|
1
|
Fagoonee S, Weiskirchen R. MicroRNAs and RNA-Binding Protein-Based Regulation of Bone Metastasis from Hepatobiliary Cancers and Potential Therapeutic Strategies. Cells 2024; 13:1935. [PMID: 39682684 PMCID: PMC11640337 DOI: 10.3390/cells13231935] [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: 10/28/2024] [Revised: 11/15/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatobiliary cancers, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are among the deadliest malignancies worldwide, leading to a significant number of cancer-related deaths. While bone metastases from these cancers are rare, they are highly aggressive and linked to poor prognosis. This review focuses on RNA-based molecular mechanisms that contribute to bone metastasis from hepatobiliary cancers. Specifically, the role of two key factors, microRNAs (miRNAs) and RNA-binding proteins (RBPs), which have not been extensively studied in the context of HCC and CCA, is discussed. These molecules often exhibit abnormal expression in hepatobiliary tumors, influencing cancer cell spread and metastasis by disrupting bone homeostasis, thereby aiding tumor cell migration and survival in the bone microenvironment. This review also discusses potential therapeutic strategies targeting these RNA-based pathways to reduce bone metastasis and improve patient outcomes. Further research is crucial for developing effective miRNA- and RBP-based diagnostic and prognostic biomarkers and treatments to prevent bone metastases in hepatobiliary cancers.
Collapse
Affiliation(s)
- Sharmila Fagoonee
- Institute of Biostructure and Bioimaging (CNR), Molecular Biotechnology Center “Guido Tarone”, 10126 Turin, Italy
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
| |
Collapse
|
|
2
|
Yagawa Y, Kobayashi Y, Fujita I, Watanabe M, Koido S, Sugiyama H, Tanigawa K. Peritoneal Dissemination and Malignant Ascites in Duodenal Cancer Successfully Treated With Adoptive Cell Therapy Using WT1- and MUC1-Pulsed Dendritic Cells and Activated T Cells With No Adverse Effects: A Case Report. Cureus 2024; 16:e74834. [PMID: 39737308 PMCID: PMC11684412 DOI: 10.7759/cureus.74834] [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: 11/30/2024] [Indexed: 01/01/2025] Open
Abstract
A satisfactory treatment for the dissemination of duodenal cancer has not yet been established. We describe a case of peritoneal dissemination and malignant ascites in duodenal cancer that was successfully treated with adoptive cell therapy with no adverse effects. A 72-year-old Japanese male patient with primary duodenal cancer with distal lymph node metastases received chemotherapy with S-1, an oral pyrimidine fluoride-derived agent, and oxaliplatin after gastrojejunal bypass, which resulted in tumor shrinkage; however, peritoneal dissemination developed. Despite the administration of a second-line chemotherapy regimen comprising irinotecan, peritoneal dissemination, malignant ascites, and cachexia continued to progress, ultimately resulting in the failure of chemotherapy. He then received adoptive cell therapy with Wilms' tumor 1 (WT1)- and mucin 1 (MUC1) peptide-pulsed dendritic cells (WT1/MUC1-DC) and CD3-activated T lymphocytes (CAT). Following the administration of this treatment eight times per week, the patient's symptoms and malignant ascites surrounding his cancer disappeared. He developed no adverse effects from this treatment and was able to resume his usual activities without any symptoms. He has continued this treatment every few months as maintenance therapy and has been free of relapse for 54 months. This case suggests a possible beneficial effect of adoptive cell therapy with WT1/MUC1-DC and CAT for peritoneal dissemination and malignant ascites in duodenal cancer.
Collapse
Affiliation(s)
- Yohsuke Yagawa
- Department of Immunotherapy, Bio-Thera Clinic, Tokyo, JPN
| | | | - Izumi Fujita
- Department of Surgery, Ebara Hospital, Tokyo, JPN
| | - Manabu Watanabe
- Department of Surgery, Toho University Ohashi Medical Center, Tokyo, JPN
| | - Shigeo Koido
- Internal Medicine, The Jikei University School of Medicine, Tokyo, JPN
| | - Haruo Sugiyama
- Department of Cancer Immunology, Osaka University Graduate School of Medcine, Osaka, JPN
| | | |
Collapse
|
|
3
|
Wang X, Bai Y, Chai N, Li Y, Linghu E, Wang L, Liu Y. Chinese national clinical practice guideline on diagnosis and treatment of biliary tract cancers. Chin Med J (Engl) 2024; 137:2272-2293. [PMID: 39238075 PMCID: PMC11441919 DOI: 10.1097/cm9.0000000000003258] [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: 02/25/2024] [Indexed: 09/07/2024] Open
Abstract
BACKGROUND Biliary tract carcinoma (BTC) is relatively rare and comprises a spectrum of invasive tumors arising from the biliary tree. The prognosis is extremely poor. The incidence of BTC is relatively high in Asian countries, and a high number of cases are diagnosed annually in China owing to the large population. Therefore, it is necessary to clarify the epidemiology and high-risk factors for BTC in China. The signs associated with BTC are complex, often require collaborative treatment from surgeons, endoscopists, oncologists, and radiation therapists. Thus, it is necessary to develop a comprehensive Chinese guideline for BTC. METHODS This clinical practice guideline (CPG) was developed following the process recommended by the World Health Organization. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the certainty of evidence and make recommendations. The full CPG report was reviewed by external guideline methodologists and clinicians with no direct involvement in the development of this CPG. Two guideline reporting checklists have been adhered to: Appraisal of Guidelines for Research and Evaluation (AGREE) and Reporting Items for practice Guidelines in Healthcare (RIGHT). RESULTS The guideline development group, which comprised 85 multidisciplinary clinical experts across China. After a controversies conference, 17 clinical questions concerning the prevention, diagnosis, and treatment of BTC were proposed. Additionally, detailed descriptions of the surgical principles, perioperative management, chemotherapy, immunotherapy, targeted therapy, radiotherapy, and endoscopic management were proposed. CONCLUSIONS The guideline development group created a comprehensive Chinese guideline for the diagnosis and treatment of BTC, covering various aspects of epidemiology, diagnosis, and treatment. The 17 clinical questions have important reference value for the management of BTC.
Collapse
Affiliation(s)
- Xu’an Wang
- Department of Biliary and Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine; State Key Laboratory of Systems Medicine for Cancers, Shanghai Cancer Institute; Shanghai Key Laboratory for Cancer Systems Regulation and Clinical Translation, Shanghai 200127, China
| | - Yongrui Bai
- Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Ningli Chai
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Yexiong Li
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100853, China
| | - Enqiang Linghu
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Liwei Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute; Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yingbin Liu
- Department of Biliary and Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine; State Key Laboratory of Systems Medicine for Cancers, Shanghai Cancer Institute; Shanghai Key Laboratory for Cancer Systems Regulation and Clinical Translation, Shanghai 200127, China
| | | |
Collapse
|
|
4
|
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.
Collapse
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
| |
Collapse
|
|
5
|
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.
Collapse
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
| |
Collapse
|
|
6
|
Sawaisorn P, Gaballa A, Saimuang K, Leepiyasakulchai C, Lertjuthaporn S, Hongeng S, Uhlin M, Jangpatarapongsa K. Human Vγ9Vδ2 T cell expansion and their cytotoxic responses against cholangiocarcinoma. Sci Rep 2024; 14:1291. [PMID: 38221530 PMCID: PMC10788337 DOI: 10.1038/s41598-024-51794-1] [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: 02/13/2023] [Accepted: 01/09/2024] [Indexed: 01/16/2024] Open
Abstract
Human Vγ9Vδ2 T lymphocytes are regarded as promising effector cells for cancer immunotherapy since they have the ability to eliminate several tumor cells through non-peptide antigen recognition. However, the cytotoxic function and the mechanism of Vγ9Vδ2 T cells leading to specific killing of cholangiocarcinoma cells are yet to be confirmed. In this study, we established a protocol for ex vivo expansion of Vγ9Vδ2 T cells from healthy donors' peripheral blood mononuclear cells by culture with zoledronate and addition of IL-2, and IL-15 or IL-18 or neither. Testing the cytotoxic capacity of cultured Vγ9Vδ2 T cells against cholangiocarcinoma cell lines showed higher reactivity than against control cells. Surface expression of CD107 was detected on the Vγ9Vδ2 T cells, suggesting that these cells limit in vitro growth of cholangiocarcinoma cells via degranulation of the perforin and granzyme pathway. Analysis of molecular signaling was used to demonstrate expression of pro- and anti-survival genes and a panel of cytokine genes in Vγ9Vδ2 T cells. We found that in the presence of either IL-15 or IL-18, levels of caspase 3 were significantly reduced. Also, IL-15 and IL-18 stimulated cells contained cytotoxicity against cholangiocarcinoma cells, suggesting that stimulated Vγ9Vδ2 T cells may provide a feasible therapy for cholangiocarcinoma.
