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Huang M, Ji Q, Huang H, Wang X, Wang L. Gut microbiota in hepatocellular carcinoma immunotherapy: immune microenvironment remodeling and gut microbiota modification. Gut Microbes 2025; 17:2486519. [PMID: 40166981 PMCID: PMC11970798 DOI: 10.1080/19490976.2025.2486519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 03/05/2025] [Accepted: 03/25/2025] [Indexed: 04/02/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with limited treatment options at advanced stages. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a pivotal role in regulating immune responses through the gut-liver axis. Emerging evidence underscores its impact on HCC progression and the efficacy of immunotherapy. This review explores the intricate interactions between gut microbiota and the immune system in HCC, with a focus on key immune cells and pathways involved in tumor immunity. Additionally, it highlights strategies for modulating the gut microbiota - such as fecal microbiota transplantation, dietary interventions, and probiotics - as potential approaches to enhancing immunotherapy outcomes. A deeper understanding of these mechanisms could pave the way for novel therapeutic strategies aimed at improving patient prognosis.
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Affiliation(s)
- Mingyao Huang
- School of Basic Medicine, Putian University, Putian, Fujian, China
- Department of Breast Surgery, Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, China
| | - Quansong Ji
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Huiyan Huang
- Ward 3, De’an Hospital, Xianyou County, Putian, Fujian, China
| | - Xiaoqian Wang
- Department of Rehabilitation Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Lin Wang
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Aoki T, Kudo M, Nishida N, Ueshima K, Tsuchiya K, Tada T, Morita M, Chishina H, Takita M, Hagiwara S, Ida H, Minami Y, Kuroda H, Nakamura N, Hiraoka A, Tomonari T, Tani J, Naganuma A, Kakizaki S, Ogawa C, Hatanaka T, Ishikawa T, Kawata K, Takebe A, Matsumoto I, Hidaka M, Kurosaki M, Kumada T, Izumi N. Proposal of discontinuation criteria of atezolizumab plus bevacizumab after curative conversion therapy for unresectable early-to-intermediate-stage hepatocellular carcinoma: a multicenter proof-of-concept study. J Gastroenterol 2025; 60:738-753. [PMID: 40055288 PMCID: PMC12095402 DOI: 10.1007/s00535-025-02233-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 02/18/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Achieving complete response (CR) is a desirable goal in early-to-intermediate-stage hepatocellular carcinoma (HCC). While systemic and locoregional therapies show promise, optimal drug discontinuation criteria remain unclear. This study aims to investigate drug-off criteria for atezolizumab plus bevacizumab as a proof-of-concept study. METHODS This retrospective multicenter study included child-pugh class A patients with unresectable HCC without extrahepatic spread or macrovascular invasion who received atezolizumab plus bevacizumab as first-line therapy. Modified clinical CR (mCCR) was defined as CR per mRECIST with sustained normal alpha-fetoprotein (AFP) levels (< 10.0 ng/dl). Recurrence-free survival (RFS) and overall survival (OS) were analyzed based on the "drug-off" criteria defined by following: (1) mRECIST CR with locoregional therapies, (2) sustained normalization of AFP/AFP-L3/ des-gamma-carboxy prothrombin (DCP) for 12-24 weeks, and (3) complete tumor vascularity disappearance by contrast-enhanced ultrasonography (CEUS) or pathological curative resection. RESULTS The median follow-up was 16.5 months (95% CI 15.2-17.8). Among 51 patients achieving mCCR, 11 underwent surgery, with pathological CR in three cases. In contrast, viable lesions were observed in 7 of 40 cases assessed using CEUS. All patients meeting the drug-off criteria (n = 9) showed no recurrence and none of them experienced mortality, while 45.2% (19/42) of those not meeting the criteria experienced recurrence (median RFS: 12.8 months, p = 0.007). The median OS was not reached in dug-off criteria met patients (n = 9), 37.7 months (95% CI: NA) in non-criteria met patients (n = 42), and 27.1 months (95% CI 16.7-37.6) in non-mCCR patients (n = 184) (p < 0.001). CONCLUSION In patients with unresectable and TACE-unsuitable early-to-intermediate-stage HCC who met the drug-off criteria, significantly improved RFS and OS were observed compared those who did not meet the criteria. However, further validation studies are required to confirm the utility of the criteria.
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Affiliation(s)
- Tomoko Aoki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Masahiro Morita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Hirokazu Chishina
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Masahiro Takita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Hiroshi Ida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Hidekatsu Kuroda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Noriaki Nakamura
- Department of General Surgery, Shuuwa General Hospital, Saitama, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Tetsu Tomonari
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, NHO Takasaki General Medical Center, Takasaki, Japan
| | - Satoru Kakizaki
- Department of Clinical Research, NHO Takasaki General Medical Center, Takasaki, Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Japan
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Atsushi Takebe
- Department of Surgery, Kindai University Faculty of Medicine, Osaka, Japan
| | - Ippei Matsumoto
- Department of Surgery, Kindai University Faculty of Medicine, Osaka, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Takashi Kumada
- Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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Zhao X, Dufault T, Sapisochin G, Saborowski A, Vogel A. The clinical implications of trial endpoints in immunotherapy for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2025:1-13. [PMID: 40320908 DOI: 10.1080/17474124.2025.2500369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 04/28/2025] [Indexed: 05/14/2025]
Abstract
INTRODUCTION Investigative work in the treatment of hepatocellular carcinoma is rapidly growing with the advent of immunotherapy. Nonetheless, trial endpoints and, more importantly, clinically meaningful endpoints need to be accurately chosen depending on the phase of trial and the patient population studied. We provide a scoping review focusing on trial endpoints on the use of immunotherapy in hepatocellular carcinoma. AREAS COVERED We searched PubMed and Google Scholar for prospective phase II and III trials using immunotherapy, whether in the neoadjuvant, adjuvant, bridging, downstaging, or palliative settings, while discussing the clinical implications of trial endpoints. EXPERT OPINION The field of immune oncology is rapidly progressing and has become the standard of care in advanced hepatocellular carcinoma. However, the role of immunotherapy in the treatment of early and intermediate stage hepatocellular carcinoma is yet to be defined. Prospective trials for all stages of disease must strive for endpoints that are not only statistically significant but also clinically consequential. Whereas overall response rate may be a reasonable trial endpoint in phase II trials, phase III trials should rather aim for the improvement of overall survival or quality of life to have clinically meaningful impacts.
