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1
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Zhang M, Huang K, Yin Q, Wu X, Zhu M, Li M. Spatial heterogeneity of the hepatocellular carcinoma microenvironment determines the efficacy of immunotherapy. Discov Oncol 2025; 16:15. [PMID: 39775241 PMCID: PMC11706828 DOI: 10.1007/s12672-025-01747-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge owing to its widespread incidence and high mortality. HCC has a specific immune tolerance function because of its unique physiological structure, which limits the efficacy of chemotherapy, radiotherapy, and molecular targeting. In recent years, new immune approaches, including adoptive cell therapy, tumor vaccines, and oncolytic virus therapy, have shown great potential. As the efficacy of immunotherapy mainly depends on the spatial heterogeneity of the tumor immune microenvironment, it is necessary to elucidate the crosstalk between the composition of the liver cancer immune environment, from which potential therapeutic targets can be selected to provide more appropriate individualized treatment programs. The role of spatial heterogeneity of immune cells in the microenvironment of HCC in the progression and influence of immunotherapy on improving the treatment and prognosis of HCC were comprehensively analyzed, providing new inspiration for the subsequent clinical treatment of liver cancer.
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Affiliation(s)
- Minni Zhang
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
- The First Affiliated Hospital, Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases, The Hainan Branch of National Clinical Research Center for Cancer, Hainan Medical University, Haikou, 570102, Hainan, People's Republic of China
| | - Kailin Huang
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Qiushi Yin
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Xueqin Wu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical University, Haikou, 570023, Hainan, People's Republic of China.
- Key Laboratory of Tropical Translational Medicine, Ministry of Education, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
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2
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Chan YT, Zhang C, Wu J, Lu P, Xu L, Yuan H, Feng Y, Chen ZS, Wang N. Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma. Mol Cancer 2024; 23:189. [PMID: 39242496 PMCID: PMC11378508 DOI: 10.1186/s12943-024-02101-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/23/2024] [Indexed: 09/09/2024] Open
Abstract
Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.
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Affiliation(s)
- Yau-Tuen Chan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Cheng Zhang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Junyu Wu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Pengde Lu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Lin Xu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Hongchao Yuan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Zhe-Sheng Chen
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY, 11439, USA.
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
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3
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He YL, Liu JY, Almgrami RT, Fan YZ, Zhang Y. Cancer immunotherapy of Wilms tumor: a narrative review. Future Oncol 2024; 20:2293-2302. [PMID: 39235074 PMCID: PMC11508995 DOI: 10.1080/14796694.2024.2386929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 07/29/2024] [Indexed: 09/06/2024] Open
Abstract
Wilms tumor (WT) is the most common malignant tumor of the urinary system in children. Though the traditional treatment of surgery plus radiotherapy and chemotherapy achieves exciting clinical efficacy, in relapsed and refractory cases, the long-term overall survival rates are poor. Besides, chemotherapy and radiation have serious long-term toxic side effects on children. Cancer immunotherapy is a new tumor therapy that works by activating the body's immune system to allow immune cells to kill tumor cells more efficiently. Currently, cancer immunotherapy has been tested in clinical trials or basic studies in WT. This article reviews the current status of clinical trials and basic research of cancer immunotherapy in WT to promote the application of cancer immunotherapy in WT patients.
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Affiliation(s)
- Yu Lin He
- Second Ward of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jin Yan Liu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Rahma Taher Almgrami
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ying Zhong Fan
- Second Ward of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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4
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Yin Y, Feng W, Chen J, Chen X, Wang G, Wang S, Xu X, Nie Y, Fan D, Wu K, Xia L. Immunosuppressive tumor microenvironment in the progression, metastasis, and therapy of hepatocellular carcinoma: from bench to bedside. Exp Hematol Oncol 2024; 13:72. [PMID: 39085965 PMCID: PMC11292955 DOI: 10.1186/s40164-024-00539-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 07/10/2024] [Indexed: 08/02/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.
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Affiliation(s)
- Yue Yin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Weibo Feng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Jie Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Xilang Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Guodong Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Daiming Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Kaichun Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Limin Xia
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
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5
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Papadakos SP, Chatzikalil E, Vakadaris G, Reppas L, Arvanitakis K, Koufakis T, Siakavellas SI, Manolakopoulos S, Germanidis G, Theocharis S. Exploring the Role of GITR/GITRL Signaling: From Liver Disease to Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:2609. [PMID: 39061246 PMCID: PMC11275207 DOI: 10.3390/cancers16142609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and presents a continuously growing incidence and high mortality rates worldwide. Besides advances in diagnosis and promising results of pre-clinical studies, established curative therapeutic options for HCC are not currently available. Recent progress in understanding the tumor microenvironment (TME) interactions has turned the scientific interest to immunotherapy, revolutionizing the treatment of patients with advanced HCC. However, the limited number of HCC patients who benefit from current immunotherapeutic options creates the need to explore novel targets associated with improved patient response rates and potentially establish them as a part of novel combinatorial treatment options. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and promotes CD8+ and CD4+ effector T-cell function with simultaneous inhibition of Tregs function, when activated by its ligand, GITRL. GITR is currently considered a potential immunotherapy target in various kinds of neoplasms, especially with the concomitant use of programmed cell-death protein-1 (PD-1) blockade. Regarding liver disease, a high GITR expression in liver progenitor cells has been observed, associated with impaired hepatocyte differentiation, and decreased progenitor cell-mediated liver regeneration. Considering real-world data proving its anti-tumor effect and recently published evidence in pre-clinical models proving its involvement in pre-cancerous liver disease, the idea of its inclusion in HCC therapeutic options theoretically arises. In this review, we aim to summarize the current evidence supporting targeting GITR/GITRL signaling as a potential treatment strategy for advanced HCC.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (E.C.)
| | - Elena Chatzikalil
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (E.C.)
| | - Georgios Vakadaris
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.V.); (K.A.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Lampros Reppas
- 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece;
| | - Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.V.); (K.A.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Theocharis Koufakis
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, 54642 Thessaloniki, Greece;
| | - Spyros I. Siakavellas
- 2nd Academic Department of Internal Medicine, Liver-GI Unit, General Hospital of Athens “Hippocration”, National and Kapodistrian University of Athens, 114 Vas. Sofias str, 11527 Athens, Greece; (S.I.S.); (S.M.)
| | - Spilios Manolakopoulos
- 2nd Academic Department of Internal Medicine, Liver-GI Unit, General Hospital of Athens “Hippocration”, National and Kapodistrian University of Athens, 114 Vas. Sofias str, 11527 Athens, Greece; (S.I.S.); (S.M.)
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.V.); (K.A.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (E.C.)