Collapse
Affiliation(s)
- Piamsiri Sawaisorn
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
| | - Ahmed Gaballa
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Kween Saimuang
- Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
| | - Chaniya Leepiyasakulchai
- Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
| | - Sakaorat Lertjuthaporn
- Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
| | - Suradej Hongeng
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Michael Uhlin
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
- Department of Applied Physics, Royal Institute of Technology, Stockholm, Sweden.
- Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Huddinge, Sweden.
| | - Kulachart Jangpatarapongsa
- Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand.
| |
Collapse
|
|
7
|
Zhou X, Zhang B, Hu J, Shen J, Chen Z, Zhang J, Wu B, Zhou E, Peng S, Wong TW, Yang G, Cao J, Chen M. Igniting cold tumors of intrahepatic cholangiocarcinoma: An insight into immune evasion and tumor immune microenvironment. THE INNOVATION MEDICINE 2024; 2:100052. [DOI: 10.59717/j.xinn-med.2024.100052] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
<p>Intrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer that originates from the epithelium of the intrahepatic bile duct. The various treatments for ICC, such as chemotherapy, radiotherapy, and locoregional therapy, confer only modest improvements in survival rates. Immunotherapy, although revolutionary in cancer treatment, has found limited application in the treatment of ICCs due to the “cold” nature of these tumors, which is marked by scant T-cell infiltration. This characteristic makes immune checkpoint inhibitors (ICIs) unsuitable for the majority of ICC patients. Therefore, comprehensively understanding the mechanisms underlying these “cold” tumors is crucial for harnessing the potential of immunotherapy for treating ICC patients. This paper explores immune evasion mechanisms and the complex tumor immune microenvironment of ICC. This study provides a comprehensive overview of therapeutic strategies aimed at activating cold tumors and enhancing their immunogenicity. Furthermore, potential and promising targets for cancer vaccines and adoptive cellular therapy in the context of ICC are discussed. This endeavor strives to reveal new pathways for innovative immunotherapy strategies, with a focus on overcoming the key challenge of triggering an effective immune response in ICC patients.</p>
Collapse
|
|
8
|
Lu X, Green BL, Xie C, Liu C, Chen X. Preclinical and clinical studies of immunotherapy for the treatment of cholangiocarcinoma. JHEP Rep 2023; 5:100723. [PMID: 37229173 PMCID: PMC10205436 DOI: 10.1016/j.jhepr.2023.100723] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 02/10/2023] [Accepted: 02/16/2023] [Indexed: 05/27/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a rare primary liver cancer associated with high mortality and few systemic treatment options. The behaviour of the immune system has come into focus as a potential treatment modality for many cancer types, but immunotherapy has yet to dramatically alter the treatment paradigm for CCA as it has for other diseases. Herein, we review recent studies describing the relevance of the tumour immune microenvironment (TIME) in CCA. Various non-parenchymal cell types are critically important in controlling CCA progression, prognosis, and response to systemic therapy. Knowledge of the behaviour of these leukocytes could help generate hypotheses to guide the development of potential immune-directed therapies. Recently, an immunotherapy-containing combination was approved for the treatment of advanced-stage CCA. However, despite level 1 evidence demonstrating the improved efficacy of this therapy, survival remained suboptimal. In the current manuscript, we provide a comprehensive review of the TIME in CCA, preclinical studies of immunotherapies against CCA, as well as ongoing clinical trials applying immunotherapies for the treatment of CCA. Particular emphasis is placed on microsatellite unstable tumours, a rare CCA subtype that demonstrates heightened sensitivity to approved immune checkpoint inhibitors. We also discuss the challenges involved in applying immunotherapies to the treatment of CCA and the importance of understanding the TIME.
Collapse
Affiliation(s)
- Xinjun Lu
- Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Benjamin L. Green
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Changqing Xie
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Chao Liu
- Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xin Chen
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| |
Collapse
|
|
9
|
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.
Collapse
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,
| |
Collapse
|
|
10
|
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.
Collapse
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,
| |
Collapse
|
|
11
|
Xue JN, Wang YY, Wang YC, Zhang N, Zhang LH, Lu ZH, Zhao LJ, Zhao HT. Novel cellular therapies for hepatobiliary malignancies. Hepatobiliary Pancreat Dis Int 2022; 21:450-454. [PMID: 36100543 DOI: 10.1016/j.hbpd.2022.08.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/30/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND The mortalities of hepatobiliary malignancies are high. With the failure of conventional chemotherapy and unsatisfactory outcome of molecular targeted drugs, immune-based therapy has become a new focus of research in hepatobiliary cancers treatment. DATA SOURCES We performed a PubMed search with relevant articles published up to May 2022 and the following keywords: cellular immunotherapy, hepatobiliary cancer, antigen receptor T cell therapy, and receptor-engineered T cell. Information of clinical trials was obtained from https://clinicaltrials.gov/. RESULTS Cell therapies for hepatobiliary malignancies are at early stage of development. The current review showed that cellular therapies are safe and feasible in patients. These findings provide an important platform for future lager scale clinical trials on immunotherapy in patients with hepatobiliary malignancies. CONCLUSIONS With the continuous advances of cellular immunotherapy, the combination of cellular immunotherapy with surgery, chemotherapy and radiotherapy will be new therapeutic strategies for patients with hepatobiliary cancer.
Collapse
Affiliation(s)
- Jing-Nan Xue
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Yan-Yu Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yun-Chao Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Nan Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Long-Hao Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Zheng-Hui Lu
- Hepatobiliary and Pancreatic Surgery, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen 518000, China
| | - Li-Jin Zhao
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Hai-Tao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
| |
Collapse
|
|
12
|
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: 73] [Impact Index Per Article: 24.3] [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.
Collapse
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.
| |
Collapse
|
|
13
|
Tang TY, Huang X, Zhang G, Lu MH, Liang TB. mRNA vaccine development for cholangiocarcinoma: a precise pipeline. Mil Med Res 2022; 9:40. [PMID: 35821067 PMCID: PMC9277828 DOI: 10.1186/s40779-022-00399-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 06/23/2022] [Indexed: 11/29/2022] Open
Abstract
Cholangiocarcinoma (CHOL) is one of the most aggressive tumors worldwide and cannot be effectively treated by conventional and novel treatments, including immune checkpoint blockade therapy. The mRNA vaccine-based immunotherapeutic strategy has attracted much attention for various diseases, however, its application in CHOL is limited due to the thoughtlessness in the integration of vaccine design and patient selection. A recent study established an integrated path for identifying potent CHOL antigens for mRNA vaccine development and a precise stratification for identifying CHOL patients who can benefit from the mRNA vaccines. In spite of a promising prospect, further investigations should identify immunogenic antigens and onco-immunological characteristics of CHOL to guide the clinical application of CHOL mRNA vaccines in the future.