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Affiliation(s)
- Xun Zhao
- Division of Gastroenterology and Hepatology, McGill University Health Center, Montreal, Canada
| | - Talia Dufault
- Division of Internal Medicine, Université de Laval, Québec, Canada
| | - Gonzalo Sapisochin
- Abdominal Transplant & HPB Surgical Oncology, University Health Network, University of Toronto, Toronto, Canada
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Division of Hepatology, Toronto General Hospital, Toronto, Canada
- Division of Gastrointestinal Oncology, Princess Margeret Cancer Center, Toronto, Canada
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Myojin Y, Babaei S, Trehan R, Hoffman C, Kedei N, Ruf B, Benmebarek MR, Bauer KC, Huang P, Ma C, Monge C, Xie C, Hrones D, Duffy AG, Armstrong P, Kocheise L, Desmond F, Buchalter J, Galligan M, Cantwell C, Ryan R, McCann J, Bourke M, Mac Nicholas R, McDermott R, Awosika J, Cam M, Krebs R, Budhu A, Revsine M, Figg WD, Kleiner DE, Redd B, Wood BJ, Wang XW, Korangy F, Claassen M, Greten TF. Multiomics analysis of immune correlatives in hepatocellular carcinoma patients treated with tremelimumab plus durvalumab. Gut 2025; 74:983-995. [PMID: 39965889 DOI: 10.1136/gutjnl-2024-334026] [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: 10/04/2024] [Accepted: 02/06/2025] [Indexed: 02/20/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. The combination of tremelimumab and durvalumab is now a standard treatment option for advanced HCC. OBJECTIVE To study immune responses in HCC patients treated with tremelimumab and durvalumab. DESIGN We treated 28 HCC patients with durvalumab, tremelimumab and locoregional therapies. We performed a high-dimensional multiomics analysis including whole exome sequencing, single-cell RNA seq, CO-Detection by indEXing, flow cytometry and multiplex cytokine/chemokine analysis of patients' blood and tumour samples and integrated this data to elucidate immune correlatives and response mechanisms. Mice with syngeneic HCC were treated with anti-PD-L1 plus anti-CTLA4 for hepatic lymphocytes, tumour-infiltrating lymphocytes and peripheral blood mononuclear cell analysis. RESULTS The median overall survival was 19.2 months. Tumour tissue analysis revealed enhanced interferon responses, with stronger effects in responders. Gene set variation analysis indicated enhanced antigen presentation in responders. Spatial analysis revealed that non-responder tumours had higher numbers of Tregs located in neighbourhoods enriched with immune cells and expressed higher levels of ICOS and PD-1. Conversely, non-responder PD1+CD8+T in these Treg-enriched neighbourhoods expressed lower ICOS. Cell-communication analysis demonstrated that Treg-CD8+T interaction was enhanced in non-responder tissue. Peripheral blood analysis showed increased classical monocytes in responders and Tregs in non-responders. Treg-CD8+T interaction was confirmed in preclinical models. Finally, single-patient computational analysis from the all-across analysis was performed on 860 features, which led to the identification of multiomics feature sets including Treg features. CONCLUSION Our study provides a blueprint for in-depth analysis of immune correlates in immunotherapy studies and demonstrates the importance of Treg distribution in HCC. TRIAL REGISTRATION NUMBERS NCT02821754 and the EudraCT identifier: 2019-002767-98.
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MESH Headings
- Aged
- Animals
- Female
- Humans
- Male
- Mice
- Middle Aged
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/genetics
- Liver Neoplasms/drug therapy
- Liver Neoplasms/immunology
- Liver Neoplasms/genetics
- Lymphocytes, Tumor-Infiltrating/immunology
- Multiomics
- T-Lymphocytes, Regulatory/immunology
- Antibodies, Monoclonal
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Affiliation(s)
- Yuta Myojin
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Sepideh Babaei
- Interfaculty Institute for Biomedical Informatics (IBMI), University of Tübingen, Tubingen, Germany
- Department of Internal Medicine I (Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectious Diseases and Geriatrics), University Hospital Tübingen, Tübingen, Germany
- M3 Research Center, University Hospital Tübingen, Tübingen, Germany
| | - Rajiv Trehan
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Christoph Hoffman
- Interfaculty Institute for Biomedical Informatics (IBMI), University of Tübingen, Tubingen, Germany
- Department of Internal Medicine I (Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectious Diseases and Geriatrics), University Hospital Tübingen, Tübingen, Germany
- M3 Research Center, University Hospital Tübingen, Tübingen, Germany
| | - Noemi Kedei
- Collaborative Protein Technology Resources, Office of Science and Technology Resources, National Institutes of Health, Bethesda, Maryland, USA
| | - Benjamin Ruf
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Department of Internal Medicine I (Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectious Diseases and Geriatrics), University Hospital Tübingen, Tübingen, Germany
- M3 Research Center, University Hospital Tübingen, Tübingen, Germany
| | - Mohamed-Reda Benmebarek
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Kylynda C Bauer
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Patrick Huang
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Chi Ma
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Cecilia Monge
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Changqing Xie
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Donna Hrones
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Austin G Duffy
- Mater Misericordiae University Hospital, Dublin, Ireland
| | - Paul Armstrong
- Mater Misericordiae University Hospital, Dublin, Ireland
| | - Lorenz Kocheise
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Fiona Desmond
- Mater Misericordiae University Hospital, Dublin, Ireland
| | | | - Marie Galligan
- Clinical Research Centre, University College Dublin, Dublin, Ireland
| | - Colin Cantwell
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Ronan Ryan
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Jeff McCann
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Michele Bourke
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Ross Mac Nicholas
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Ray McDermott
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Joy Awosika
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Maggie Cam
- Center for Collaborative Bioinformatics, National Institutes of Health, Bethesda, Maryland, USA
| | - Rosanna Krebs
- Interfaculty Institute for Biomedical Informatics (IBMI), University of Tübingen, Tubingen, Germany
- Department of Internal Medicine I (Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectious Diseases and Geriatrics), University Hospital Tübingen, Tübingen, Germany
- M3 Research Center, University Hospital Tübingen, Tübingen, Germany
| | - Anuradha Budhu
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Mahler Revsine
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - William D Figg
- Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - David E Kleiner
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Bernadette Redd
- Radiology and Imaging Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Bradford J Wood
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Radiology and Imaging Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Center for Interventional Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Firouzeh Korangy
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Manfred Claassen
- Interfaculty Institute for Biomedical Informatics (IBMI), University of Tübingen, Tubingen, Germany
- Department of Internal Medicine I (Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectious Diseases and Geriatrics), University Hospital Tübingen, Tübingen, Germany
- M3 Research Center, University Hospital Tübingen, Tübingen, Germany
| | - Tim F Greten
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Tong J, Tan Y, Ouyang W, Chang H. Targeting immune checkpoints in hepatocellular carcinoma therapy: toward combination strategies with curative potential. Exp Hematol Oncol 2025; 14:65. [PMID: 40317077 PMCID: PMC12046748 DOI: 10.1186/s40164-025-00636-5] [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: 01/20/2025] [Accepted: 03/07/2025] [Indexed: 05/04/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by poor immune cell infiltration and a strongly immunosuppressive microenvironment. Traditional treatments have often yielded unsatisfactory outcomes due to the insidious onset of the disease. Encouragingly, the introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the approach to HCC treatment. Moreover, combining ICIs with other therapies or novel materials is considered the most promising opportunity in HCC, with some of these combinations already being evaluated in large-scale clinical trials. Unfortunately, most clinical trials fail to meet their endpoints, and the few successful ones also face challenges. This indicates that the potential of ICIs in HCC treatment remains underutilized, prompting a reevaluation of this promising therapy. Therefore, this article provides a review of the role of immune checkpoints in cancer treatment, the research progress of ICIs and their combination application in the treatment of HCC, aiming to open up avenues for the development of safer and more efficient immune checkpoint-related strategies for HCC treatment.