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6
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Hsu CY, Mustafa MA, Kumar A, Pramanik A, Sharma R, Mohammed F, Jawad IA, Mohammed IJ, Alshahrani MY, Ali Khalil NAM, Shnishil AT, Abosaoda MK. Exploiting the immune system in hepatic tumor targeting: Unleashing the potential of drugs, natural products, and nanoparticles. Pathol Res Pract 2024; 256:155266. [PMID: 38554489 DOI: 10.1016/j.prp.2024.155266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/05/2024] [Accepted: 03/15/2024] [Indexed: 04/01/2024]
Abstract
Hepatic tumors present a formidable challenge in cancer therapeutics, necessitating the exploration of novel treatment strategies. In recent years, targeting the immune system has attracted interest to augment existing therapeutic efficacy. The immune system in hepatic tumors includes numerous cells with diverse actions. CD8+ T lymphocytes, T helper 1 (Th1) CD4+ T lymphocytes, alternative M1 macrophages, and natural killer (NK) cells provide the antitumor immunity. However, Foxp3+ regulatory CD4+ T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) are the key immune inhibitor cells. Tumor stroma can also affect these interactions. Targeting these cells and their secreted molecules is intriguing for eliminating malignant cells. The current review provides a synopsis of the immune system components involved in hepatic tumor expansion and highlights the molecular and cellular pathways that can be targeted for therapeutic intervention. It also overviews the diverse range of drugs, natural products, immunotherapy drugs, and nanoparticles that have been investigated to manipulate immune responses and bolster antitumor immunity. The review also addresses the potential advantages and challenges associated with these approaches.
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Affiliation(s)
- Chou-Yi Hsu
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan
| | | | - Ashwani Kumar
- Department of Life Sciences, School of Sciences, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Pharmacy, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Atreyi Pramanik
- Institute of Pharma Sciences and Research, Chandigarh University, Mohali, India
| | - Rajiv Sharma
- Institute of Pharma Sciences and Research, Chandigarh University, Mohali, India
| | - Faraj Mohammed
- Department of Pharmacy, Al-Manara College for Medical Sciences, Maysan, Iraq
| | | | - Imad Jasim Mohammed
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia.
| | | | | | - Munther Kadhim Abosaoda
- College of technical engineering, the Islamic University, Najaf, Iraq; College of technical engineering, the Islamic University of Al Diwaniyah, Iraq; College of technical engineering, the Islamic University of Babylon, Iraq
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7
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Yang D, Duan Z, Yuan P, Ding C, Dai X, Chen G, Wu D. How does TCR-T cell therapy exhibit a superior anti-tumor efficacy. Biochem Biophys Res Commun 2023; 687:149209. [PMID: 37944471 DOI: 10.1016/j.bbrc.2023.149209] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/26/2023] [Accepted: 10/31/2023] [Indexed: 11/12/2023]
Abstract
TCR-engineered T cells have achieved great progress in solid tumor therapy, some of which have been applicated in clinical trials. Deep knowledge about the current progress of TCR-T in tumor therapy would be beneficial to understand the direction. Here, we classify tumor antigens into tumor-associated antigens, tumor-specific antigens, tumor antigens expressed by oncogenic viruses, and tumor antigens caused by abnormal protein modification; Then we detail the TCR-T cell therapy effects targeting those tumor antigens in clinical or preclinical trials, and propose that neoantigen specific TCR-T cell therapy is expected to be a promising approach for solid tumors; Furthermore, we summarize the optimization strategies, such as tumor microenvironment, TCR pairing and affinity, to improve the therapeutic effect of TCR-T. Overall, this review provides inspiration for the antigen selection and therapy strategies of TCR-T in the future.
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Affiliation(s)
- Dandan Yang
- Laboratory of Structural Immunology, Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Zhihui Duan
- Laboratory of Structural Immunology, Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Ping Yuan
- Laboratory of Structural Immunology, Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Chengming Ding
- Laboratory of Structural Immunology, Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiaoming Dai
- Laboratory of Structural Immunology, Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Guodong Chen
- Laboratory of Structural Immunology, Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Daichao Wu
- Laboratory of Structural Immunology, Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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8
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Wu D, Li Y. Application of adoptive cell therapy in hepatocellular carcinoma. Immunology 2023; 170:453-469. [PMID: 37435926 DOI: 10.1111/imm.13677] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 06/20/2023] [Indexed: 07/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge. Novel treatment modalities are urgently needed to extend the overall survival of patients. The liver plays an immunomodulatory function due to its unique physiological structural characteristics. Therefore, following surgical resection and radiotherapy, immunotherapy regimens have shown great potential in the treatment of hepatocellular carcinoma. Adoptive cell immunotherapy is rapidly developing in the treatment of hepatocellular carcinoma. In this review, we summarize the latest research on adoptive immunotherapy for hepatocellular carcinoma. The focus is on chimeric antigen receptor (CAR)-T cells and T cell receptor (TCR) engineered T cells. Then tumour-infiltrating lymphocytes (TILs), natural killer (NK) cells, cytokine-induced killer (CIK) cells, and macrophages are briefly discussed. The main overview of the application and challenges of adoptive immunotherapy in hepatocellular carcinoma. It aims to provide the reader with a comprehensive understanding of the current status of HCC adoptive immunotherapy and offers some strategies. We hope to provide new ideas for the clinical treatment of hepatocellular carcinoma.
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Affiliation(s)
- Dengqiang Wu
- Department of Clinical Laboratory, Ningbo No. 6 Hospital, Ningbo, China
| | - Yujie Li
- Clinical Laboratory of Ningbo Medical Centre Lihuili Hospital, Ningbo University, Zhejiang, Ningbo, China
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9
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Yu SJ. Immunotherapy for hepatocellular carcinoma: Recent advances and future targets. Pharmacol Ther 2023; 244:108387. [PMID: 36948423 DOI: 10.1016/j.pharmthera.2023.108387] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/12/2023] [Accepted: 03/15/2023] [Indexed: 03/24/2023]
Abstract
Immunotherapy is a promising approach to treating various types of cancers, including hepatocellular carcinoma (HCC). While single immunotherapy drugs show limited effectiveness on a small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab has shown significant improvement in survival compared to sorafenib as a first-line treatment. However, the current treatment options still have a low success rate of about 30%. Thus, more effective treatments for HCC are urgently required. Several novel immunotherapeutic methods, including the use of novel immune checkpoint inhibitors, innovative immune cell therapies like chimeric antigen receptor T cells (CAR-T), TCR gene-modified T cells and stem cells, as well as combination strategies are being tested in clinical trials for the treatment of HCC. However, some crucial issues still exist such as the presence of heterogeneous antigens in solid tumors, the immune-suppressive environment within tumors, the risk of on-target/off-tumor, infiltrating CAR-T cells, immunosuppressive checkpoint molecules, and cytokines. Overall, immunotherapy is on the brink of major advancements in the fight against HCC.
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Affiliation(s)
- Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
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10
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Głowska-Ciemny J, Szymański M, Kuszerska A, Malewski Z, von Kaisenberg C, Kocyłowski R. The Role of Alpha-Fetoprotein (AFP) in Contemporary Oncology: The Path from a Diagnostic Biomarker to an Anticancer Drug. Int J Mol Sci 2023; 24:ijms24032539. [PMID: 36768863 PMCID: PMC9917199 DOI: 10.3390/ijms24032539] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/21/2023] [Accepted: 01/22/2023] [Indexed: 01/31/2023] Open
Abstract
This article presents contemporary opinion on the role of alpha-fetoprotein in oncologic diagnostics and treatment. This role stretches far beyond the already known one-that of the biomarker of hepatocellular carcinoma. The turn of the 20th and 21st centuries saw a significant increase in knowledge about the fundamental role of AFP in the neoplastic processes, and in the induction of features of malignance and drug resistance of hepatocellular carcinoma. The impact of AFP on the creation of an immunosuppressive environment for the developing tumor was identified, giving rise to attempts at immunotherapy. The paper presents current and prospective therapies using AFP and its derivatives and the gene therapy options. We directed our attention to both the benefits and risks associated with the use of AFP in oncologic therapy.
