin Zhou
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden; The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden
| | - Dingyuan Hu
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden
| | - Monika Bauden
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden
| | - Theresa Kristl
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden
| | - Agata Sasor
- Department of Pathology, Skåne University Hospital, Lund, Sweden
| | - Krzysztof Pawłowski
- Department of Experimental Design and Bioinformatics, Warsaw University of Life Sciences, Warsaw, Poland; Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Indira Pla
- Department of Biomedical Engineering, Clinical Protein Science and Imaging, Lund University, Lund, Sweden
| | - Katarzyna Said Hilmersson
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden
| | - Mengtao Zhou
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fan Lu
- The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - György Marko-Varga
- Department of Biomedical Engineering, Clinical Protein Science and Imaging, Lund University, Lund, Sweden
| | - Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden.
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Tariq NUA, McNamara MG, Valle JW. Biliary tract cancers: current knowledge, clinical candidates and future challenges. Cancer Manag Res 2019; 11:2623-2642. [PMID: 31015767 PMCID: PMC6446989 DOI: 10.2147/cmar.s157092] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Biliary tract cancers (BTCs) are rare with poor prognosis. Due to the advent of genomic sequencing, new data have emerged regarding the molecular makeup of this disease. To add to the complexity, various subtypes also harbor a varied genetic composition. The commonly mutated genes associated with this cancer are KRAS, EGFR, IDH, FGFR and BAP1. Various clinical studies are looking at targeting these genetic mutations. Another therapeutic area of note is the potential for the use of immunotherapy in patients with BTC. Although BTC may be a result of chronic inflammation, this does not necessarily translate into increased immunogenicity. This literature review discusses the diverse molecular and immune-related pathways in patients with BTC and their potential therapeutic implications.
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Affiliation(s)
- Noor-Ul-Ain Tariq
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
| | - Mairéad G McNamara
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
| | - Juan W Valle
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
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Perkhofer L, Beutel AK, Ettrich TJ. Immunotherapy: Pancreatic Cancer and Extrahepatic Biliary Tract Cancer. Visc Med 2019; 35:28-37. [PMID: 31312647 DOI: 10.1159/000497291] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 01/28/2019] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and extrahepatic biliary tract cancer (BTC) are among the malignancies with the highest morbidity and mortality. Despite increasing knowledge on biology and novel therapies, outcome remains poor in these patients. Recent progress in immunotherapies created new hopes in the treatment of PDAC and extrahepatic BTC. Several trials tested immunotherapies in various therapeutic situations as monotherapies or in combinations. Although responses were seen in some of the trials, the value of immunotherapy in PDAC and extrahepatic BTC remains unclear in the current situation, especially regarding the complex biological characteristics with a high stroma component, intrinsic resistance mechanisms and an immunosuppressive, hypoxic microenvironment. These major hurdles have to be taken into account and overcome if immunotherapies should be successful in these tumor entities. Thereby, combinational approaches that allow on the one hand targeted therapy and on the other restore or boost the function of immune cells are promising.