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Affiliation(s)
- Jing Tong
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Yongci Tan
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Wenwen Ouyang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Haocai Chang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China.
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China.
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Miri H, Rahimzadeh P, Hashemi M, Nabavi N, Aref AR, Daneshi S, Razzaghi A, Abedi M, Tahmasebi S, Farahani N, Taheriazam A. Harnessing immunotherapy for hepatocellular carcinoma: Principles and emerging promises. Pathol Res Pract 2025; 269:155928. [PMID: 40184729 DOI: 10.1016/j.prp.2025.155928] [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: 06/30/2024] [Revised: 03/12/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
HCC is considered as one of the leadin causes of death worldwide, with the ability of resistance towards therapeutics. Immunotherapy, particularly ICIs, have provided siginficant insights towards harnessing the immune system. The present review introduces the concepts and possibilities of immunotherapy for HCC treatment, emphasizing its underlying mechanisms and capacity to enhance patient results, focusing on both pre-clinical and clinical insights. The functions of TME and immune evasion mechanisms typical of HCC would be evaluated along with how contemporary immunotherapeutic approaches are designed to address these challenges. Furthermore, the clinical application of immunotherapy in HCC is discussed, emphasizing recent trial findings demonstrating the effectiveness and safety of drugs. In addition, the problems caused by immune evasion and resistance would be discussed to increase potential of immunotherapy along with combination therapy.
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Affiliation(s)
- Hossein Miri
- Faculty of Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University Of Medical Sciences, Jiroft, Iran
| | - Alireza Razzaghi
- Social Determinants of Health Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Abedi
- Department of Pathology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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7
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Mc Neil V, Lee SW. Advancing Cancer Treatment: A Review of Immune Checkpoint Inhibitors and Combination Strategies. Cancers (Basel) 2025; 17:1408. [PMID: 40361336 PMCID: PMC12071127 DOI: 10.3390/cancers17091408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/18/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025] Open
Abstract
A groundbreaking milestone in oncology has been the recognition and targeted elimination of malignant cells through cancer immunotherapy, which harnesses the body's immune system to attack cancer [...].
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Affiliation(s)
- Valencia Mc Neil
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea;
| | - Seung Won Lee
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea;
- Department of Artificial Intelligence, Sungkyunkwan University, Suwon 16419, Republic of Korea
- Department of Metabiohealth, Sungkyunkwan University, Suwon 16419, Republic of Korea
- Personalized Cancer Immunotherapy Research Center, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea
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8
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Xie D, Liu Y, Xu F, Dang Z, Li M, Zhang Q, Dang Z. Immune microenvironment and immunotherapy in hepatocellular carcinoma: mechanisms and advances. Front Immunol 2025; 16:1581098. [PMID: 40242773 PMCID: PMC12000014 DOI: 10.3389/fimmu.2025.1581098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally. The tumor microenvironment (TME) plays a pivotal role in HCC progression, characterized by dynamic interactions between stromal components, immune cells, and tumor cells. Key immune players, including tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs), MDSCs, dendritic cells (DCs), and natural killer (NK) cells, contribute to immune evasion and tumor progression. Recent advances in immunotherapy, such as immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell therapy (ACT), and combination therapies, have shown promise in enhancing anti-tumor responses. Dual ICI combinations, ICIs with molecular targeted drugs, and integration with local treatments or radiotherapy have demonstrated improved outcomes in HCC patients. This review highlights the evolving understanding of the immune microenvironment and the therapeutic potential of immunotherapeutic strategies in HCC management.
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Affiliation(s)
- Dong Xie
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Yang Liu
- College of Traditional Chinese Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Fangbiao Xu
- Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhibo Dang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Mengge Li
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Qinsheng Zhang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Zhongqin Dang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
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9
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Zhong BY, Fan W, Guan JJ, Peng Z, Jia Z, Jin H, Jin ZC, Chen JJ, Zhu HD, Teng GJ. Combination locoregional and systemic therapies in hepatocellular carcinoma. Lancet Gastroenterol Hepatol 2025; 10:369-386. [PMID: 39993404 DOI: 10.1016/s2468-1253(24)00247-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 07/20/2024] [Accepted: 07/25/2024] [Indexed: 02/26/2025]
Abstract
Locoregional therapies play a fundamental role in the treatment of patients with early and intermediate and locally advanced hepatocellular carcinomas. With encouraging recent advances in immunotherapy-based systemic therapies, locoregional therapies are being both promoted and challenged by new systemic therapy options. Combined locoregional and systemic therapies might enhance treatment outcomes compared with either option alone. This Series paper summarises the existing data on locoregional and systemic therapies for hepatocellular carcinoma, and discusses evidence from studies investigating their combination with a focus on their synergistic efficacy and safety.
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Affiliation(s)
- Bin-Yan Zhong
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China; Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wenzhe Fan
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Justin J Guan
- Division of Interventional Radiology, Department of Radiology, Cleveland Clinic, Cleveland, OH, USA
| | - Zhenwei Peng
- Department of Radiation Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhongzhi Jia
- Department of Interventional and Vascular Surgery, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
| | - Haojie Jin
- Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi-Cheng Jin
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Jian-Jian Chen
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Hai-Dong Zhu
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Gao-Jun Teng
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.
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10
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Kudo M. Systemic Therapy Combined with Locoregional Therapy in Intermediate-stage Hepatocellular Carcinoma. INTERVENTIONAL RADIOLOGY (HIGASHIMATSUYAMA-SHI (JAPAN) 2025; 10:e20230035. [PMID: 40384918 PMCID: PMC12078074 DOI: 10.22575/interventionalradiology.2023-0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 02/24/2024] [Indexed: 05/20/2025]
Abstract
Recent advances in systemic therapy for hepatocellular carcinoma are remarkable. The treatment goal for advanced hepatocellular carcinoma is to prolong survival, while for intermediate-stage hepatocellular carcinoma, it is to achieve a cancer-free and drug-free status. Patients unsuitable for transarterial chemoembolization may benefit from prior systemic therapy with lenvatinib or atezolizumab plus bevacizumab. The TACTICS-L trial, a prospective phase II trial, demonstrated favorable progression-free and overall survival by lenvatinib-transarterial chemoembolization sequential therapy. The REPLACEMENT trial, a multicenter, prospective, single-arm phase II trial, confirmed combination immunotherapy efficacy with atezolizumab plus bevacizumabin a population exceeding up-to-seven criteria. In a proof-of-concept study, atezolizumab plus bevacizumab plus curative therapy showed a 35% complete response rate and 23% drug-free status in intermediate-stage hepatocellular carcinoma patients with a tumor burden exceeding up-to-seven criteria.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
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11
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Cereda V, D’Andrea MR. Pancreatic cancer: failures and hopes-a review of new promising treatment approaches. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2025; 6:1002299. [PMID: 40124650 PMCID: PMC11926728 DOI: 10.37349/etat.2025.1002299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/22/2025] [Indexed: 03/25/2025] Open
Abstract
Pancreatic cancer is a challenging disease with limited treatment options and a high mortality rate. Just few therapy advances have been made in recent years. Tumor microenvironment, immunosuppressive features and mutational status represent important obstacles in the improvement of survival outcomes. Up to now, first-line therapy did achieve a median overall survival of less than 12 months and this discouraging data lead clinicians all over the world to focus their efforts on various fields of investigation: 1) sequential cycling of different systemic therapy in order to overcome mechanisms of resistance; 2) discovery of new predictive bio-markers, in order to target specific patient population; 3) combination treatment, in order to modulate the tumor microenvironment of pancreatic cancer; 4) new modalities of the delivery of drugs in order to pass the physical barrier of desmoplasia and tumor stroma. This review shows future directions of treatment strategies in advanced pancreatic cancer through a deep analysis of these recent macro areas of research.