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Affiliation(s)
- Joanna Głowska-Ciemny
- PreMediCare New Med Medical Center, ul. Czarna Rola 21, 61-625 Poznań, Poland
- Correspondence: (J.G.-C.); (R.K.)
| | - Marcin Szymański
- PreMediCare New Med Medical Center, ul. Czarna Rola 21, 61-625 Poznań, Poland
| | - Agata Kuszerska
- PreMediCare New Med Medical Center, ul. Czarna Rola 21, 61-625 Poznań, Poland
| | - Zbyszko Malewski
- Department of Perinatology and Gynecology, Poznan University of Medical Sciences, 60-535 Poznań, Poland
| | - Constantin von Kaisenberg
- Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
| | - Rafał Kocyłowski
- PreMediCare New Med Medical Center, ul. Czarna Rola 21, 61-625 Poznań, Poland
- Correspondence: (J.G.-C.); (R.K.)
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11
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Laface C, Ranieri G, Maselli FM, Ambrogio F, Foti C, Ammendola M, Laterza M, Cazzato G, Memeo R, Mastrandrea G, Lioce M, Fedele P. Immunotherapy and the Combination with Targeted Therapies for Advanced Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:654. [PMID: 36765612 PMCID: PMC9913568 DOI: 10.3390/cancers15030654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/11/2023] [Accepted: 01/17/2023] [Indexed: 01/24/2023] Open
Abstract
One of the most important abilities of a tumor is to establish a state of immunosuppression inside the tumor microenvironment. This is made possible through numerous mechanisms of tumor immune escape that have been identified in experimental studies during the last decades. In addition, the hepatic microenvironment is commonly oriented towards a state of immune tolerance because the liver receives blood from the hepatic arteries and portal veins containing a variety of endogenous antigens. Therefore, the hepatic microenvironment establishes an autoimmune tolerance, preventing an autoimmune reaction in the liver. On this basis, hepatic tumor cells may escape the immune system, avoiding being recognized and destroyed by immune cells. Moreover, since the etiology of Hepatocellular Carcinoma (HCC) is often related to cirrhosis, and hepatitis B or C, this tumor develops in the context of chronic inflammation. Thus, the HCC microenvironment is characterized by important immune cell infiltration. Given these data and the poor prognosis of advanced HCC, different immunotherapeutic strategies have been developed and evaluated for these patients. In this review, we describe all the clinical applications of immunotherapy for advanced HCC, from the drugs that have already been approved to the ongoing clinical trials.
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Affiliation(s)
- Carmelo Laface
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | | | | | - Francesca Ambrogio
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Caterina Foti
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Michele Ammendola
- Department of Health Science, General Surgery, Medicine School of Germaneto, Magna Graecia University, 88100 Catanzaro, Italy
| | - Marigia Laterza
- Division of Cardiac Surgery, University of Bari, 70124 Bari, Italy
| | - Gerardo Cazzato
- Department of Emergency and Organ Transplantation, Pathology Section, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Riccardo Memeo
- Unit of Hepato-Pancreatic-Biliary Surgery, “F. Miulli” General Regional Hospital, 70021 Acquaviva Delle Fonti, Italy
| | | | - Marco Lioce
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
| | - Palma Fedele
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
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12
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Shen J, Yang D, Ding Y. Advances in Promoting the Efficacy of Chimeric Antigen Receptor T Cells in the Treatment of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:5018. [PMID: 36291802 PMCID: PMC9599749 DOI: 10.3390/cancers14205018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/07/2022] [Accepted: 10/11/2022] [Indexed: 09/14/2023] Open
Abstract
HCC, one of the most common and deadly cancers worldwide, develops from hepatocytes and accounts for more than 90% of primary liver cancers. The current widely used treatment modalities are far from meeting the needs of liver cancer patients. CAR-T cell therapy, which has recently emerged, has shown promising efficacy in lymphoma and hematologic cancers, but there are still many challenges to overcome in its application to the clinical treatment of HCC, including osmotic barriers, the inhibition of hepatocellular carcinoma microenvironment activity, the limited survival and killing ability of CAR-T cells, and inevitable side effects, among others. As a result, a number of studies have begun to address the suboptimal efficacy of CAR-T cells in HCC, and many of these schemes hold good promise. This review focuses on advances in the past five years aimed at promoting the efficacy of CAR-T cell therapy for treatment of HCC.
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Affiliation(s)
| | | | - Youming Ding
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
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13
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Munson PV, Adamik J, Butterfield LH. Immunomodulatory impact of α-fetoprotein. Trends Immunol 2022; 43:438-448. [PMID: 35550875 DOI: 10.1016/j.it.2022.04.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 03/31/2022] [Accepted: 04/03/2022] [Indexed: 11/18/2022]
Abstract
α-Fetoprotein (AFP) is a fetal glycoprotein produced by most human hepatocellular carcinoma tumors. Research has focused on its immunosuppressive properties in pregnancy, autoimmunity, and cancer, and human AFP directly limits the viability and functionality of human natural killer (NK) cells, monocytes, and dendritic cells (DCs). AFP-altered DCs can promote the differentiation of naïve T cells into regulatory T cells. These properties may work to shield tumors from the immune system. Recent efforts to define the molecular characteristics of AFP identified key structural immunoregulatory domains and bioactive roles of AFP-bound ligands in immunomodulation. We propose that a key mechanism of AFP immunomodulation skews DC function through cellular metabolism. Delineating differences between fetal 'normal' AFP (nAFP) and tumor-derived AFP (tAFP) has uncovered a novel role for tAFP in altering metabolism via lipid-binding partners.
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Affiliation(s)
- Paul V Munson
- Parker Institute for Cancer Immunotherapy (PICI), San Francisco, CA, USA; Department of Microbiology and Immunology, University of California San Francisco (UCSF), San Francisco, CA, USA
| | - Juraj Adamik
- Parker Institute for Cancer Immunotherapy (PICI), San Francisco, CA, USA; Department of Microbiology and Immunology, University of California San Francisco (UCSF), San Francisco, CA, USA
| | - Lisa H Butterfield
- Parker Institute for Cancer Immunotherapy (PICI), San Francisco, CA, USA; Department of Microbiology and Immunology, University of California San Francisco (UCSF), San Francisco, CA, USA.
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14
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Fan Y, Xue H, Zheng H. Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook. J Hepatocell Carcinoma 2022; 9:233-263. [PMID: 35388357 PMCID: PMC8977221 DOI: 10.2147/jhc.s358082] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has emerged the culprit of cancer-related mortality worldwide with its dismal prognosis climbing. In recent years, ground-breaking progress has been made in systemic therapy for HCC. Targeted therapy based on specific signaling molecules, including sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab, has been widely used for advanced HCC (aHCC). Immunotherapies such as pembrolizumab and nivolumab greatly improve the survival of aHCC patients. More recently, synergistic combination therapy has boosted first-line (atezolizumab in combination with bevacizumab) and second-line (ipilimumab in combination with nivolumab) therapeutic modalities for aHCC. This review aims to summarize recent updates of systemic therapy relying on the biological mechanisms of HCC, particularly highlighting the approved agents for aHCC. Adjuvant and neoadjuvant therapy, as well as a combination with locoregional therapies (LRTs), are also discussed. Additionally, we describe the promising effect of traditional Chinese medicine (TCM) as systemic therapy on HCC. In this setting, the challenges and future directions of systemic therapy for HCC are also explored.