Collapse
Affiliation(s)
- Tian-Yu Tang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Xing Huang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Gang Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Ming-Hao Lu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Ting-Bo Liang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| |
Collapse
|
|
14
|
Chen R, Zheng D, Li Q, Xu S, Ye C, Jiang Q, Yan F, Jia Y, Zhang X, Ruan J. Immunotherapy of cholangiocarcinoma: Therapeutic strategies and predictive biomarkers. Cancer Lett 2022; 546:215853. [DOI: 10.1016/j.canlet.2022.215853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 11/02/2022]
|
|
15
|
Chen W, Hu Z, Song J, Wu Y, Zhang B, Zhang L. The state of therapy modalities in clinic for biliary tract cancer. FRONT BIOSCI-LANDMRK 2022; 27:185. [PMID: 35748261 DOI: 10.31083/j.fbl2706185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 01/26/2022] [Accepted: 01/27/2022] [Indexed: 11/06/2022]
Abstract
Biliary tract cancers (BTCs) include intrahepatic cholangiocarcinoma (iCCA), perihilar and distal cholangiocarcinoma (pCCA and dCCA), and gallbladder carcinoma based on the epithelial site of origin. BTCs are highly aggressive tumors associated with poor prognosis due to widespread metastasis and high recurrence. Surgery is the typical curative-intent treatment, yet the cornerstone of cure depends on the anatomical site of the primary tumor, and only a minority of patients (approximately 30%) has an indication necessitating surgery. Similarly, only a small subset of carefully selected patients with early iCCA who are not candidates for liver resection can opt for liver transplantation. Chemotherapy, target therapy, and immunotherapy are the main treatment options for patients who have advanced stage or unresectable disease. The genetic background of each cholangiocarcinoma subtype has been accurately described based on whole gene exome and transcriptome sequencing. Accordingly, precision medicine in targeted therapies has been identified to be aimed at distinct patient subgroups harboring unique molecular alterations. Immunotherapy such as immune checkpoint inhibitors (ICIs) was identified as antitumor responses in a minority of select patients. Current studies indicate that immunotherapy of adoptive cell therapy represents a promising approach in hematological and solid tumor malignancies, yet clinical trials are needed to validate its effectiveness in BTC. Herein, we review the progress of BTC treatment, stratified patients according to the anatomic subtypes of cholangiocarcinoma and the gene drivers of cholangiocarcinoma progression, and compare the efficacy and safety of chemotherapy, targeted therapy, and immunotherapy, which will be conducive to the design of individualized therapies.
Collapse
Affiliation(s)
- Weixun Chen
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Zhengnan Hu
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Jia Song
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Yu Wu
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Bixiang Zhang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Lei Zhang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University; Shanxi Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 030032 Taiyuan, Shanxi, China
| |
Collapse
|
|
16
|
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.
Collapse
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
| |
Collapse
|
|
17
|
Ariizumi SI, Yamamoto M, Kotera Y, Higuchi R, Yamashita S, Kato T, Hirata Y, Katagiri S, Honda G, Egawa H. Intrahepatic Cholangiocarcinoma With Neither Intrahepatic Metastasis Nor Lymph Node Metastasis Is the Optimal Indication for Hepatectomy With Adjuvant Therapy. CANCER DIAGNOSIS & PROGNOSIS 2022; 2:160-166. [PMID: 35399165 PMCID: PMC8962804 DOI: 10.21873/cdp.10090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 12/23/2021] [Indexed: 06/14/2023]
Abstract
Background/Aim The optimal indication of hepatectomy with adjuvant therapy for intrahepatic cholangiocarcinoma (ICC) has not been evaluated in detail. Patients and Methods We retrospectively studied 224 patients with ICC who underwent hepatectomy between 2000 and 2019. Prognostic factors for overall survival (OS) were evaluated by univariate and multivariate analysis. A total of 127 patients were treated with adjuvant therapy (62 patients with chemotherapy and 65 patients with immunotherapy) after hepatectomy, and 97 patients were treated with hepatectomy alone. Results Intrahepatic metastasis (IM), lymph node metastasis (LNM) of ICC, adjuvant chemotherapy, and adjuvant immunotherapy were significant prognostic factors for OS on multivariate analysis. In 127 patients with neither IM nor LNM, the 5-year OS rate was significantly higher in 36 patients with adjuvant chemotherapy (81%) and in 34 patients with adjuvant immunotherapy (68%) than in 57 patients with hepatectomy alone (45%). Conclusion The absence of IM or LNM is the optimal indication for hepatectomy with adjuvant therapy in patients with ICC.
Collapse
Affiliation(s)
- Shun-Ichi Ariizumi
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Masakazu Yamamoto
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoshihito Kotera
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Ryota Higuchi
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Shingo Yamashita
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Takaaki Kato
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoshihiro Hirata
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Satoshi Katagiri
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Goro Honda
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Hiroto Egawa
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| |
Collapse
|
|
18
|
Kumar-Sinha C, Sahai V. T-Cell Subsets as Potential Biomarkers for Hepatobiliary Cancers and Selection of Immunotherapy Regimens as a Treatment Strategy. J Natl Compr Canc Netw 2022; 20:203-214. [PMID: 35130506 DOI: 10.6004/jnccn.2021.7097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 09/22/2021] [Indexed: 11/17/2022]
Abstract
Patients with advanced hepatocellular or biliary cancers have a dismal prognosis with limited efficacy from standard systemic therapies. The benefit of precision medicine has so far been limited to a subset of biliary cancers, including FGFR rearrangements; hotspot mutations in IDH1/2, BRAF, and BRCA1/2; and other rare alterations. In contrast, hepatocellular carcinoma, an inflammation-driven cancer with an immune-infiltrated microenvironment, provides a promising opportunity for immunotherapy, compared with the highly desmoplastic immune desert or excluded stromal microenvironment in biliary cancers. The immune contexture in hepatobiliary cancers is mostly immunosuppressive, protumorigenic, and exhausted, which together with low tumor mutation burden and decreased neoantigens provides challenges for immunotherapy. A better understanding of the spatiotemporal profile of T cells within the tumor microenvironment and the dynamic interplay of immune modulators in the context of standard or experimental therapies is crucial to define additional markers of response and design evidence-based combinatorial regimens. This review considers recent literature in this area and highlights promising leads and emerging trends.
Collapse
Affiliation(s)
| | - Vaibhav Sahai
- Division of Hematology and Oncology, Department of Internal Medicine, and.,Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
| |
Collapse
|
|
19
|
Kankeu Fonkoua LA, Serrano Uson Junior PL, Mody K, Mahipal A, Borad MJ, Roberts LR. Novel and emerging targets for cholangiocarcinoma progression: therapeutic implications. Expert Opin Ther Targets 2022; 26:79-92. [PMID: 35034558 DOI: 10.1080/14728222.2022.2029412] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Cholangiocarcinoma (CCA) is a heterogeneous group of aggressive biliary malignancies. While surgery and liver transplantation are the only potentially curative modalities for early-stage disease, limited options are available for most patients with incurable-stage disease. Survival outcomes remain dismal. Recent molecular profiling efforts have led to improved understanding of the genomic landscape of CCA and to the identification of subgroups with distinct diagnostic, prognostic, and therapeutic implications. AREAS COVERED : We provide an updated review and future perspectives on features of cholangiocarcinogenesis that can be translated into therapeutic biomarkers and targets. We highlight the critical studies that have established current systemic chemotherapy and targeted therapeutics, while elaborating on novel targeted and immunotherapeutic approaches in development. Relevant literature and clinical studies were identified by searching PubMed and www.ClinicalTrials.gov. EXPERT OPINION : While therapies targeting the various molecular subgroups of CCA are rapidly emerging and changing treatment paradigms, their success has been limited by the genetic heterogeneity of CCA and the plasticity of the targets. Novel strategies aiming to combine immunotherapy, chemotherapy, and molecularly-targeted therapeutics will be required to offer durable clinical benefit and maximize survival.