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Affiliation(s)
- Vittore Cereda
- Asl Roma 4, Hospital S. Paolo Civitavecchia, 00053 Civitavecchia, Italy
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12
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Abdo EL, Ajib I, El Mounzer J, Husseini M, Kalaoun G, Matta TM, Mosleh R, Nasr F, Richani N, Khalil A, Shayya A, Ghanem H, Faour WH. Molecular biology of the novel anticancer medications: a focus on kinases inhibitors, biologics and CAR T-cell therapy. Inflamm Res 2025; 74:41. [PMID: 39960501 DOI: 10.1007/s00011-025-02008-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 01/28/2025] [Accepted: 02/10/2025] [Indexed: 05/09/2025] Open
Abstract
INTRODUCTION Cancer treatment underwent significant changes in the last few years with the introduction of novel treatments targeting the immune system. OBJECTIVES The objective of this review is to discuss novel anticancer drugs including kinase inhibitors, biologics and cellular therapy with CAR-T cells. METHODS Most recent research articles were extracted from PubMed using keywords such as "kinases inhibitors", "CAR-T cell therapy". RESULTS AND DISCUSSION The number of kinase inhibitors is significantly increasing due to their demonstrated effectiveness in combination with biologics. CAR-T represented a major breakthrough in the field. Also, it focused on their mechanisms of action and the rational of their use either alone or in combination in relation to their modes of action.
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Affiliation(s)
- Elia-Luna Abdo
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Imad Ajib
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Jason El Mounzer
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Mohammad Husseini
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Gharam Kalaoun
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Tatiana-Maria Matta
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Reine Mosleh
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Fidel Nasr
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Nour Richani
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Alia Khalil
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Anwar Shayya
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
- Department of Hematology-Oncology, Lebanese American University Medical Center- Rizk Hospital, Beirut, Lebanon
| | - Hady Ghanem
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
- Department of Hematology-Oncology, Lebanese American University Medical Center- Rizk Hospital, Beirut, Lebanon
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon.
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13
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Ren Z, Wang Y, Jiang D, Liu Y, Yang X, Wang T, Zhu J, Wang W, Chen Q, Zhang Y. PD1 + Treg cell remodeling promotes immune homeostasis within peripheral blood and tumor microenvironment after microparticles-transarterial chemoembolization in hepatocellular carcinoma. Cancer Immunol Immunother 2025; 74:109. [PMID: 39937280 PMCID: PMC11822157 DOI: 10.1007/s00262-025-03962-z] [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: 12/23/2024] [Accepted: 01/28/2025] [Indexed: 02/13/2025]
Abstract
The effects of transarterial chemoembolization (TACE) on the systemic immune in hepatocellular carcinoma (HCC) are not well understood. We aimed to reveal the temporal and spatial changes in the immune profile of peripheral blood and tumor tissues in HCC patients following TACE. Eighty-four HCC patients were included, 20 of whom received TACE with a median follow-up of 28 months. Immune cell proportion within peripheral blood was profiled with flow cytometry, and therapeutic efficacy was evaluated by imaging examinations. Additionally, cell distribution within tumor microenvironment (TME) were compared between the necrotic tumor infiltration zone (N-IZ) and the residual tumor infiltration zone (R-IZ) by multiplex immunofluorescence. Among 20 patients, 25% (5/20) achieved complete response, and 75% (15/20) showed partial response. Fourteen patients received combinational targeted therapy and immunotherapy and the median progression-free survival was 15.5 months. Compared to healthy individuals, HCC exhibited significantly higher proportions of regulatory T cells (Tregs) and programmed death-1 receptor (PD1)+ Tregs within peripheral blood. PD1+ Treg cells, PD1+ CD4+ T cells and PD1+ CD8+ T cells decreased significantly within peripheral blood after TACE. In TME, N-IZ showed significantly lower CD4+ T, CD8+ T and FOXP3+ Tregs, higher PD1+ CD8+/CD8+ and PD1+ CD8+/ PD1+ FOXP3+. Moreover, the spatial distance between CD8+ T cells and the nearest FOXP3+ Tregs in N-IZ was significantly greater than in R-IZ. Our findings demonstrated that TACE could both remodel the immune components in peripheral blood and TME, strengthening the rationale for developing immunotherapy alongside TACE.
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Affiliation(s)
- Zhizhong Ren
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Yaqin Wang
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | | | - Ying Liu
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Xiaowei Yang
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Tianxiao Wang
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Junqi Zhu
- Thorgene Co., Ltd., Beijing, 100176, China
| | - Wenya Wang
- Medical Research Center, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing, 102218, China.
| | - Qian Chen
- Thorgene Co., Ltd., Beijing, 100176, China.
| | - Yuewei Zhang
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China.
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14
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Liu Q, Zhang R, Shen W. Advancements in locoregional therapy for advanced hepatocellular carcinoma: Emerging perspectives on combined treatment strategies. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109502. [PMID: 39615292 DOI: 10.1016/j.ejso.2024.109502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/17/2024] [Accepted: 11/23/2024] [Indexed: 01/03/2025]
Abstract
Hepatocellular carcinoma (HCC) persists as a leading cause of cancer-related mortality, often diagnosed at advanced stages with limited treatment options. Locoregional therapies (LRTs) are crucial in HCC management, playing significant roles in neoadjuvant and palliative treatments, among others. However, the unique disease background of HCC necessitates multidisciplinary and integrated treatment strategies. The therapeutic landscape for advanced HCC has been significantly broadened by the advent of combined therapies, presenting multiple approaches aimed at improving long-term survival, which remains a critical challenge. This review offers a comprehensive overview of major LRTs for HCC, highlighting recent technological advancements and exploring the challenges and limitations in their application, and presents the latest developments in combination therapies, including combinations between different LRTs and their integration with systemic treatments. Additionally, we outline future directions for the development of integrated treatment modalities for advanced HCC.
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Affiliation(s)
- Qi Liu
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China; The Second Clinical Medical College of Harbin Medical University, Harbin, 150081, People's Republic of China
| | - Renjie Zhang
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China; The Second Clinical Medical College of Harbin Medical University, Harbin, 150081, People's Republic of China
| | - Weixi Shen
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China.