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Affiliation(s)
- Yinjie Fan
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, People’s Republic of China
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Hang Xue
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Huachuan Zheng
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
- Correspondence: Huachuan Zheng, Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China, Tel +86-0314-2279458, Fax +86-0314-2279458, Email
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15
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Zhao K, Zhou X, Xiao Y, Wang Y, Wen L. Research Progress in Alpha-Fetoprotein-Induced Immunosuppression of Liver Cancer. Mini Rev Med Chem 2022; 22:2237-2243. [PMID: 35184712 DOI: 10.2174/1389557522666220218124816] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/14/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022]
Abstract
Abstract:
Liver cancer is one of the most common malignant tumors, with limited treatment and 8.2% high mortality. Liver cancer is the fourth leading cause of cancer-related deaths, which seriously endangers human life and health. Approximately 70% of liver cancer patients show increased serum alpha-fetoprotein (AFP) levels. AFP is the main diagnostic and prognostic indicator of liver cancer. AFP, a key marker of liver cancer, plays a crucial role in regulating the proliferation of tumor cells, apoptosis, and induction of cellular immune escape. High levels of AFP during embryonic development protect the embryos from maternal immune attack. AFP also promotes immune escape of liver cancer cells by inhibiting tumor-infiltrating lymphocytes (TILs), natural killer cells (NK), dendritic cells (DC), and macrophages; thus, it is also used as a target antigen in immunotherapy for liver cancer. AFP is highly expressed in liver cancer cells. In addition to being used in the diagnosis of liver cancer, it has become a target of immunotherapy for liver cancer as a tumor-associated antigen. In immunotherapy, it was also confirmed that early AFP response was positively correlated with the efficacy of immunotherapy. Early AFP responders had longer PFS and OS than non-responders. At present, the methods of immunotherapy for liver cancer mainly include Adoptive Cell Transfer Therapy (ACT), tumor vaccine therapy, immune checkpoint inhibitors (ICIs) therapy and so on. A large number of studies have shown that AFP mainly plays a role in ACT and liver cancer vaccines. This review presents the research progress of AFP and immunosuppression of liver cancer.
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Affiliation(s)
- Kailiang Zhao
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xiaoquan Zhou
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yuchun Xiao
- People\'s Hospital of Shangdang District, Changzhi, 047100, China
| | - Yanni Wang
- Taizhou Institute for Drug Control, Jiangsu Taizhou, 225300, China
| | - Lu Wen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
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16
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Hu X, Chen R, Wei Q, Xu X. The Landscape Of Alpha Fetoprotein In Hepatocellular Carcinoma: Where Are We? Int J Biol Sci 2022; 18:536-551. [PMID: 35002508 PMCID: PMC8741863 DOI: 10.7150/ijbs.64537] [Citation(s) in RCA: 117] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 10/15/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has been acknowledged as a leading cause of death among cirrhosis patients. Difficulties in early diagnosis and heterogeneity are obstacles to effective treatment, especially for advanced HCC. Liver transplantation (LT) is considered the best therapy for HCC. Although many biomarkers are being proposed, alpha-fetoprotein (AFP), which was identified over 60 years ago, remains the most utilized. Recently, much hope has been placed in the immunogenicity of AFP to develop novel therapies, such as AFP vaccines and AFP-specific adoptive T-cell transfer (ACT). This review summarizes the performance of AFP as a biomarker for HCC diagnosis and prognosis, as well as its correlation with molecular classes. In addition, the role of AFP in LT is also described. Finally, we highlight the mechanism and application prospects of two immune therapies (AFP vaccine and ACT) for HCC. In general, our review points out the prevalence of AFP in HCC, accompanied by some controversies and novel directions for future research.
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Affiliation(s)
- Xin Hu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Zhejiang University Cancer Center, Hangzhou, 310058, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Ronggao Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Zhejiang University Cancer Center, Hangzhou, 310058, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China
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17
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Abstract
Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Systemic therapy is used in the advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy with checkpoint inhibitors has shown strong anti-tumour activity in a subset of patients and the combination of the anti-PDL1 antibody atezolizumab and the VEGF-neutralizing antibody bevacizumab has or will soon become the standard of care as a first-line therapy for HCC, whereas the anti-PD1 agents nivolumab and pembrolizumab are used after TKIs in several regions. Other immune strategies such as adoptive T-cell transfer, vaccination or virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges in HCC checkpoint immunotherapy are the discovery and validation of predictive biomarkers, advancing treatment to earlier stages of the disease, applying the treatment to patients with liver dysfunction and the discovery of more effective combinatorial or sequential approaches. Combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC and some are already under evaluation in large-scale clinical trials. This Review provides up-to-date information on the best use of currently available immunotherapies in HCC and the therapeutic strategies under development.
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Affiliation(s)
- Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain.
| | - Pablo Sarobe
- Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain
| | - Sandra Hervás-Stubbs
- Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain
- Department of Immunology and Immunotherapy, Clinica Universidad de Navarra-IDISNA and CIBERONC, Pamplona, Spain
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18
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Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches. Cells 2021; 10:cells10061332. [PMID: 34071188 PMCID: PMC8227136 DOI: 10.3390/cells10061332] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/13/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Natural killer (NK) cells account for 25–50% of the total number of hepatic lymphocytes, which implicates that NK cells play an important role in liver immunity. The frequencies of both circulating and tumor infiltrating NK cells are positively correlated with survival benefit in hepatocellular cancer (HCC) and have prognostic implications, which suggests that functional impairment in NK cells and HCC progression are strongly associated. In HCC, T cell exhaustion is accompanied by the interaction between immune checkpoint ligands and their receptors on tumor cells and antigen presenting cells (APC). Immune checkpoint inhibitors (ICIs) have been shown to interfere with this interaction and have altered the therapeutic landscape of multiple cancer types including HCC. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as first-line therapy for HCC. NK cells are the first line effectors in viral hepatitis and play an important role by directly eliminating virus infected cells or by activating antigen specific T cells through IFN-γ production. Furthermore, chimeric antigen receptor (CAR)-engineered NK cells and T cells offer unique opportunities to create CAR-NK with multiple specificities learning from the experience gained with CAR-T cells with potentially less adverse effects. This review focus on the abnormalities of NK cells, T cells, and their functional impairment in patients with chronic viral hepatitis, which contributes to progression to hepatic malignancy. Furthermore, we discuss and summarize recent advances in the NK cell and T cell based immunotherapeutic approaches in HCC.
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19
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Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2021; 18:525-543. [PMID: 33850328 PMCID: PMC8042636 DOI: 10.1038/s41575-021-00438-0] [Citation(s) in RCA: 827] [Impact Index Per Article: 206.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/05/2021] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Systemic therapy is used in the advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy with checkpoint inhibitors has shown strong anti-tumour activity in a subset of patients and the combination of the anti-PDL1 antibody atezolizumab and the VEGF-neutralizing antibody bevacizumab has or will soon become the standard of care as a first-line therapy for HCC, whereas the anti-PD1 agents nivolumab and pembrolizumab are used after TKIs in several regions. Other immune strategies such as adoptive T-cell transfer, vaccination or virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges in HCC checkpoint immunotherapy are the discovery and validation of predictive biomarkers, advancing treatment to earlier stages of the disease, applying the treatment to patients with liver dysfunction and the discovery of more effective combinatorial or sequential approaches. Combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC and some are already under evaluation in large-scale clinical trials. This Review provides up-to-date information on the best use of currently available immunotherapies in HCC and the therapeutic strategies under development.