Collapse
Affiliation(s)
| | | | - Kabir Mody
- Rochester, MN, and Oncology in Jacksonville, FL, Mayo Clinic, USA
| | | | | | | |
Collapse
|
|
20
|
Krenzien F, Nevermann N, Krombholz A, Benzing C, Haber P, Fehrenbach U, Lurje G, Pelzer U, Pratschke J, Schmelzle M, Schöning W. Treatment of Intrahepatic Cholangiocarcinoma-A Multidisciplinary Approach. Cancers (Basel) 2022; 14:cancers14020362. [PMID: 35053523 PMCID: PMC8773654 DOI: 10.3390/cancers14020362] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/07/2022] [Accepted: 01/10/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary This review discusses multimodality treatment strategies for intrahepatic cholangiocarcinoma (iCC). Surgical resection remains the only potentially curative therapeutic option and the central cornerstone of treatment. Adjuvant systemic treatment will be recommended after resection or in the palliative setting. Increasing knowledge of phenotypic subclassification and molecular profiling allows investigation of targeted therapies as (neo-)adjuvant treatment. High-dose brachytherapy, internal radiation therapy, and transarterial chemoembolization are among the interventional treatment options being evaluated for unresectable iCC. Given the multiple options of multidisciplinary management, any treatment strategy should be discussed in a multidisciplinary tumor board and treatment should be directed by a specialized treatment center. Abstract Intrahepatic cholangiocarcinoma (iCC) is distinguished as an entity from perihilar and distal cholangiocarcinoma and gallbladder carcinoma. Recently, molecular profiling and histopathological features have allowed further classification. Due to the frequent delay in diagnosis, the prognosis for iCC remains poor despite major technical advances and multimodal therapeutic approaches. Liver resection represents the therapeutic backbone and only curative treatment option, with the functional residual capacity of the liver and oncologic radicality being deciding factors for postoperative and long-term oncological outcome. Furthermore, in selected cases and depending on national guidelines, liver transplantation may be a therapeutic option. Given the often advanced tumor stage at diagnosis or the potential for postoperative recurrence, locoregional therapies have become increasingly important. These strategies range from radiofrequency ablation to transarterial chemoembolization to selective internal radiation therapy and can be used in combination with liver resection. In addition, adjuvant and neoadjuvant chemotherapies as well as targeted therapies and immunotherapies based on molecular profiles can be applied. This review discusses multimodal treatment strategies for iCC and their differential use.
Collapse
Affiliation(s)
- Felix Krenzien
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany; (F.K.); (A.K.); (C.B.); (P.H.); (G.L.); (J.P.); (M.S.); (W.S.)
- Berlin Institute of Health (BIH), 13353 Berlin, Germany
| | - Nora Nevermann
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany; (F.K.); (A.K.); (C.B.); (P.H.); (G.L.); (J.P.); (M.S.); (W.S.)
- Correspondence:
| | - Alina Krombholz
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany; (F.K.); (A.K.); (C.B.); (P.H.); (G.L.); (J.P.); (M.S.); (W.S.)
| | - Christian Benzing
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany; (F.K.); (A.K.); (C.B.); (P.H.); (G.L.); (J.P.); (M.S.); (W.S.)
| | - Philipp Haber
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany; (F.K.); (A.K.); (C.B.); (P.H.); (G.L.); (J.P.); (M.S.); (W.S.)
| | - Uli Fehrenbach
- Clinic for Radiology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Georg Lurje
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany; (F.K.); (A.K.); (C.B.); (P.H.); (G.L.); (J.P.); (M.S.); (W.S.)
| | - Uwe Pelzer
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany; (F.K.); (A.K.); (C.B.); (P.H.); (G.L.); (J.P.); (M.S.); (W.S.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany; (F.K.); (A.K.); (C.B.); (P.H.); (G.L.); (J.P.); (M.S.); (W.S.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany; (F.K.); (A.K.); (C.B.); (P.H.); (G.L.); (J.P.); (M.S.); (W.S.)
| |
Collapse
|
|
21
|
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.
Collapse
|
|
22
|
Hung TH, Hung JT, Wu CE, Huang Y, Lee CW, Yeh CT, Chung YH, Lo FY, Lai LC, Tung JK, Yu J, Yeh CN, Yu AL. Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma. Hepatol Commun 2022; 6:194-208. [PMID: 34558839 PMCID: PMC8710794 DOI: 10.1002/hep4.1800] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/09/2021] [Accepted: 07/14/2021] [Indexed: 12/29/2022] Open
Abstract
Recent studies support the development of cancer therapeutics to target Globo H-ceramide, the most prevalent tumor-associated carbohydrate antigen in epithelial cancers. Herein, we evaluated the expression of Globo H and its prognostic significance in intrahepatic cholangiocarcinoma (ICC) and conducted preclinical studies to assess the antitumor activity of Globo H-specific antibody in thioacetamide (TAA)-induced ICC in rats. Globo H-ceramide in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry. Antitumor efficacy of anti-Globo H mAbVK9 was evaluated in TAA-induced ICC in rat. Natural killer (NK) cells and their related genes were analyzed by IHC and quantitative real-time polymerase chain reaction. Data mining revealed that B3GALT5 and FUT2, the key enzymes for Globo H biosynthesis, were significantly up-regulated in human ICC. In addition, Globo H expression was detected in 41% (63 of 155) of ICC tumor specimens by IHC staining, and validated by mass spectrometric analysis of two IHC-positive tumors. Patients with Globo H positive tumors had significantly shorter relapse-free survival (RFS) and overall survival (P = 0.0003 and P = 0.002, respectively). Multivariable Cox regression analysis identified Globo H expression as an independent unfavorable predictor for RFS (hazard ratio: 1.66, 95% confidence interval: 1.08-2.36, P = 0.02) in ICC. Furthermore, gradual emergence of Globo H in liver tissues over 6 months in TAA-treated rats recapitulated the multistage progression of ICC in vivo. Importantly, administration of anti-Globo H mAbVK9 in rats bearing TAA-induced ICC significantly suppressed tumor growth with increased NK cells in the tumor microenvironment. Conclusion: Globo H is a theranostic marker in ICC.
Collapse
Affiliation(s)
- Tsai-Hsien Hung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Jung-Tung Hung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chiao-En Wu
- Department of Hematology-Oncology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Yenlin Huang
- Department of Anatomic Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang Gung University, Taoyuan, Taiwan
| | - Chien-Wei Lee
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Hsiu Chung
- Department of Medical Research and Development, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Fei-Yun Lo
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Li-Chun Lai
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - John K Tung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - John Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
- Chang Gung University, Taoyuan, Taiwan
| | - Chun-Nan Yeh
- Department of Surgery and Liver Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Alice L Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Department of Pediatrics, University of California in San Diego, San Diego, CA
- Chang Gung University, Taoyuan, Taiwan
| |
Collapse
|
|
23
|
Zhang R, Puzzoni M, Mariani S, Zheng Y, Liscia N, Guo Y, Donisi C, Liu Y, Impera V, Fang W, Scartozzi M. Emerging treatment evolutions and integrated molecular characteristics of biliary tract cancers. Cancer Sci 2021; 112:4819-4833. [PMID: 34534382 PMCID: PMC8645726 DOI: 10.1111/cas.15139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 08/05/2021] [Accepted: 09/07/2021] [Indexed: 12/13/2022] Open
Abstract
Biliary tract cancers (BTCs) consist of a group of highly heterogeneous malignancies that are characterized by genomic differences among tumors from different anatomic sites. The current treatment for BTC includes surgery, chemotherapy, target therapy, and immunotherapy. Although surgery remains the primary option for localized disease, representing the only potential curative treatment, a high risk of recurrence cannot be neglected. Chemotherapy has been considered the standard of care for both advanced and metastatic disease and in adjuvant settings. However, drug resistance is a major obstacle associated with chemotherapy. The development of genetic testing technologies, including next-generation sequencing, has opened the door for the identification of drug targets and candidate molecules. A series of preclinical studies has demonstrated the role of gene mutations, abnormal signaling pathways, and immunosuppression in the pathogenesis of BTC, laying the foundation for the application of targeted therapy and immunotherapy. A variety of molecularly targeted agents, including pemigatinib, have shown promising survival benefits in patients with advanced disease. The rapidly evolving role of multimodal therapy represents the subject of this review.