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15
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Saccenti L, Varble N, Borde T, Mikhail AS, Kassin M, Levy E, Xu S, Hazen LA, Ukeh I, Vasco C, Duffy AG, Xie C, Monge C, Mabry D, Greten TF, Wood BJ. Quantifying morphologic variations as an alternate to standard response criteria for unresectable primary liver tumors after checkpoint inhibition therapy. LA RADIOLOGIA MEDICA 2025; 130:226-234. [PMID: 39656418 PMCID: PMC11870906 DOI: 10.1007/s11547-024-01937-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 11/26/2024] [Indexed: 01/04/2025]
Abstract
PURPOSE The aim of this study was to assess the feasibility of quantifying morphologic changes in tumors during immunotherapy, as a reflection of response or survival. METHODS AND MATERIALS A retrospective single-center analysis was performed in patients with unresectable liver cancer previously enrolled in clinical trials combining immunotherapy (tremelimumab ± durvalumab) and locoregional treatment (either ablation or transarterial chemoembolization). Conventional response (RECIST 1.1) was assessed at 6-month follow-up. For morphologic assessment, the largest target lesion was manually segmented on axial slices in two dimensions using contrast-enhanced CT. Solidity and circularity of tumors were calculated at baseline, 3-month follow-up, and at 6-months follow-up. Survival analysis was performed. RESULTS From the 68 patients enrolled in clinical trials, 28 did not have target lesions separate from lesions treated by locoregional therapies, and 3 had no follow-up imaging. Thirty-seven patients (9 with biliary cancer and 28 with hepatocellular carcinoma) were included. Shape features and shape variation were not correlated with RECIST 1.1 status at 6-month follow-up. However, patients with low solidity tumors at 6-month follow-up showed poorer prognosis compared with patients with high solidity tumors at 6-month follow-up (p = 0.01). Solidity variation analysis confirmed that a decrease of tumor solidity at 6-month follow-up was associated with poorer prognosis (p = 0.01). No association was found between shape features at baseline or shape features at 3-month follow-up with overall survival. CONCLUSION Evolution and variation of tumor morphology during treatment may reflect or correlate with outcomes and contribute toward adapted response criteria.
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Affiliation(s)
- Laetitia Saccenti
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA.
- Henri Mondor's Institute of Biomedical Research - Inserm, U955 Team No. 18, Créteil, France.
| | - Nicole Varble
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
- Philips Research of North America, Cambridge, MA, USA
| | - Tabea Borde
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Andrew S Mikhail
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Michael Kassin
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Elliot Levy
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Sheng Xu
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Lindsey A Hazen
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Ifechi Ukeh
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Cyndi Vasco
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Austin G Duffy
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer, Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Changqing Xie
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer, Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Cecilia Monge
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer, Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Donna Mabry
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer, Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tim F Greten
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer, Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Bradford J Wood
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
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16
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Hwang SY, Danpanichkul P, Agopian V, Mehta N, Parikh ND, Abou-Alfa GK, Singal AG, Yang JD. Hepatocellular carcinoma: updates on epidemiology, surveillance, diagnosis and treatment. Clin Mol Hepatol 2025; 31:S228-S254. [PMID: 39722614 PMCID: PMC11925437 DOI: 10.3350/cmh.2024.0824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 11/08/2024] [Accepted: 12/20/2024] [Indexed: 12/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global burden, ranking as the third leading cause of cancer-related mortality. HCC due to chronic hepatitis B virus (HBV) or C virus (HCV) infection has decreased due to universal vaccination for HBV and effective antiviral therapy for both HBV and HCV, but HCC related to metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease is increasing. Biannual liver ultrasonography and serum α-fetoprotein are the primary surveillance tools for early HCC detection among high-risk patients (e.g., cirrhosis, chronic HBV). Alternative surveillance tools such as blood-based biomarker panels and abbreviated magnetic resonance imaging (MRI) are being investigated. Multiphasic computed tomography or MRI is the standard for HCC diagnosis, but histological confirmation should be considered, especially when inconclusive findings are seen on cross-sectional imaging. Staging and treatment decisions are complex and should be made in multidisciplinary settings, incorporating multiple factors including tumor burden, degree of liver dysfunction, patient performance status, available expertise, and patient preferences. Early-stage HCC is best treated with curative options such as resection, ablation, or transplantation. For intermediate-stage disease, locoregional therapies are primarily recommended although systemic therapies may be preferred for patients with large intrahepatic tumor burden. In advanced-stage disease, immune checkpoint inhibitor-based therapy is the preferred treatment regimen. In this review article, we discuss the recent global epidemiology, risk factors, and HCC care continuum encompassing surveillance, diagnosis, staging, and treatments.
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Affiliation(s)
- Soo Young Hwang
- Department of Internal Medicine, University of Maryland Medical Center, Midtown Campus, Baltimore, Maryland, USA
| | - Pojsakorn Danpanichkul
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Vatche Agopian
- Dumont-UCLA Transplant and Liver Cancer Centers, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Neil Mehta
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, California, USA
| | - Neehar D. Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ghassan K. Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, USA
- Trinity College Dublin, Dublin, Ireland
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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17
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Xie GL, Zhong ZH, Ye TW, Xiao ZQ. Radiofrequency ablation combined with immunotherapy to treat hepatocellular carcinoma: a comprehensive review. BMC Surg 2025; 25:47. [PMID: 39875933 PMCID: PMC11776151 DOI: 10.1186/s12893-025-02778-z] [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: 03/27/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is a highly immunogenic tumor and the third leading cause of cancer-related deaths worldwide with an increasing incidence. Therefore, the combination of immunotherapy with other approaches, such as anti-angiogenic agents and local area therapy, has become a new strategy for HCC treatment. METHODS We searched PubMed and Web of Science and extracted publications relating to the radiofrequency ablation (RFA) and immunotherapy. The search terms were: "radiofrequency ablation", "immunotherapy" and "hepatocellular carcinoma", and manual searches of eligible articles from literature reference lists were performed. We then thoroughly reviewed the literature on ablation combined with immunotherapy for HCC, analyzed the relevant mechanism, and explored the safety and effectiveness of this form of combination therapy. RESULTS RFA combined with immunotherapy in HCC is reported to have good efficacy and controllable safety. On the one hand, RFA can induce the immunogenic substances including Ficolin-3, IL-1 and heat shock protein and regulate the immune cells by mediating the Th1/Th2 ratio, increasing Th17 cells, etc. On the other hand, RFA treatment can lead to tumor immune microenvironment reconstruction, increasing the proportion of functional T cells and upregulate PD-1 in T cells in distant tumors without RFA. This combined strategy has the ability to enhance the anti-tumor immune response through synergies, significantly reduce the risk of recurrence and improve survival. CONCLUSIONS RFA combined with immunotherapy yields a good synergistic effect: it can further strengthen anti-tumor response, delay distant tumor growth, reduce tumor recurrence and metastasis, providing new options for HCC systemic treatment.