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Affiliation(s)
- Bruno Sangro
- grid.411730.00000 0001 2191 685XLiver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain
| | - Pablo Sarobe
- grid.5924.a0000000419370271Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain
| | - Sandra Hervás-Stubbs
- grid.5924.a0000000419370271Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain
| | - Ignacio Melero
- grid.5924.a0000000419370271Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain ,grid.411730.00000 0001 2191 685XDepartment of Immunology and Immunotherapy, Clinica Universidad de Navarra-IDISNA and CIBERONC, Pamplona, Spain
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20
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Ruf B, Heinrich B, Greten TF. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol 2021; 18:112-127. [PMID: 33235387 PMCID: PMC7852696 DOI: 10.1038/s41423-020-00572-w] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 09/29/2020] [Indexed: 12/24/2022] Open
Abstract
Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types. The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma (HCC). Nevertheless, current immunotherapeutic approaches induce durable responses in only a subset of HCC patients. Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation, development, and progression of HCC, it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer. The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial, viral, and fungal antigens through the gut-liver axis. Here, we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them. We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.
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Affiliation(s)
- Benjamin Ruf
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Bernd Heinrich
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
- NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, 20892, USA.
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21
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Atypical immunometabolism and metabolic reprogramming in liver cancer: Deciphering the role of gut microbiome. Adv Cancer Res 2020; 149:171-255. [PMID: 33579424 DOI: 10.1016/bs.acr.2020.10.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide. Much recent research has delved into understanding the underlying molecular mechanisms of HCC pathogenesis, which has revealed to be heterogenous and complex. Two major hallmarks of HCC include: (i) a hijacked immunometabolism and (ii) a reprogramming in metabolic processes. We posit that the gut microbiota is a third component in an entanglement triangle contributing to HCC progression. Besides metagenomic studies highlighting the diagnostic potential in the gut microbiota profile, recent research is pinpointing the gut microbiota as an instigator, not just a mere bystander, in HCC. In this chapter, we discuss mechanistic insights on atypical immunometabolism and metabolic reprogramming in HCC, including the examination of tumor-associated macrophages and neutrophils, tumor-infiltrating lymphocytes (e.g., T-cell exhaustion, regulatory T-cells, natural killer T-cells), the Warburg effect, rewiring of the tricarboxylic acid cycle, and glutamine addiction. We further discuss the potential involvement of the gut microbiota in these characteristics of hepatocarcinogenesis. An immediate highlight is that microbiota metabolites (e.g., short chain fatty acids, secondary bile acids) can impair anti-tumor responses, which aggravates HCC. Lastly, we describe the rising 'new era' of immunotherapies (e.g., immune checkpoint inhibitors, adoptive T-cell transfer) and discuss for the potential incorporation of gut microbiota targeted therapeutics (e.g., probiotics, fecal microbiota transplantation) to alleviate HCC. Altogether, this chapter invigorates for continuous research to decipher the role of gut microbiome in HCC from its influence on immunometabolism and metabolic reprogramming.
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22
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Patel K, Lamm R, Altshuler P, Dang H, Shah AP. Hepatocellular Carcinoma-The Influence of Immunoanatomy and the Role of Immunotherapy. Int J Mol Sci 2020; 21:ijms21186757. [PMID: 32942580 PMCID: PMC7555667 DOI: 10.3390/ijms21186757] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality worldwide. Most patients are diagnosed with advanced disease, limiting their options for treatment. While current treatments are adequate for lower staged disease, available systemic treatments are limited, with marginal benefit at best. Chimeric antigen receptor (CAR) T cell therapy, effective in treating liquid tumors such as B-cell lymphoma, presents a potentially promising treatment option for advanced HCC. However, new challenges specific to solid tumors, such as tumor immunoanatomy or the immune cell presence and position anatomically and the tumor microenvironment, need to be defined and overcome. Immunotherapy currently in use must be re-engineered and re-envisioned to treat HCC with the hopes of ushering in an answer to advanced stage solid tumor disease processes. Future therapy options must address the uniqueness of the tumors under the umbrella of HCC. This review strives to summarize HCC, its staging system, current therapy and immunotherapy medications currently being utilized or studied in the treatment of HCC with the hopes of highlighting what is being done and suggesting what needs to be done in the future to champion this therapy as an effective option.
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Affiliation(s)
- Keyur Patel
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Ryan Lamm
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Peter Altshuler
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Hien Dang
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
- Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA
- Correspondence: (H.D.); (A.P.S.)
| | - Ashesh P. Shah
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
- Correspondence: (H.D.); (A.P.S.)
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23
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Shi D, Shi Y, Kaseb AO, Qi X, Zhang Y, Chi J, Lu Q, Gao H, Jiang H, Wang H, Yuan D, Ma H, Wang H, Li Z, Zhai B. Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials. Clin Cancer Res 2020; 26:3979-3989. [PMID: 32371538 DOI: 10.1158/1078-0432.ccr-19-3259] [Citation(s) in RCA: 230] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 02/17/2020] [Accepted: 04/27/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC. PATIENTS AND METHODS In two prospective phase I studies, adult patients with advanced GPC3+ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide- and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1). RESULTS A total of 13 patients received a median of 19.9 × 108 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response. CONCLUSIONS This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.
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Affiliation(s)
- Donghua Shi
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yaoping Shi
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xingxing Qi
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan Zhang
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiachang Chi
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Lu
- Department of Radiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Hua Jiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | | | - Hong Ma
- CARsgen Therapeutics Corp., Houston, Texas
| | - Hongyang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China
| | - Zonghai Li
- CARsgen Therapeutics Ltd., Shanghai, China. .,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bo Zhai
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Luo X, Cui H, Cai L, Zhu W, Yang WC, Patrick M, Zhu S, Huang J, Yao X, Yao Y, He Y, Ji Y. Selection of a Clinical Lead TCR Targeting Alpha-Fetoprotein-Positive Liver Cancer Based on a Balance of Risk and Benefit. Front Immunol 2020; 11:623. [PMID: 32425926 PMCID: PMC7203609 DOI: 10.3389/fimmu.2020.00623] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 03/19/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a poor prognosis and limited therapeutic options. Alpha-fetoprotein (AFP), an established clinical biomarker of HCC, has been employed as an attractive target for T cell-based immunotherapy against this disease given its high expression in the tumor and restricted expression in normal tissues. We have identified a number of T cell receptors (TCRs) recognizing the HLA-A*02:01 restricted AFP158-166 peptide FMNKFIYEI, providing a TCR candidate pool for identifying TCRs with optimal clinical benefit. To select the ideal AFP TCR for clinical use, we evaluated the efficacy and safety profile of 7 TCRs by testing their potency toward AFP-expressing HCC cells and their specificity based upon reactivity to normal and transformed cells covering a wide variety of primary cell types and HLA serotypes. Furthermore, we assessed their cross-reactivity to potential protein candidates in the human genome by an extensive alanine scan (X-scan). We first selected three TCR candidates based on the in vitro anti-tumor activity. Next we eliminated two potential cross-reactive TCRs based on their reactivity against normal and transformed cells covering a variety of primary cell types and HLA serotypes, respectively. We then excluded the potential cross-reactivity of the selected TCR with a protein candidate identified by X-scan. At present we have selected an AFP TCR with the optimal affinity, function, and safety profile, bearing properties that are expected to allow AFP TCR redirected T cells to specifically differentiate between AFP levels on tumor and normal tissues. An early phase clinical trial using T cells transduced with this TCR to treat HCC patients (NCT03971747) has been initiated.