Collapse
Affiliation(s)
- Ruyi Zhang
- Department of Medical OncologySchool of MedicineThe First Affiliated HospitalZhejiang UniversityHangzhouChina
| | - Marco Puzzoni
- Department of Medical OncologyMedical OncologyUniversity Hospital of CagliariUniversity of CagliariCagliariItaly
| | - Stefano Mariani
- Department of Medical OncologyMedical OncologyUniversity Hospital of CagliariUniversity of CagliariCagliariItaly
| | - Yi Zheng
- Department of Medical OncologySchool of MedicineThe First Affiliated HospitalZhejiang UniversityHangzhouChina
| | - Nicole Liscia
- Medical Oncology UnitSapienza University of RomeRomeItaly
| | - Yixuan Guo
- Department of Medical OncologySchool of MedicineThe First Affiliated HospitalZhejiang UniversityHangzhouChina
| | - Clelia Donisi
- Department of Medical OncologyMedical OncologyUniversity Hospital of CagliariUniversity of CagliariCagliariItaly
| | - Yu Liu
- Department of Medical OncologySchool of MedicineThe First Affiliated HospitalZhejiang UniversityHangzhouChina
| | | | - Weijia Fang
- Department of Medical OncologySchool of MedicineThe First Affiliated HospitalZhejiang UniversityHangzhouChina
| | - Mario Scartozzi
- Department of Medical OncologyMedical OncologyUniversity Hospital of CagliariUniversity of CagliariCagliariItaly
| |
Collapse
|
|
24
|
Wang J, Loeuillard E, Gores GJ, Ilyas SI. Cholangiocarcinoma: what are the most valuable therapeutic targets - cancer-associated fibroblasts, immune cells, or beyond T cells? Expert Opin Ther Targets 2021; 25:835-845. [PMID: 34806500 DOI: 10.1080/14728222.2021.2010046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION CCAs are dense and desmoplastic tumors with an abundant tumor microenviroment (TME). The evolving TME is characterized by reciprocal interactions between cancer cells and their environment and is essential in facilitating tumor progression. The TME has nonimmune and immune components. Nonimmune cell types include cancer-associated fibroblasts (CAFs) and endothelial cells accompanying tumor angiogenesis. Immune cell types include elements of the innate and adaptive immune response, and can have pro-tumor or antitumor roles. The TME can shape treatment response and resistance. Therefore, elements of the TME are attractive therapeutic targets. TME targeting therapies have been evaluated in preclinical and clinical studies but only a small subset of patients has a meaningful response. AREAS COVERED We discuss the TME components and potential TME targeting strategies. Literature search was performed on PubMed and ClinicalTrials.gov until October 2021. EXPERT OPINION Elucidating the CCA TME is essential for developing effective treatment strategies. Preclinical models that recapitulate the disease (such as organoids) are important tools in uncovering the intricate cross talk in the CCA TME. Characterization of patient-derived specimens using multi-omic and single-omic technologies can dissect the cellular interplay in the CCA TME, which can guide development of effective treatment strategies and identify biomarkers for patient stratification.
Collapse
Affiliation(s)
- Juan Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Emilien Loeuillard
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
25
|
Adoptive T-cell immunotherapy in digestive tract malignancies: Current challenges and future perspectives. Cancer Treat Rev 2021; 100:102288. [PMID: 34525422 DOI: 10.1016/j.ctrv.2021.102288] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/15/2022]
Abstract
Multiple systemic treatments are currently available for advanced cancers of the digestive tract, but none of them is curative. Adoptive T-cell immunotherapy refers to the extraction, modification and re-infusion of autologous or allogenic T lymphocytes for therapeutic purposes. A number of clinical trials have investigated either non-engineered T cells (i.e., lymphokine-activated killer cells, cytokine induced killer cells, or tumor-infiltrating lymphocytes) or engineered T cells (T cell receptor-redirected T cells or chimeric antigen receptor T cells) in patients with digestive tract malignancies over the past two decades, with variable degrees of success. While the majority of completed trials have been primarily aimed at assessing the safety of T-cell transfer strategies, a new generation of studies is being designed to formally evaluate the antitumor potential of adoptive T-cell immunotherapy in both the metastatic and adjuvant settings. In this review, we provide an overview of completed and ongoing clinical trials of passive T-cell immunotherapy in patients with cancers of the digestive tract, focusing on present obstacles and future strategies for achieving potential success.
Collapse
|
|
26
|
Xue R, Li R, Wang J, Tong W, Hao J. Horizons on the Therapy of Biliary Tract Cancers: A State-of-the-art Review. J Clin Transl Hepatol 2021; 9:559-567. [PMID: 34447686 PMCID: PMC8369023 DOI: 10.14218/jcth.2021.00007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 03/24/2021] [Accepted: 04/14/2021] [Indexed: 12/14/2022] Open
Abstract
Biliary tract cancers (BTCs) comprise a group of heterogeneous poor prognosis cancers with increasing incidence recent years. The combination chemotherapy with cisplatin and gemcitabine is the first-line therapy for advanced BTC. There remains no accepted standard treatment in the second-line setting. Nowadays, more and more novel treatment strategies have entered development, with some encouraging results being seen. Here, we review the current treatment status and clinical characteristics of BTC, the role of immunotherapy in BTC as well as the design of clinical trials for oncology drugs for BTC which aim to focus on the future profiles of clinical care and resolution of BTC.
Collapse
Affiliation(s)
- Ran Xue
- Key Laboratory of Carcinogenesis & Translational Research (Ministry of Education/Beijing), Early Drug Development Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Rong Li
- Department of Gastroenterology, Beijing Shuang-Qiao Hospital, Beijing, China
| | - Jianxin Wang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Weiping Tong
- Department of Gastroenterology, Beijing Shuang-Qiao Hospital, Beijing, China
| | - Jianyu Hao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Correspondence to: Jianyu Hao, Department of Gastroenterology, Beijing Chao-yang Hospital, Capital Medical University, Chao yang Area, Beijing 100020, China. Tel: +86-10-85231000, E-mail:
| |
Collapse
|
|
27
|
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.
Collapse
|
|
28
|
Zheng Y, Li Y, Feng J, Li J, Ji J, Wu L, Yu Q, Dai W, Wu J, Zhou Y, Guo C. Cellular based immunotherapy for primary liver cancer. J Exp Clin Cancer Res 2021; 40:250. [PMID: 34372912 PMCID: PMC8351445 DOI: 10.1186/s13046-021-02030-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023] Open
Abstract
Primary liver cancer (PLC) is a common malignancy with high morbidity and mortality. Poor prognosis and easy recurrence on PLC patients calls for optimizations of the current conventional treatments and the exploration of novel therapeutic strategies. For most malignancies, including PLC, immune cells play crucial roles in regulating tumor microenvironments and specifically recognizing tumor cells. Therefore, cellular based immunotherapy has its instinctive advantages in PLC therapy as a novel therapeutic strategy. From the active and passive immune perspectives, we introduced the cellular based immunotherapies for PLC in this review, covering both the lymphoid and myeloid cells. Then we briefly review the combined cellular immunotherapeutic approaches and the existing obstacles for PLC treatment.
Collapse
Affiliation(s)
- Yuanyuan Zheng
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Yan Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jingjing Li
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jie Ji
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Qiang Yu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Weiqi Dai
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China.
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China.
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| |
Collapse
|
|
29
|
Ji GW, Wang K, Xia YX, Wang JS, Wang XH, Li XC. Integrating Machine Learning and Tumor Immune Signature to Predict Oncologic Outcomes in Resected Biliary Tract Cancer. Ann Surg Oncol 2021; 28:4018-4029. [PMID: 33230745 DOI: 10.1245/s10434-020-09374-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 10/27/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Improved methods are needed to predict outcomes in biliary tract cancers (BTCs). We aimed to build an immune-related signature and establish holistic models using machine learning. METHODS Samples were from 305 BTC patients treated with curative-intent resection, divided into derivation and validation cohorts in a two-to-one ratio. Spatial resolution of T cell infiltration and PD-1/PD-L1 expression was assessed by immunohistochemistry. An immune signature was constructed using classification and regression tree. Machine learning was applied to develop prediction models for disease-specific survival (DSS) and recurrence-free survival (RFS). RESULTS The immune signature composed of CD3+, CD8+, and PD-1+ cell densities and PD-L1 expression within tumor epithelium significantly stratified patients into three clusters, with median DSS varying from 11.7 to 80.8 months and median RFS varying from 6.2 to 62.0 months. Gradient boosting machines (GBM) outperformed rival machine-learning algorithms and selected the same 11 covariates for DSS and RFS prediction: immune signature, tumor site, age, bilirubin, albumin, carcinoembryonic antigen, cancer antigen 19-9, tumor size, tumor differentiation, resection margin, and nodal metastasis. The clinical-immune GBM models accurately predicted DSS and RFS, with respective concordance index of 0.776-0.816 and 0.741-0.781. GBM models showed significantly improved performance compared with tumor-node-metastasis staging system. CONCLUSIONS The immune signature promises to stratify prognosis and allocate treatment in resected BTC. The clinical-immune GBM models accurately predict recurrence and death from BTC following surgery.