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Affiliation(s)
- Gui-Lin Xie
- Department of Hepatobiliary Surgery, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Zhi-Han Zhong
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Tai-Wei Ye
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Zun-Qiang Xiao
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
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Kudo M, Ren Z, Guo Y, Han G, Lin H, Zheng J, Ogasawara S, Kim JH, Zhao H, Li C, Madoff DC, Ghobrial RM, Kawaoka T, Gerolami R, Ikeda M, Kumada H, El-Khoueiry AB, Vogel A, Peng X, Mody K, Dutcus C, Dubrovsky L, Siegel AB, Finn RS, Llovet JM. Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study. Lancet 2025; 405:203-215. [PMID: 39798578 DOI: 10.1016/s0140-6736(24)02575-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/15/2024] [Accepted: 11/22/2024] [Indexed: 01/15/2025]
Abstract
BACKGROUND Transarterial chemoembolisation (TACE) is standard care for unresectable, non-metastatic hepatocellular carcinoma. We aimed to evaluate the addition of lenvatinib and pembrolizumab to TACE versus dual placebo plus TACE in patients with unresectable, non-metastatic hepatocellular carcinoma. METHODS In this multicentre, randomised, double-blind, phase 3 study (LEAP-012), patients were recruited from 137 global sites in 33 countries or regions. Eligible patients were age 18 years or older with unresectable, non-metastatic hepatocellular carcinoma not amenable to curative treatment, but with tumours amenable to TACE, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and Child-Pugh class A disease. Eligible participants were randomly assigned (1:1), stratified by study site, α-fetoprotein level, ECOG performance status, albumin-bilirubin grade, and tumour burden, by a central interactive response system, to receive TACE and either oral lenvatinib (bodyweight ≥60 kg: 12 mg; bodyweight <60 kg: 8 mg; once daily) plus intravenous pembrolizumab (400 mg once every 6 weeks for up to 2 years) or matched dual placebo (oral and intravenous). Primary endpoints were progression-free survival (threshold one-sided p=0·025), per Response Evaluation Criteria in Solid Tumours version 1.1 (modified for the current study to allow for up to five target tumours in the liver and requiring new intrahepatic tumours to meet LI-RADS 5 criteria to be considered progressive disease) by blinded independent central review, and overall survival (threshold one-sided p=0·0012) in the intention-to-treat (ITT) population (ie, all participants randomly assigned to treatment). Safety was assessed in the as-treated population (ie, all participants who were randomly assigned and received at least one dose of any study treatment). Here, we report results from the first interim analysis (final analysis for progression-free survival). This study is registered with ClinicalTrials.gov, NCT04246177, and is active but not recruiting. FINDINGS Between May 22, 2020, and Jan 11, 2023, 847 patients were screened, of whom 480 (57%) were enrolled and randomly assigned to receive TACE plus lenvatinib plus pembrolizumab (n=237) or TACE plus dual placebo (n=243; ITT population). Median age was 66 years (IQR 58-73), 82 (17%) of 480 participants were female, 398 (83%) were male, 98 (20%) were White, 347 (72%) were Asian, four (1%) were Black or African American, and five (1%) were American Indian or Alaska Native. Median follow-up as of data cutoff (Jan 30, 2024) was 25·6 months (IQR 19·5-32·4). Median progression-free survival was 14·6 months (95% CI 12·6-16·7; 132 events [20 deaths and 112 progressions]) with lenvatinib plus pembrolizumab and 10·0 months (8·1-12·2; 154 events [eight deaths and 146 progressions]) with placebo (hazard ratio [HR] 0·66 [95% CI 0·51-0·84]; one-sided p=0·0002). 69 (29%) of 237 in the lenvatinib plus pembrolizumab group and 82 (34%) of 243 from the placebo group died, with a 24-month overall survival rate of 75% (95% CI 68-80) in the lenvatinib plus pembrolizumab group and 69% (62-74) in the placebo group (HR 0·80 [95% CI 0·57-1·11]; one-sided p=0·087). Grade 3 or worse treatment-related adverse events occurred in 169 (71%) of 237 participants in the lenvatinib plus pembrolizumab group and in 76 (32%) of 241 in the placebo group, the most common of which were hypertension (57 [24%] vs 18 [7%]) and platelet count decreased (27 [11%] vs 15 [6%]). Deaths due to treatment-related adverse events occurred in four (2%) participants in the lenvatinib plus pembrolizumab group (n=1 each due to hepatic failure, gastrointestinal haemorrhage, myositis, and immune-mediated hepatitis) and one (<1%) in the placebo group (due to brain stem haemorrhage). INTERPRETATION TACE plus lenvatinib plus pembrolizumab showed significant, clinically meaningful improvement in progression-free survival in patients with unresectable, non-metastatic hepatocellular carcinoma compared with TACE plus placebo. The numerical improvement in overall survival is encouraging, but longer follow-up is necessary. FUNDING Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and Eisai, Nutley, NJ, USA.
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MESH Headings
- Humans
- Quinolines/administration & dosage
- Quinolines/therapeutic use
- Quinolines/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Liver Neoplasms/therapy
- Liver Neoplasms/mortality
- Liver Neoplasms/drug therapy
- Male
- Female
- Double-Blind Method
- Phenylurea Compounds/administration & dosage
- Phenylurea Compounds/therapeutic use
- Phenylurea Compounds/adverse effects
- Carcinoma, Hepatocellular/therapy
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/drug therapy
- Middle Aged
- Aged
- Chemoembolization, Therapeutic/methods
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Adult
- Combined Modality Therapy
- Progression-Free Survival
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Zhenggang Ren
- Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yabing Guo
- Nanfang Hospital, Guangzhou Southern Medical University, Guangzhou, China
| | - Guohong Han
- Department of Liver Diseases and Digestive Interventional Radiology, Digestive Diseases Hospital, Xi'an International Medical Center Hospital, Northwest University, Xi'an, China
| | - Hailan Lin
- Department of Tumor Interventional Radiology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Jinfang Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ji Hoon Kim
- Department of Gastroenterology and Hepatology, Korea University Guro Hospital, Seoul, South Korea
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Dongcheng, Beijing, China
| | - Chuan Li
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - David C Madoff
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, CT, USA
| | - R Mark Ghobrial
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, J C Walter Jr Center for Transplantation, Houston Methodist Hospital, Houston, TX, USA
| | - Tomokazu Kawaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - René Gerolami
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU Méditerranée Infection, Marseille, France; Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Timone, Unité d'hépatologie, Marseille, France
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | | | - Arndt Vogel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hanover, Germany; Department of Gastroenterology and Hepatology, Toronto General Hospital, Medical Oncology, UHN Princess Margaret Cancer Centre, Toronto, ON, Canada
| | | | | | | | | | | | - Richard S Finn
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Josep M Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
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Song W, Li M, Liu W, Xu W, Zhou H, Wei S, Chi J. Role of immune cell homeostasis in research and treatment response in hepatocellular carcinoma. Clin Exp Med 2025; 25:42. [PMID: 39826024 PMCID: PMC11742861 DOI: 10.1007/s10238-024-01543-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 12/20/2024] [Indexed: 01/20/2025]
Abstract
Introduction Recently, immune cells within the tumor microenvironment (TME) have become crucial in regulating cancer progression and treatment responses. The dynamic interactions between tumors and immune cells are emerging as a promising strategy to activate the host's immune system against various cancers. The development and progression of hepatocellular carcinoma (HCC) involve complex biological processes, with the role of the TME and tumor phenotypes still not fully understood. Therefore, it is essential to investigate the importance of immune cell homeostasis in HCC. Additionally, understanding the molecular mechanisms and biological functions underlying tumor-immune cell interactions is increasingly recognized as vital for improving therapeutic outcomes in clinical settings. Methods A total of 790 HCC samples were selected from public databases and real-world independent clinical cohorts. Machine learning methods, focusing on immune-related indicators, were applied to these samples. The Boruta algorithm was employed to develop an ICI score, which was used to assess patient prognosis and predict responses to immunotherapy. Additionally, a new immune subtype analysis of HCC was performed. Cellular-level experiments confirmed the interaction between TME-related factors and the tumor microenvironment in HCC. To further validate the predictive power of the ICI score, a clinical cohort study was conducted at an independent clinical center. Results By evaluating immune gene expression levels, immune cell abundance, Immunescore, and Stromalscore, we initially identified three distinct immune subtypes of HCC, each showing significant differences in survival rates and heterogeneity. Subsequently, DEGs from 1022 immune subtypes were used to classify HCC samples into three immune genotypes, each characterized by distinct prognosis and tumor immune microenvironment (TIME) profiles. Furthermore, we developed the ICI score, a novel immunophenotyping method for HCC, which revealed significant variations based on gender, stage, progression, and DNA mutation profiles (p < 0.05). The ICI score also effectively predicted responses to immunotherapies, particularly through the chemokine signaling, focal adhesion, and JAK/STAT signaling pathways. Conclusion This research demonstrated that TME and immunophenotyping clusters can enhance prognostic accuracy for HCC patients. The independent prognostic indicators identified underscore the connection between tumor phenotype and the immune environment in HCC.