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Affiliation(s)
- Lukas Perkhofer
- Klinik für Innere Medizin I, Universitätsklinikum Ulm, Ulm, Germany
| | - Alica K Beutel
- Klinik für Innere Medizin I, Universitätsklinikum Ulm, Ulm, Germany
| | - Thomas J Ettrich
- Klinik für Innere Medizin I, Universitätsklinikum Ulm, Ulm, Germany
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Kanai T, Ito Z, Oji Y, Suka M, Nishida S, Takakura K, Kajihara M, Saruta M, Fujioka S, Misawa T, Akiba T, Yanagisawa H, Shimodaira S, Okamoto M, Sugiyama H, Koido S. Prognostic significance of Wilms' tumor 1 expression in patients with pancreatic ductal adenocarcinoma. Oncol Lett 2018; 16:2682-2692. [PMID: 30008944 DOI: 10.3892/ol.2018.8961] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 05/16/2018] [Indexed: 02/07/2023] Open
Abstract
The only current curative treatment for patients with pancreatic ductal adenocarcinoma (PDA) is surgical resection, and certain patients still succumb to disease shortly after complete surgical resection. Wilms' tumor 1 (WT1) serves an oncogenic role in various types of tumors; therefore, in the present study, WT1 protein expression in patients with PDA was analyzed and the association with overall survival (OS) and disease-free survival (DFS) time in patients with PDA was assessed following surgical resection. A total of 50 consecutive patients with PDA who received surgical resection between January 2005 and December 2015 at the Jikei University Kashiwa Hospital (Kashiwa, Chiba, Japan) were enrolled. WT1 protein expression in PDA tissue was measured using immunohistochemical staining. Furthermore, laboratory parameters were measured within 2 weeks of surgery, and systemic inflammatory response markers were evaluated. WT1 protein expression was detected in the nucleus and cytoplasm of all PDA cells and in tumor vessels. WT1 exhibited weak staining in the nuclei of all PDA cells; however, the cytoplasmic expression of WT1 levels was classified into four groups: Negative (n=0), weak (n=19), moderate (n=23) and strong (n=8). In patients with PDA, it was demonstrated that the OS and DFS times of patients with weak cytoplasmic WT1 expression were significantly prolonged compared with those of patients with moderate-to-strong cytoplasmic WT1 expression, as determined by log-rank test (P=0.0005 and P=0.0001, respectively). Furthermore, an association between the density of WT1-expressing tumor vessels and worse OS/DFS times was detected. Multivariate analysis also indicated a significant association between the overexpression of WT1 in PDA tissue and worse OS/DFS times. To the best of our knowledge, the present study is the first to demonstrate that moderate-to-strong overexpression of WT1 in the cytoplasm of PDA cells is significantly associated with worse OS/DFS times. Therefore, overexpression of WT1 in the cytoplasm of PDA cells may impact the recurrence and prognosis of patients with PDA following surgical resection. The results further support the development of WT1-targeted therapies to prolong survival in all patients with PDA.
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Affiliation(s)
- Tomoya Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Zensho Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Yusuke Oji
- Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Machi Suka
- Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, Tokyo 105-8571, Japan
| | - Sumiyuki Nishida
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Kazuki Takakura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Mikio Kajihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8571, Japan
| | - Shuichi Fujioka
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Takeyuki Misawa
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Tadashi Akiba
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Hiroyuki Yanagisawa
- Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, Tokyo 105-8571, Japan
| | - Shigetaka Shimodaira
- Department of Regenerative Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan
| | - Masato Okamoto
- Department of Advanced Immunotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Haruo Sugiyama
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan.,Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa, Chiba 277-8567, Japan
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Abstract
OPINION STATEMENT Biliary tract cancers (BTCs) are rare aggressive neoplasms with a poor prognosis and a median survival of less than 1 year in the locally advanced or metastatic setting. Among the few patients who undergo curative resection the recurrence rates are high. About 90% of patients are detected at advanced stages, and systemic chemotherapy is the mainstay of their treatment. The treatment options for these patients are limited and multiple modalities of therapy from targeted therapy to immunotherapy and combination therapies (immunotherapy, targeted therapy, and chemotherapy) have been tested in this disease. Targeted therapies have failed to show a survival benefit. The deregulation of the immune system plays a significant role in the pathogenesis of BTCs. Therefore, immunotherapy, especially, immune checkpoint inhibitors hold great promise for this group of cancers. Numerous trials of immunotherapy in BTC are currently ongoing. In this review, we will discuss the available data and evidence for immunotherapy in BTC.
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Affiliation(s)
- Urvi A Shah
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY, 10461, USA
| | - Amara G Nandikolla
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY, 10461, USA
| | - Lakshmi Rajdev
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY, 10461, USA.
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