Collapse
Affiliation(s)
- Gu-Wei Ji
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, People's Republic of China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, People's Republic of China
| | - Ke Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, People's Republic of China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, People's Republic of China
| | - Yong-Xiang Xia
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, People's Republic of China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, People's Republic of China
| | - Jin-Song Wang
- Department of Pathology, Nanjing First Hospital, Nanjing, People's Republic of China
| | - Xue-Hao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, People's Republic of China.
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, People's Republic of China.
| | - Xiang-Cheng Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, People's Republic of China.
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, People's Republic of China.
| |
Collapse
|
|
30
|
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.
Collapse
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
| |
Collapse
|
|
31
|
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: 8] [Impact Index Per Article: 2.0] [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.
Collapse
|
|
32
|
Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma. Sci Rep 2021; 11:6276. [PMID: 33737613 PMCID: PMC7973425 DOI: 10.1038/s41598-021-85747-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 03/05/2021] [Indexed: 12/14/2022] Open
Abstract
Current treatments for cholangiocarcinoma (CCA) are largely unsuccessful due to late diagnosis at advanced stage, leading to high mortality rate. Consequently, improved therapeutic approaches are urgently needed. Chimeric antigen receptor (CAR) T cell therapy is a newly potential therapy that can recognize specific surface antigen without major histocompatibility complex (MHC) restriction. Mucin 1 (MUC1) is an attractive candidate antigen as it is highly expressed and associated with poor prognosis and survival in CCA. We, therefore, set forth to create the fourth-generation CAR (CAR4) construct containing anti-MUC1-single-chain variable fragment (scFv) and three co-stimulatory domains (CD28, CD137, and CD27) linked to CD3ζ and evaluate anti-MUC1-CAR4 T cells in CCA models. Compared to untransduced T cells, anti-MUC1-CAR4 T cells produced increased levels of TNF-α, IFN-γ and granzyme B when exposed to MUC1-expressing KKU-100 and KKU-213A CCA cells (all p < 0.05). Anti-MUC1-CAR4 T cells demonstrated specific killing activity against KKU-100 (45.88 ± 7.45%, p < 0.05) and KKU-213A cells (66.03 ± 3.14%, p < 0.001) at an effector to target ratio of 5:1, but demonstrated negligible cytolytic activity against immortal cholangiocytes. Furthermore, the anti-MUC1-CAR4 T cells could effectively disrupt KKU-213A spheroids. These activities of anti-MUC1-CAR4 T cells supports the development of this approach as an adoptive T cell therapeutic strategy for CCA.
Collapse
|
|
33
|
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.
Collapse
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.
| |
Collapse
|
|
34
|
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.
Collapse
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
| |
Collapse
|
|
35
|
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.
Collapse
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.)
| |
Collapse
|
|
36
|
Guo X, Shen W. Latest evidence on immunotherapy for cholangiocarcinoma. Oncol Lett 2020; 20:381. [PMID: 33154779 PMCID: PMC7608025 DOI: 10.3892/ol.2020.12244] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 10/06/2020] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a type of aggressive tumor that involves the intrahepatic, perihilar and distal biliary tree, and is usually diagnosed at an advanced stage. The standard first-line systemic therapy for patients with advanced CCA is a combination of gemcitabine and cisplatin; targeted therapies and angiogenesis inhibitors are not widely used clinically at present. However, with the development of precision medicine, immunotherapy has started to play a more important role. Programmed cell death protein 1 inhibitors are now considered a good therapeutic option for CCA. Treatments using chimeric antigen receptor T cells, bispecific antibodies, oncolytic viruses and cancer vaccines have also achieved satisfactory results. In addition, combinations of immunotherapy with a variety of conventional therapies have shown some efficacy, and several studies have provided insights into their use in antitumor therapy. Although there are numerous challenges in the treatment of advanced CCA, immunotherapy remains a noteworthy breakthrough. The current evidence on the immunotherapy of CCA is discussed in the present review.
Collapse
Affiliation(s)
- Xurui Guo
- Department of Oncology and Hematology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Weizhang Shen
- Department of Oncology and Hematology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| |
Collapse
|
|
37
|
Wakai T, Nagahashi M, Shimada Y, Prasoon P, Sakata J. Genetic analysis in the clinical management of biliary tract cancer. Ann Gastroenterol Surg 2020; 4:316-323. [PMID: 32724874 PMCID: PMC7382432 DOI: 10.1002/ags3.12334] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/24/2020] [Accepted: 03/12/2020] [Indexed: 12/15/2022] Open
Abstract
Biliary tract cancer (BTC) is clinically and pathologically heterogeneous and responds inadequately to treatment. A small section of patients develop resectable disease, although the relapse rates are high; the benefits of adjuvant capecitabine chemotherapy for BTC are now understood, and gemcitabine-based combination chemotherapy is the first line of therapeutic strategy for BTC; however, alternative therapy for BTC is not known. Genomic profiling can provide detailed information regarding the carcinogenesis, identification, and therapy for BTC. Currently, confirmed restorative targets for BTC are lacking. In this review, we aimed to analyze the preclinical and clinical implications of a spectrum of genomic alterations associated with new potentially remedial targets. We focused on eight draggable genes for BTC, which were described as having evidence of therapeutic impact (evidence level 2A-3B) based on the clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment; these include ERBB2, NTRK1, RNF43, CDK6, CDKN2B, FGFR2, IDH1, and IDH2. Moreover, some of the BTC present microsatellite instability, hypermutation, and germline variants, which we also reviewed. Finally, we discussed the therapeutic options based on the next-generation sequencing findings in BTC. Studies have demonstrated that BTC includes subgroups with individually distinct driver mutations, most of which will be targeted with new treatment plans.
Collapse
Affiliation(s)
- Toshifumi Wakai
- Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Masayuki Nagahashi
- Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Yoshifumi Shimada
- Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Pankaj Prasoon
- Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Jun Sakata
- Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| |
Collapse
|
|
38
|
Immunotherapy in gastrointestinal cancer: The current scenario and future perspectives. Cancer Treat Rev 2020; 88:102030. [PMID: 32505807 DOI: 10.1016/j.ctrv.2020.102030] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 05/07/2020] [Accepted: 05/09/2020] [Indexed: 02/06/2023]
Abstract
Gastrointestinal cancers include colorectal, gastric, oesophageal, pancreatic and liver cancers. They continue to be a significant cause of mortality and morbidity worldwide. Current treatment strategies include chemotherapy, surgery, radiotherapy and targeted therapies. Immunotherapy has recently been incorporated in treatment regimens for some gastrointestinal malignancies and research into different immune modifying treatments is being carried out in this context. Approaches to immune modulation such as vaccination, adoptive cell therapy and checkpoint inhibition have shown varying clinical benefit, with most of the benefit seen in checkpoint inhibition. This review summarises recent advances and future direction of immunotherapy in patients with gastrointestinal malignancies.
Collapse
|
|
39
|
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]
|
|
40
|
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.