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Affiliation(s)
- Weihua Song
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Meng Li
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Wangrui Liu
- Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Wenhao Xu
- Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Hongyun Zhou
- Department of Radiology, Department of Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
| | - Shiyin Wei
- Key Laboratory of Molecular Pathology in Tumors of Guangxi Higher Education Institutions, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, China.
| | - Jiachang Chi
- Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
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20
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Oura K, Morishita A, Tadokoro T, Fujita K, Tani J, Kobara H. Immune Microenvironment and the Effect of Vascular Endothelial Growth Factor Inhibition in Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:13590. [PMID: 39769351 PMCID: PMC11679663 DOI: 10.3390/ijms252413590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/12/2024] [Accepted: 12/17/2024] [Indexed: 01/03/2025] Open
Abstract
Systemic therapy for unresectable hepatocellular carcinoma (HCC) has progressed with the development of multiple kinases, such as vascular endothelial growth factor (VEGF) signaling, targeting cancer growth and angiogenesis. Additionally, the efficacy of sorafenib, regorafenib, lenvatinib, ramucirumab, and cabozantinib has been demonstrated in various clinical trials, and they are now widely used in clinical practice. Furthermore, the development of effective immune checkpoint inhibitors has progressed in systemic therapy for unresectable HCC, and atezolizumab + bevacizumab (atezo/bev) therapy and durvalumab + tremelimumab therapy are now recommended as first-line treatment. Atezo/bev therapy, which combines an anti-programmed cell death 1 ligand 1 antibody with an anti-VEGF antibody, is the first cancer immunotherapy to demonstrate efficacy against unresectable HCC. With the increasing popularity of these treatments, VEGF inhibition is attracting attention from the perspective of its anti-angiogenic effects and impact on the cancer-immune cycle. In this review, we outline the role of VEGF in the tumor immune microenvironment and cancer immune cycle in HCC and outline the potential immune regulatory mechanisms of VEGF. Furthermore, we consider the potential significance of the dual inhibition of angiogenesis and immune-related molecules by VEGF, and ultimately aim to clarify the latest treatment strategies that maximizes efficacy.
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Affiliation(s)
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita 761-0793, Kagawa, Japan; (K.O.)
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21
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Zhou H, Menzel L, Baish JW, O'Melia MJ, Darragh LB, Specht E, Effiom DN, Czapla J, Lei PJ, Rajotte JJ, Liu L, Nikmaneshi MR, Razavi MS, Vander Heiden MG, Ubellacker JM, Munn LL, Karam SD, Boland GM, Cohen S, Padera TP. Cancer immunotherapy response persists after lymph node resection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.09.19.558262. [PMID: 37781599 PMCID: PMC10541098 DOI: 10.1101/2023.09.19.558262] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Lymphatic transport facilitates the presentation of cancer antigens in tumor-draining lymph nodes (tdLNs), leading to T cell activation and the generation of systemic antitumor immune surveillance. Surgical removal of LNs to control cancer progression is routine in clinical practice. However, whether removing tdLNs impairs immune checkpoint blockade (ICB) is still controversial. Our analysis demonstrates that melanoma patients remain responsive to PD-1 checkpoint blockade after LN dissection. We were able to recapitulate the persistent response to ICB after complete LN resection in murine melanoma and mammary carcinoma models. Mechanistically, soluble antigen and antigen-carrying migratory dendritic cells are diverted to non-directly tumor draining LNs (non-tdLNs) after tdLN dissection. Consistently, robust ICB responses in patients with head and neck cancer after primary tumor and tdLN resection correlated with the presence of reactive LNs in distant areas. These findings indicate that non-tdLNs sufficiently compensate for the removal of direct tdLNs and sustain the response to ICB.
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22
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Tzang CC, Lee YW, Lin WC, Lin LH, Kang YF, Lin TY, Wu WT, Chang KV. Evaluation of immune checkpoint inhibitors for colorectal cancer: A network meta‑analysis. Oncol Lett 2024; 28:569. [PMID: 39390977 PMCID: PMC11465421 DOI: 10.3892/ol.2024.14702] [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: 07/10/2024] [Accepted: 09/11/2024] [Indexed: 10/12/2024] Open
Abstract
Colorectal cancer (CRC) is challenging to treat due to its high metastatic rate. Recent strategies have focused on combining immune checkpoint inhibitors (ICIs) with other treatments. The aim of the present study was to conduct a network meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and adverse effects of different ICI treatments for CRC. A literature search for RCTs was conducted using PubMed, the Cochrane Library, Embase, ClinicalTrials.gov and Web of Science databases, covering the period from the inception of each database until April 2024. A total of 12 RCTs involving 2,050 participants were selected for inclusion in the analysis. The network meta-analysis employed the MetaInsight tool to assess multiple endpoints. The criteria for study selection were based on the Population, Intervention, Comparison, Outcome and Studies framework as follows: i) Population, patients with CRC; ii) intervention, studies using ICI to treat CRC; iii) comparison, active comparators, including placebo; iv) outcome, overall survival, progression-free survival, objective response rate and adverse events; and v) study design, RCTs. The results of the analysis revealed that programmed cell death-ligand 1 (PD-L1) inhibitors significantly improved overall survival time [mean difference (MD), 2.28 months; 95% confidence interval (CI), 0.44 to 4.11], while programmed cell death protein 1 (PD-1) inhibitors exhibited a superior progression-free survival time (MD, 4.79 months; 95% CI, 3.18 to 6.40) compared with active comparators. However, none of the ICI treatments had significant differences in odds ratios for the objective response rate and adverse events compared with active comparators. These findings indicate that treatment with PD-L1 and PD-1 inhibitors improved the overall survival time and delayed disease progression in patients with CRC. These findings offer valuable insights for future research aimed at improving CRC patient outcomes.