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Affiliation(s)
- Xiaobing Luo
- Cellular Biomedicine Group Inc., Gaithersburg, MD, United States
| | - Huijuan Cui
- Cellular Biomedicine Group Inc., Gaithersburg, MD, United States
| | - Lun Cai
- Georgia Cancer Center, Medical College of Georgia, Augusta, GA, United States
| | - Wei Zhu
- CodexSage LLC., Germantown, MD, United States
| | - Wei-Chih Yang
- Cellular Biomedicine Group Inc., Gaithersburg, MD, United States
| | - Michael Patrick
- Cellular Biomedicine Group Inc., Gaithersburg, MD, United States
| | - Shigui Zhu
- Cellular Biomedicine Group Inc., Gaithersburg, MD, United States
| | - Jiaqi Huang
- Cellular Biomedicine Group Inc., Gaithersburg, MD, United States
| | - Xin Yao
- Cellular Biomedicine Group Inc., Gaithersburg, MD, United States
| | - Yihong Yao
- Cellular Biomedicine Group Inc., Gaithersburg, MD, United States
| | - Yukai He
- Georgia Cancer Center, Medical College of Georgia, Augusta, GA, United States
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Yun Ji
- Cellular Biomedicine Group Inc., Gaithersburg, MD, United States
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25
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Recent Advances in Immunotherapy for Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12040775. [PMID: 32218257 PMCID: PMC7226090 DOI: 10.3390/cancers12040775] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 03/22/2020] [Accepted: 03/24/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of cancer therapy. Since HCC is characterized by metachronous multicentric occurrence, immunotherapies that induce systemic and durable responses could be an appealing treatment option. Despite the suppressive milieu of the liver and tumor immunosurveillance escape mechanisms, clinical studies of checkpoint inhibitors in patients with advanced HCC have yielded promising results. Here, we provide an update on recent advances in HCC immunotherapies. First, we describe the unique tolerogenic properties of hepatic immunity and its interaction with HCC and then review the status of already or nearly available immune checkpoint blockade-based therapies as well as other immunotherapy strategies at the preclinical or clinical trial stage.
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26
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Jost C, Darowski D, Challier J, Pulko V, Hanisch LJ, Xu W, Mössner E, Bujotzek A, Klostermann S, Umana P, Kontermann RE, Klein C. CAR-J cells for antibody discovery and lead optimization of TCR-like immunoglobulins. MAbs 2020; 12:1840709. [PMID: 33136521 PMCID: PMC7646475 DOI: 10.1080/19420862.2020.1840709] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 09/15/2020] [Accepted: 10/19/2020] [Indexed: 01/07/2023] Open
Abstract
T-cell bispecific antibodies (TCBs) are a novel class of engineered immunoglobulins that unite monovalent binding to the T-cell receptor (TCR) CD3e chain and bivalent binding to tumor-associated antigens in order to recruit and activate T-cells for tumor cell killing. In vivo, T-cell activation is usually initiated via the interaction of the TCR with the peptide-HLA complex formed by the human leukocyte antigen (HLA) and peptides derived from intracellular proteins. TCR-like antibodies (TCRLs) that recognize pHLA-epitopes extend the target space of TCBs to peptides derived from intracellular proteins, such as those overexpressed during oncogenesis or created via mutations found in cancer. One challenge during lead identification of TCRL-TCBs is to identify TCRLs that specifically, and ideally exclusively, recognize the desired pHLA, but not unrelated pHLAs. In order to identify TCRLs suitable for TCRL-TCBs, large numbers of TCRLs have to be tested in the TCB format. Here, we propose a novel approach using chimeric antigen receptors (CARs) to facilitate the identification of highly selective TCRLs. In this new so-called TCRL-CAR-J approach, TCRL-candidates are transduced as CARs into Jurkat reporter-cells, and subsequently assessed for their specificity profile. This work demonstrates that the CAR-J reporter-cell assay can be applied to predict the profile of TCRL-TCBs without the need to produce each candidate in the final TCB format. It is therefore useful in streamlining the identification of TCRL-TCBs.
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Affiliation(s)
- Christian Jost
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland
- Athebio AG, Zurich, Switzerland
| | - Diana Darowski
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland
| | - John Challier
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland
| | - Vesna Pulko
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland
| | - Lydia J Hanisch
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland
| | - Wei Xu
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland
| | - Ekkehard Mössner
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland
| | - Alexander Bujotzek
- Roche Innovation Center Munich, Roche Pharma Research & Early Development, Penzberg, Germany
| | - Stefan Klostermann
- Roche Innovation Center Munich, Roche Pharma Research & Early Development, Penzberg, Germany
| | - Pablo Umana
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland
| | | | - Christian Klein
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland
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27
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Hendrickson PG, Olson M, Luetkens T, Weston S, Han T, Atanackovic D, Fine GC. The promise of adoptive cellular immunotherapies in hepatocellular carcinoma. Oncoimmunology 2019; 9:1673129. [PMID: 32002284 PMCID: PMC6959455 DOI: 10.1080/2162402x.2019.1673129] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 09/22/2019] [Accepted: 09/24/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Current systemic therapies result only in modest benefits and new therapeutic options are critically needed. Some patients show promising clinical responses to immune checkpoint inhibitors, however, additional immunotherapeutic approaches, such as adoptive cell therapies (ACT), need to be developed. This review summarizes recent ACT studies and discusses the promise and obstacles of this approach. We further discuss ways of improving the efficacy of ACT in HCC including the use of combination therapies and locoregional delivery methods.
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Affiliation(s)
- Peter G. Hendrickson
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, USA
| | - Michael Olson
- Hematology and Hematologic Malignancies, University of Utah/Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Tim Luetkens
- Hematology and Hematologic Malignancies, University of Utah/Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Siani Weston
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, USA
| | - Tiffany Han
- Department of Radiology, Norwalk Hospital, Norwalk, CT, USA
| | - Djordje Atanackovic
- Hematology and Hematologic Malignancies, University of Utah/Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Gabriel C. Fine
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, USA
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28
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Chen J, Gingold JA, Su X. Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma. Trends Mol Med 2019; 25:1010-1023. [PMID: 31353124 DOI: 10.1016/j.molmed.2019.06.007] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 06/14/2019] [Accepted: 06/20/2019] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is an inflammation-induced and chemotherapy-resistant cancer. Dysregulated signaling in the transforming growth factor beta (TGF-β) pathway plays a central role in inflammation, fibrogenesis, and immunomodulation in the HCC microenvironment. This review dissects the genetic landscape of the TGF-β superfamily genes in HCC and discusses the essential effects of this pathway on the tumor immune microenvironment. We highlight the TGF-β signature as a potential biomarker for identifying individualized immunotherapeutic approaches in HCC. An improved understanding of the detailed mechanisms of liver cancer immunogenicity and the specific role of TGF-β in mediating immunotherapy resistance in HCC will provide important insights into HCC immune escape and promote the development of biomarker-derived combination immunotherapies for HCC.