Collapse
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
| |
Collapse
|
|
41
|
Jiraviriyakul A, Songjang W, Kaewthet P, Tanawatkitichai P, Bayan P, Pongcharoen S. Honokiol-enhanced cytotoxic T lymphocyte activity against cholangiocarcinoma cells mediated by dendritic cells pulsed with damage-associated molecular patterns. World J Gastroenterol 2019; 25:3941-3955. [PMID: 31413529 PMCID: PMC6689815 DOI: 10.3748/wjg.v25.i29.3941] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/21/2019] [Accepted: 07/05/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cholangiocarcinoma or biliary tract cancer has a high mortality rate resulting from late presentation and ineffective treatment strategy. Since immunotherapy by dendritic cells (DC) may be beneficial for cholangiocarcinoma treatment but their efficacy against cholangiocarcinoma was low. We suggest how such anti-tumor activity can be increased using cell lysates derived from an honokiol-treated cholangiocarcinoma cell line (KKU-213L5). AIM To increase antitumour activity of DCs pulsed with cell lysates derived from honokiol-treated cholangiocarcinoma cell line (KKU-213L5). METHODS The effect of honokiol, a phenolic compound isolated from Magnolia officinalis, on choangiocarcinoma cells was investigated in terms of the cytotoxicity and the expression of damage-associated molecular patterns (DAMPs). DCs were loaded with tumour cell lysates derived from honokiol-treated cholangiocarcinoma cells their efficacy including induction of T lymphocyte proliferation, proinflammatory cytokine production and cytotoxicity effect on target cholangiocarcinoma cells were evaluated. RESULTS Honokiol can effectively activate cholangiocarcinoma apoptosis and increase the release of damage-associated molecular patterns. DCs loaded with cell lysates derived from honokiol-treated tumour cells enhanced priming and stimulated T lymphocyte proliferation and type I cytokine production. T lymphocytes stimulated with DCs pulsed with cell lysates of honokiol-treated tumour cells significantly increased specific killing of human cholangiocarcinoma cells compared to those associated with DCs pulsed with cell lysates of untreated cholangiocarcinoma cells. CONCLUSION The present findings suggested that honokiol was able to enhance the immunogenicity of cholangiocarcinoma cells associated with increased effectiveness of DC-based vaccine formulation. Treatment of tumour cells with honokiol offers a promising approach as an ex vivo DC-based anticancer vaccine.
Collapse
Affiliation(s)
- Arunya Jiraviriyakul
- Biomedical Science Graduate School, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Department of Medical technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Worawat Songjang
- Biomedical Science Graduate School, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Department of Medical technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Pongsathorn Kaewthet
- Department of Medical technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Phachsita Tanawatkitichai
- Department of Medical technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Punyapat Bayan
- Department of Medical technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Sutatip Pongcharoen
- Biomedical Science Graduate School, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Division of Immunology, Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand
- Research Centre of Academic Excellence in Petroleum, Petrochemical, and Advanced Materials, Faculty of Science, Naresuan University, Phitsanulok 65000, Thailand
- Centre of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand
| |
Collapse
|
|
42
|
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]
|
|
43
|
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.
Collapse
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.
| |
Collapse
|
|
44
|
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.
Collapse
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,
| |
Collapse
|
|
45
|
Li J, Huang S, Zhou Z, Lin W, Chen S, Chen M, Ye Y. Exosomes derived from rAAV/AFP-transfected dendritic cells elicit specific T cell-mediated immune responses against hepatocellular carcinoma. Cancer Manag Res 2018; 10:4945-4957. [PMID: 30464595 PMCID: PMC6214341 DOI: 10.2147/cmar.s178326] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Dendritic cell (DC)-derived exosomes (Dexs) have been proved to induce and enhance antigen-specific T cell responses in vivo, and previous clinical trials have shown the feasibility and safety of Dexs in multiple human cancers. However, there is little knowledge on the efficacy of Dexs against hepatocellular carcinoma (HCC) until now. Methods In this study, human peripheral blood-derived DCs were loaded with recombinant adeno-associated viral vector (rAAV)-carrying alpha-fetoprotein (AFP) gene (rAAV/AFP), and high-purity Dexs were generated. Then naive T cells were stimulated with Dexs to investigate the specific T cell-mediated immune responses against HCC. Results Our findings showed that Dexs were effective to stimulate naive T cell proliferation and induce T cell activation to become antigen-specific cytotoxic T lymphocytes (CTLs), thereby exhibiting antitumor immune responses against HCC. In addition, Dex-sensitized DC precursors seemed more effective to trigger major histocompatibility complex class I (MHC I)-restricted CTL response and allow DCs to make full use of the minor antigen peptides, thereby maximally activating specific immune responses against HCC. Conclusion It is concluded that Dexs, which combine the advantages of DCs and cell-free vectors, are promising to completely, or at least in part, replace mature DCs (mDCs) to function as cancer vaccines or natural antitumor adjuvant.
Collapse
Affiliation(s)
- Jieyu Li
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China, .,Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou 350014, China, .,Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China,
| | - Shenglan Huang
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China,
| | - Zhifeng Zhou
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou 350014, China, .,Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China,
| | - Wansong Lin
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou 350014, China, .,Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China,
| | - Shuping Chen
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou 350014, China, .,Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China,
| | - Mingshui Chen
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou 350014, China, .,Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China,
| | - Yunbin Ye
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China, .,Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou 350014, China, .,Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China,
| |
Collapse
|
|
46
|
Panya A, Thepmalee C, Sawasdee N, Sujjitjoon J, Phanthaphol N, Junking M, Wongkham S, Yenchitsomanus PT. Cytotoxic activity of effector T cells against cholangiocarcinoma is enhanced by self-differentiated monocyte-derived dendritic cells. Cancer Immunol Immunother 2018; 67:1579-1588. [PMID: 30056600 PMCID: PMC11028072 DOI: 10.1007/s00262-018-2212-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 07/17/2018] [Indexed: 12/29/2022]
Abstract
Cholangiocarcinoma (CCA) is a cancer of the bile ducts that is associated with poor prognosis and poor treatment outcome. Approximately one-third of CCA patients can undergo surgery, but the recurrence rate is high and chemotherapy often cannot satisfactorily prolong survival. Cellular immunotherapy based on adoptive T-cell transfer is a potential treatment for CCA; however, the development of this technology and the search for an appropriate tumor-associated antigen are still ongoing. To enhance the cytotoxic activity of effector T cells against CCA, we developed self-differentiated monocyte-derived dendritic cells (SD-DC) presenting cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A), which is an overexpressed protein that plays a role in the regulation of tumor growth to activate T cells for CCA cell killing. Dendritic cells (DCs) transduced with lentivirus harboring tri-cistronic cDNA sequences (SD-DC-PR) could produce granulocyte-macrophage colony-stimulating factor, interleukin-4, and PRKAR1A. SD-DC showed similar phenotypes to those of DCs derived by conventional method. Autologous effector T cells (CD3+, CD8+) activated by SD-DC-PR exhibited greater cytotoxic activity against CCA than those activated by conventionally-derived DCs. Effector T cells activated by SD-DC-PR killed 60% of CCA cells at an effector-to-target ratio of 15:1, which is approximately twofold greater than the cell killing performance of those stimulated with control DC. The cytotoxic activities of effector T cells activated by SD-DC-PR against CCA cells were significantly associated with the expression levels of PRKR1A in CCA cells. This finding that SD-DC-PR effectively stimulated autologous effector T cells to kill CCA cells may help to accelerate the development of novel therapies for treating CCA.
Collapse
Affiliation(s)
- Aussara Panya
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand
- Center of Excellence in Bioresources for Agriculture, Industry and Medicine, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
| | - Chutamas Thepmalee
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand
- Graduate Program in Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nunghathai Sawasdee
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand
| | - Jatuporn Sujjitjoon
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand
| | - Nattaporn Phanthaphol
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand
- Graduate Program in Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Mutita Junking
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Pa-Thai Yenchitsomanus
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand.