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Affiliation(s)
- Jian Chen
- Department of Gastroenterology, Hepatology, & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Julian A Gingold
- Women's Health Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Xiaoping Su
- Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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29
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Johnston MP, Khakoo SI. Immunotherapy for hepatocellular carcinoma: Current and future. World J Gastroenterol 2019; 25:2977-2989. [PMID: 31293335 PMCID: PMC6603808 DOI: 10.3748/wjg.v25.i24.2977] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [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: 04/24/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However, there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy, either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.
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Affiliation(s)
- Michael P Johnston
- Department of Hepatology, Southampton General Hospital, University Hospital Southampton, Southampton SO16 6YD, United Kingdom
| | - Salim I Khakoo
- Department of Clinical and Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton SO16 6YD, United Kingdom
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30
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Docta RY, Ferronha T, Sanderson JP, Weissensteiner T, Pope GR, Bennett AD, Pumphrey NJ, Ferjentsik Z, Quinn LL, Wiedermann GE, Anderson VE, Saini M, Maroto M, Norry E, Gerry AB. Tuning T-Cell Receptor Affinity to Optimize Clinical Risk-Benefit When Targeting Alpha-Fetoprotein-Positive Liver Cancer. Hepatology 2019; 69:2061-2075. [PMID: 30561769 PMCID: PMC6593660 DOI: 10.1002/hep.30477] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 12/13/2018] [Indexed: 12/21/2022]
Abstract
Patients with hepatocellular carcinoma (HCC) have a poor prognosis and limited therapeutic options. Alpha-fetoprotein (AFP) is often expressed at high levels in HCC and is an established clinical biomarker of the disease. Expression of AFP in nonmalignant liver can occur, particularly in a subset of progenitor cells and during chronic inflammation, at levels typically lower than in HCC. This cancer-specific overexpression indicates that AFP may be a promising target for immunotherapy. We verified expression of AFP in normal and diseased tissue and generated an affinity-optimized T-cell receptor (TCR) with specificity to AFP/HLA-A*02+ tumors. Expression of AFP was investigated using database searches, by qPCR, and by immunohistochemistry (IHC) analysis of a panel of human tissue samples, including normal, diseased, and malignant liver. Using in vitro mutagenesis and screening, we generated a TCR that recognizes the HLA-A*02-restricted AFP158-166 peptide, FMNKFIYEI, with an optimum balance of potency and specificity. These properties were confirmed by an extension of the alanine scan (X-scan) and testing TCR-transduced T cells against normal and tumor cells covering a variety of tissues, cell types, and human leukocyte antigen (HLA) alleles. Conclusion: We have used a combination of physicochemical, in silico, and cell biology methods for optimizing a TCR for improved affinity and function, with properties that are expected to allow TCR-transduced T cells to differentiate between antigen levels on nonmalignant and cancer cells. T cells transduced with this TCR constitute the basis for a trial of HCC adoptive T-cell immunotherapy.
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31
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Greten TF, Lai CW, Li G, Staveley-O'Carroll KF. Targeted and Immune-Based Therapies for Hepatocellular Carcinoma. Gastroenterology 2019; 156:510-524. [PMID: 30287171 PMCID: PMC6340758 DOI: 10.1053/j.gastro.2018.09.051] [Citation(s) in RCA: 196] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 09/21/2018] [Accepted: 09/24/2018] [Indexed: 02/06/2023]
Abstract
Treatment options for patients with hepatocellular carcinoma are rapidly changing based on positive results from phase 3 trials of targeted and immune-based therapies. More agents designed to target specific pathways and immune checkpoints are in clinical development. Some agents have already been shown to improve outcomes of patients with hepatocellular carcinoma, as first- and second-line therapies, and are awaiting approval by the Food and Drug Administration or have been recently approved. We summarize the targeted and immune-based agents in trials of patients with advanced hepatocellular carcinoma and discuss the future of these strategies for liver cancer.
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Affiliation(s)
- Tim F Greten
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; National Cancer Institute CCR Liver Cancer Program, Bethesda, Maryland.
| | - Chunwei Walter Lai
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland
| | - Guangfu Li
- Department of Surgery, University of Missouri-Columbia, Columbia, Missouri; Department of Molecular Microbiology & Immunology, University of Missouri-Columbia, Columbia, Missouri
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32
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Zhu J, Li Y, Li L, Wang J, Wang H, Hong W, Hao K, Xue Y, Chen B, Wang Z. A novel absorption spectrometric method, based on graphene nanomaterials, for detection of hepatocellular carcinoma-specific T lymphocyte cells. Int J Nanomedicine 2018; 13:5523-5536. [PMID: 30271145 PMCID: PMC6154735 DOI: 10.2147/ijn.s168574] [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] [Indexed: 12/05/2022] Open
Abstract
Introduction Detection of antigen-specific cytotoxic T lymphocytes (CTLs) is the foundation for understanding hepatocellular carcinoma immune pathology and hepatocellular carcinoma immunotherapy. However, the classical method for labeling CTLs, major histocompatibility complex (MHC)–peptide tetramer, has drawbacks and needs further improvement. Materials and methods Here, as a new detection probe, a graphene-based MHC–peptide multimer was developed for sensitively and selectively identifying hepatocellular carcinoma-specific T-cells. To assess its detection efficiency, reduced graphene oxide (RGO) was functionalized with hemin and streptavidin to prepare a functionalized HRGO–streptavidin complex. Biotinylated MHC–peptide monomer was subsequently constructed onto HRGO to generate a detection probe for CTL labeling. The number of T-cells was detected through the reaction between HRGO and tetramethylbenzidine. Results Using HRGO/MHC–peptide multimers, the number of T-cells was efficiently detected in both the induction system in vitro and in peripheral blood of patients. Conclusion HRGO/MHC-peptide multimers methodology has application prospects in the detection of antigen peptide-specific T cells.