| |
Collapse
|
|
47
|
Kawamoto M, Wada Y, Koya N, Takami Y, Saitsu H, Ishizaki N, Tabata M, Onishi H, Nakamura M, Morisaki T. Long-term survival of a patient with recurrent gallbladder carcinoma, treated with chemotherapy, immunotherapy, and surgery: a case report. Surg Case Rep 2018; 4:115. [PMID: 30219954 PMCID: PMC6139108 DOI: 10.1186/s40792-018-0512-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 08/19/2018] [Indexed: 12/29/2022] Open
Abstract
Background Gallbladder cancer (GBC) is one of the refractory diseases. Multidisciplinary approach including immunotherapy for such cancers has received much attention in recent years. Case presentation A 59-year-old man underwent an extended cholecystectomy for GBC (pathological stage II, T2 N0 M0, [per UICC 7th edition]) that was incidentally found during cholelithiasis surgery, and was then treated with adjuvant gemcitabine (GEM). Three months later, when a recurrence-suspected lesion was detected in segment 5 (S5) of his liver, we started adoptive immunotherapies with cytokine-activated killer (CAK) cell infusions, combined with chemotherapy. After a year of adjuvant immunochemotherapy, the S5 lesion disappeared on imaging, but lesions suspected metastatic recurrence again appeared in S7 and S8 at 4 years and 6 months post-surgery, for which GEM and cisplatin (CDDP) were administered as second-line chemotherapy. Immunochemotherapy produced stable disease (per RECIST) for 9 months, when tumor growth was detected; open microwave coagulo-necrotic therapy (MCN) was performed for these lesions. Three years after MCN, a solitary liver metastasis was detected in S4. MCN was conducted again, and peritoneal dissemination was found intraoperatively. A month after the second MCN, the patient’s carcinoembryonic antigen (CEA) level had increased. Therefore, GEM and tegafur-gimeracil-oteracil potassium (TS-1) were administered as third-line chemotherapy. We also switched the adoptive immunotherapy for tumor-associated antigen-pulsed dendritic cell-activated killer (DAK) cell immunotherapy. After nine courses of GEM and TS-1 administration, CEA had decreased to a normal level. At the time of reporting, 9 years and 6 months have passed since the initial surgery, and 18 months have passed since the peritoneal metastasis was detected. GEM and CDDP are currently administered as fourth-line chemotherapy because of re-increased CEA. Although an undeniable metastasis was found in his para-aortic lymph node, this patient visits our clinic regularly for immunotherapy. Conclusion We here report a rare case of long-term survival of recurrent GBC well controlled by multidisciplinary therapy. Immunotherapy may be a promising modality among multidisciplinary methods for advanced cancer.
Collapse
Affiliation(s)
- Makoto Kawamoto
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Departments of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshiyuki Wada
- Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Norihiro Koya
- Fukuoka General Cancer Clinic, 3-1-1 Sumiyoshi, Hakata-ku, Fukuoka, 812-0018, Japan
| | - Yuko Takami
- Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Hideki Saitsu
- Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Naoki Ishizaki
- Department of Surgery, Kagoshima Medical Association Hospital, Kagoshima, Japan
| | - Mineo Tabata
- Department of Surgery, Kagoshima Medical Association Hospital, Kagoshima, Japan
| | - Hideya Onishi
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Nakamura
- Departments of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takashi Morisaki
- Fukuoka General Cancer Clinic, 3-1-1 Sumiyoshi, Hakata-ku, Fukuoka, 812-0018, Japan.
| |
Collapse
|
|
48
|
Alieva M, van Rheenen J, Broekman MLD. Potential impact of invasive surgical procedures on primary tumor growth and metastasis. Clin Exp Metastasis 2018; 35:319-331. [PMID: 29728948 PMCID: PMC6063335 DOI: 10.1007/s10585-018-9896-8] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 04/30/2018] [Indexed: 02/08/2023]
Abstract
Surgical procedures such as tumor resection and biopsy are still the gold standard for diagnosis and (determination of) treatment of solid tumors, and are prognostically beneficial for patients. However, growing evidence suggests that even a minor surgical trauma can influence several (patho) physiological processes that might promote postoperative metastatic spread and tumor recurrence. Local effects include tumor seeding and a wound healing response that can promote tumor cell migration, proliferation, differentiation, extracellular matrix remodeling, angiogenesis and extravasation. In addition, local and systemic immunosuppression impairs antitumor immunity and contributes to tumor cell survival. Surgical manipulation of the tumor can result in cancer cell release into the circulation, thus increasing the chance of tumor cell dissemination. To prevent these undesired effects of surgical interventions, therapeutic strategies targeting immune response exacerbation or alteration have been proposed. This review summarizes the current literature regarding these local, systemic and secondary site effects of surgical interventions on tumor progression and dissemination, and discusses studies that aimed to identify potential therapeutic approaches to prevent these effects in order to further increase the clinical benefit from surgical procedures.
Collapse
Affiliation(s)
- Maria Alieva
- Princess Máxima Center for Pediatric Oncology, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
| | - Jacco van Rheenen
- Department of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Marike L D Broekman
- Department of Neurology & Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| |
Collapse
|
|
49
|
Rojas-Sepúlveda D, Tittarelli A, Gleisner MA, Ávalos I, Pereda C, Gallegos I, González FE, López MN, Butte JM, Roa JC, Fluxá P, Salazar-Onfray F. Tumor lysate-based vaccines: on the road to immunotherapy for gallbladder cancer. Cancer Immunol Immunother 2018; 67:1897-1910. [PMID: 29600445 PMCID: PMC6244977 DOI: 10.1007/s00262-018-2157-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 03/26/2018] [Indexed: 12/14/2022]
Abstract
Immunotherapy based on checkpoint blockers has proven survival benefits in patients with melanoma and other malignancies. Nevertheless, a significant proportion of treated patients remains refractory, suggesting that in combination with active immunizations, such as cancer vaccines, they could be helpful to improve response rates. During the last decade, we have used dendritic cell (DC) based vaccines where DCs loaded with an allogeneic heat-conditioned melanoma cell lysate were tested in a series of clinical trials. In these studies, 60% of stage IV melanoma DC-treated patients showed immunological responses correlating with improved survival. Further studies showed that an essential part of the clinical efficacy was associated with the use of conditioned lysates. Gallbladder cancer (GBC) is a high-incidence malignancy in South America. Here, we evaluated the feasibility of producing effective DCs using heat-conditioned cell lysates derived from gallbladder cancer cell lines (GBCCL). By characterizing nine different GBCCLs and several fresh tumor tissues, we found that they expressed some tumor-associated antigens such as CEA, MUC-1, CA19-9, Erb2, Survivin, and several carcinoembryonic antigens. Moreover, heat-shock treatment of GBCCLs induced calreticulin translocation and release of HMGB1 and ATP, both known to act as danger signals. Monocytes stimulated with combinations of conditioned lysates exhibited a potent increase of DC-maturation markers. Furthermore, conditioned lysate-matured DCs were capable of strongly inducing CD4+ and CD8+ T cell activation, in both allogeneic and autologous cell co-cultures. Finally, in vitro stimulated CD8+ T cells recognize HLA-matched GBCCLs. In summary, GBC cell lysate-loaded DCs may be considered for future immunotherapy approaches.
Collapse
Affiliation(s)
- Daniel Rojas-Sepúlveda
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 1027, building H, Third floor, 8380453, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, 8380453, Santiago, Chile.,Faculty of Science, Universidad San Sebastián, Lota 2465, 7510157, Santiago, Chile
| | - Andrés Tittarelli
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 1027, building H, Third floor, 8380453, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, 8380453, Santiago, Chile
| | - María Alejandra Gleisner
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 1027, building H, Third floor, 8380453, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, 8380453, Santiago, Chile
| | - Ignacio Ávalos
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 1027, building H, Third floor, 8380453, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, 8380453, Santiago, Chile
| | - Cristián Pereda
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 1027, building H, Third floor, 8380453, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, 8380453, Santiago, Chile
| | - Iván Gallegos
- Pathological Anatomy Service, Clinic Hospital, Universidad de Chile, 8380456, Santiago, Chile
| | - Fermín Eduardo González
- Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, 8380453, Santiago, Chile.,Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, 8380492, Santiago, Chile
| | - Mercedes Natalia López
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 1027, building H, Third floor, 8380453, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, 8380453, Santiago, Chile
| | - Jean Michel Butte
- Department of Surgery, Fundación Arturo López Pérez, Institute of Oncology, 7500921, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, 8330023, Santiago, Chile.,Center for Investigation in Translational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, 8330023, Santiago, Chile
| | - Paula Fluxá
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 1027, building H, Third floor, 8380453, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, 8380453, Santiago, Chile
| | - Flavio Salazar-Onfray
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 1027, building H, Third floor, 8380453, Santiago, Chile. .,Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, 8380453, Santiago, Chile.
| |
Collapse
|
|
50
|
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.
Collapse
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.
| |
Collapse
|