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Affiliation(s)
- Jianmeng Zhu
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, ,
| | - Yiping Li
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, ,
| | - Lei Li
- Department of Pathophysiology, School of Basic Medical Science, Southern Medical University, Guangzhou, Zhejiang, China
| | - Jian Wang
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, ,
| | - Hongqin Wang
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, ,
| | - Wenzhong Hong
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, ,
| | - Ke Hao
- Department of Blood Transfusion, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China, ,
| | - Yadan Xue
- Department of Blood Transfusion, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China, ,
| | - Bingyu Chen
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, , .,Department of Blood Transfusion, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China, ,
| | - Zhen Wang
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, , .,Department of Blood Transfusion, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China, ,
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33
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Zhu W, Peng Y, Wang L, Hong Y, Jiang X, Li Q, Liu H, Huang L, Wu J, Celis E, Merchen T, Kruse E, He Y. Identification of α-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy. Hepatology 2018; 68:574-589. [PMID: 29443377 PMCID: PMC7368991 DOI: 10.1002/hep.29844] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 01/04/2018] [Accepted: 02/12/2018] [Indexed: 12/17/2022]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there is no effective therapy. Genetic modification with T-cell receptors (TCRs) specific for HCC-associated antigens, such as α-fetoprotein (AFP), can potentially redirect human T cells to specifically recognize and kill HCC tumor cells to achieve antitumor effects. In this study, using lentivector and peptide immunization, we identified a population of cluster of differentiation 8 (CD8) T cells in human leukocyte antigen (HLA)-A2 transgenic AAD mice that recognized AFP158 epitope on human HCC cells. Adoptive transfer of the AFP158 -specific mouse CD8 T cells eradicated HepG2 tumor xenografts as large as 2 cm in diameter in immunocompromised nonobese diabetic severe combined immunodeficient gamma knockout (NSG) mice. We then established T-cell hybridoma clones from the AFP158 -specific mouse CD8 T cells and identified three sets of paired TCR genes out of five hybridomas. Expression of the murine TCR genes redirected primary human T cells to bind HLA-A2/AFP158 tetramer. TCR gene-engineered human T (TCR-T) cells also specifically recognized HLA-A2+ AFP+ HepG2 HCC tumor cells and produced effector cytokines. Importantly, the TCR-T cells could specifically kill HLA-A2+ AFP+ HepG2 tumor cells without significant toxicity to normal primary hepatocytes in vitro. Adoptive transfer of the AFP-specific TCR-T cells could eradicate HepG2 tumors in NSG mice. CONCLUSION We have identified AFP-specific murine TCR genes that can redirect human T cells to specifically recognize and kill HCC tumor cells, and those AFP158 -specific TCRs have a great potential to engineer a patient's autologous T cells to treat HCC tumors. (Hepatology 2018).
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Affiliation(s)
- Wei Zhu
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
| | - Yibing Peng
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
| | - Lan Wang
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
| | - Yuan Hong
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
| | - Xiaotao Jiang
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
| | - Qi Li
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
| | - Heping Liu
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
| | - Lei Huang
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
| | - Juan Wu
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
| | - Esteban Celis
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
| | - Todd Merchen
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA.,Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA
| | - Edward Kruse
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA.,Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA
| | - Yukai He
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA.,Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA
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Sun Y, Yao Z, Zhao Z, Xiao H, Xia M, Zhu X, Jiang X, Sun C. Natural killer cells inhibit metastasis of ovarian carcinoma cells and show therapeutic effects in a murine model of ovarian cancer. Exp Ther Med 2018; 16:1071-1078. [PMID: 30116358 PMCID: PMC6090205 DOI: 10.3892/etm.2018.6342] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 11/17/2017] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer has the highest mortality rate and is the most common of all gynecologic malignancies. Novel treatments for ovarian cancer are urgently required to improve outcomes and the overall survival of patients. The present study investigated whether immunotherapy with natural killer (NK) cells affected the survival of mice with ovarian cancer. Results analysis identified adjunctive NK cells as a potential therapeutic method in ovarian cancer. Patient-derived ovarian cells were isolated, cultured and subsequently injected subcutaneously into immune deficient BALB/c-nude mice. Human NK cells were isolated from peripheral blood mononuclear cells and cultured for expansion in vitro. The present results demonstrated that ovarian cells in BALB/c-nude mice did not induce spontaneous ovarian cancer cell metastasis in the NK-treated group. In addition, NK cells activated immune cells in the immune system, which resulted in inhibition of ovarian tumor growth in vitro and in a murine xenograft model of ovarian cancer. The data also indicated that cytotoxic activity of NK cells prevented migration and invasion of ovarian cancer cells, which contributed to prevention of systemic metastasis and suggested that NK cells could be effective cells for therapy against ovarian cancer. Furthermore, NK cells induced apoptosis and increased the number of cluster of differentiation (CD)4+, CD8+ as well as cytotoxic T lymphocyte responses by intravenous injection in a murine xenograft model of ovarian cancer. These results suggested that NK cells inhibited the systemic metastasis for ovarian cancer cells. In conclusion, the present study suggested that NK cell immunotherapy inhibited systemic metastasis of ovarian cancer cells and improved the survival rate of mice. Sufficient supplementation of NK cells may serve as a promising immunotherapeutic strategy for ovarian cancer.
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Affiliation(s)
- Yanming Sun
- Department of Interventional Radiology, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Zhitao Yao
- Department of Nuclear Medicine, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Zhihua Zhao
- Department of Nuclear Medicine, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Haifeng Xiao
- Department of Medical Oncology, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Mengting Xia
- Department of Gynecology, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiaojun Zhu
- Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Xuelu Jiang
- Department of Gynecology, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Chuntao Sun
- Department of Interventional Radiology, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
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Greten TF, Sangro B. Targets for immunotherapy of liver cancer. J Hepatol 2017; 68:S0168-8278(17)32287-0. [PMID: 28923358 PMCID: PMC5857416 DOI: 10.1016/j.jhep.2017.09.007] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 08/21/2017] [Accepted: 09/08/2017] [Indexed: 02/08/2023]
Abstract
Drug development in hepatocellular carcinoma (HCC) has been characterised by many failures in the past. Despite good rationales and promising phase II data, many phase III trials failed. Immunotherapy represents an alternative treatment approach that has been successful in many different cancer types. As an inflammation induced cancer, HCC represents a very interesting target for immune based approaches. Indeed, early results from clinical trials testing immune checkpoint inhibitors are not only promising, but have already led to evaluation in a phase III setting. Herein, we summarise our current knowledge on the rationale, mechanism of action and clinical data for immune checkpoint blockade in HCC. In addition, we provide an overview of other novel immune based approaches currently under development for the treatment of HCC, such as adoptive cell based and antibody-based approaches.
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Affiliation(s)
- Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Bruno Sangro
- Liver Unit, Clínica Universidad de Navarra-IDISNA, Pamplona, Spain, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, Spain.
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36
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Cellular and molecular targets for the immunotherapy of hepatocellular carcinoma. Mol Cell Biochem 2017; 437:13-36. [PMID: 28593566 DOI: 10.1007/s11010-017-3092-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023]
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Nakamoto Y. Promising new strategies for hepatocellular carcinoma. Hepatol Res 2017; 47:251-265. [PMID: 27558453 DOI: 10.1111/hepr.12795] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 08/16/2016] [Accepted: 08/19/2016] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. It usually arises based on a background of chronic liver diseases, defined as the hypercarcinogenic state. The current treatment options for HCC ranging from locoregional treatments to chemotherapies, including sorafenib, effectively regulate the limited sizes and numbers of the nodules. However, these treatments remain unsatisfactory because they have insufficient antitumor effects on the large and numerous nodules associated with HCC and because of a high recurrence rate in the surrounding inflamed liver. To develop novel and promising therapies with higher antitumor effects, recent progress in identifying molecular targets and developing immunological procedures for HCC are reviewed. The molecular targets discussed include the intracellular signaling pathways of protein kinase B/mammalian target of rapamycin and RAS/RAF/mitogen-activated protein kinase, Wnt/β-catenin and glutamine synthetase, insulin-like growth factor, signal transducer and activator of transcription 3, nuclear factor-κB and telomerase reverse transcriptase, and c-MET. Immunological studies have focused mainly on target identification, T cells, natural killer cells, dendritic cells, natural killer T cells, and vaccine development.
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Affiliation(s)
- Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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