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Affiliation(s)
- Chih-Chen Tzang
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C
| | - Yen-Wei Lee
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan, R.O.C
| | - Wei-Chen Lin
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C
| | - Long-Huei Lin
- School of Physical Therapy and Graduate Institute of Rehabilitation Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, R.O.C
| | - Yuan-Fu Kang
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C
| | - Ting-Yu Lin
- Department of Physical Medicine and Rehabilitation, Lo-Hsu Medical Foundation, Inc., Lotung Poh-Ai Hospital, Yilan 265, Taiwan, R.O.C
| | - Wei-Ting Wu
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei 108, Taiwan, R.O.C
| | - Ke-Vin Chang
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei 108, Taiwan, R.O.C
- Center for Regional Anesthesia and Pain Medicine, Wang-Fang Hospital, Taipei Medical University, Taipei 116, Taiwan, R.O.C
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Zhu W, Pan S, Zhang J, Xu J, Zhang R, Zhang Y, Fu Z, Wang Y, Hu C, Xu Z. The role of hyperthermia in the treatment of tumor. Crit Rev Oncol Hematol 2024; 204:104541. [PMID: 39461607 DOI: 10.1016/j.critrevonc.2024.104541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 09/19/2024] [Accepted: 10/17/2024] [Indexed: 10/29/2024] Open
Abstract
Despite recent advancements in the diagnosis and treatment options for cancer, it remains one of the most serious threats to health. Hyperthermia (HT) has emerged as a highly promising area of research due to its safety and cost-effectiveness. Currently, based on temperature, HT can be categorized into thermal ablation and mild hyperthermia. Thermal ablation involves raising the temperature within the tumor to over 60°C, resulting in direct necrosis in the central region of the tumor. In contrast, mild hyperthermia operates at relatively lower temperatures, typically in the range of 41-45°C, to induce damage to tumor cells. Furthermore, HT also serves as an immune adjuvant strategy in radiotherapy, chemotherapy, and immunotherapy, enhancing the effectiveness of radiotherapy, increasing the uptake of chemotherapy drugs, and reprogramming the tumor microenvironment through the induction of immunogenic cell death, thereby promoting the recruitment of endogenous immune cells. This article reviews the current status and development of hyperthermia, outlines potential mechanisms by which hyperthermia inhibits tumors, describes clinical trial attempts combining hyperthermia with radiotherapy, chemotherapy, and immunotherapy, and discusses the relationship between nanoparticles and hyperthermia.
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Affiliation(s)
- Weiwei Zhu
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China; Department of Gastric surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Siwei Pan
- Department of Gastric surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou 310022, China
| | - Jiaqing Zhang
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China; Department of Gastric surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Jingli Xu
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China; Department of Gastric surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Ruolan Zhang
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China; Department of Gastric surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Yanqiang Zhang
- Department of Gastric surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou 310022, China
| | - Zhenjie Fu
- Department of Gastric surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou 310022, China
| | - Yuqi Wang
- Department of Gastric surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou 310022, China
| | - Can Hu
- Department of Gastric surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou 310022, China.
| | - Zhiyuan Xu
- Department of Gastric surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou 310022, China.
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Mekers V, de Visser M, Suijkerbuijk K, Bos C, Moonen C, Deckers R, Adema G. Mechanical HIFU and immune checkpoint inhibition: toward clinical implementation. Int J Hyperthermia 2024; 41:2430333. [PMID: 39566471 DOI: 10.1080/02656736.2024.2430333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/21/2024] [Accepted: 11/11/2024] [Indexed: 11/22/2024] Open
Abstract
Objective: Immune checkpoint inhibition (ICI) has significantly advanced the field of immuno-oncology, yet not all patients benefit from this therapy. Combining ICI with other therapeutic modalities, including tumor ablation, is currently being explored as a method to enhance ICI efficacy. Mechanical High-Intensity Focused Ultrasound (M-HIFU) represents a promising tumor ablative therapy, inducing cavitation within the tumor, resulting in tumor cell destruction and the release of danger signals and tumor antigens, two key factors contributing to anti-tumor immune responses. Methods/Results: Preclinical studies on the impact of M-HIFU on the anti-tumor immune response are guiding the translational application of this technique in the clinical setting. This review provides a comprehensive overview of the current understanding of the effects of M-HIFU on the immune system. We report on the effect of M-HIFU on soluble immune modulators and immune cells in different preclinical models, and potential contributions to the anti-tumor immune response. We discuss clinical studies applying M-HIFU and studies that have combined ICI with other ablative therapies to draw parallels to clinical implementation of M-HIFU. Further, we will highlight essential questions that should be addressed in future clinical trials exploring the combination of M-HIFU and ICI in the clinical setting. Conclusion: Overall, this review offers guidance for the clinical implementation of combining M-HIFU with ICI and highlights key questions that remain to be addressed in first clinical studies.
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Affiliation(s)
- Vera Mekers
- Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Mirjam de Visser
- Division of Imaging & Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Karijn Suijkerbuijk
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Clemens Bos
- Division of Imaging & Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Chrit Moonen
- Division of Imaging & Oncology, University Medical Center Utrecht, Utrecht, Netherlands
- Focused Ultrasound Foundation, Charlottesville, VA, USA
| | - Roel Deckers
- Division of Imaging & Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Gosse Adema
- Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands
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Wang T, Liu Y, Kong J, Liu J. Identification of a novel molecular classification for hepatocellular carcinoma based on disulfideptosis-related genes and its potential prognostic significance. J Cancer Res Clin Oncol 2024; 150:506. [PMID: 39551857 PMCID: PMC11570565 DOI: 10.1007/s00432-024-06031-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/09/2024] [Indexed: 11/19/2024]
Abstract
BACKGROUND Globally, hepatocellular carcinoma (HCC) is one of the most prevalent and deadly malignant tumors. A recent study proposed disulfidptosis, a novel form of regulated cell death (RCD), offering a new avenue for identifying tumor prognosis biomarkers and developing novel therapeutic targets. METHODS Based on the expression data of 14 disulfideptosis-related genes extracted from public databases, a new molecular classification of HCC called the "disulfidptosis score" was constructed and its relationship to tumor immunity and prognosis was evaluated. RESULTS Based on the expression of disulfideptosis-related genes, we performed cluster analysis on HCC samples from the TCGA cohort, which classified these patients into three clusters: A, B, and C, and the differentially expressed genes of different clusters were analyzed. A disulfidptosis score model was constructed by differentially expressed genes associated with prognosis. Univariate and multivariate COX regression analysis showed that disulfidptosis score was an independent prognostic factor for HCC. In addition, in various disulfidptosis score groups, notable disparities were observed concerning the tumor immune microenvironment as well as the expression of immune checkpoint. CONCLUSION Disulfidptosis score have an important role in predicting HCC prognosis and help guide us in providing better immunotherapy options for patients.
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Affiliation(s)
- Tao Wang
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Jinan, 250000, China
| | - Yong Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Jinan, 250000, China
| | - Junjie Kong
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Jinan, 250000, China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Jinan, 250000, China.
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Xu P, Liu M, Liu M, Shen A. Management of non-alcoholic fatty liver disease-associated hepatocellular carcinoma. Biosci Trends 2024; 18:431-443. [PMID: 39428499 DOI: 10.5582/bst.2024.01295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2024]
Abstract
In recent years, with the decline in HBV and HCV infections, there has been a corresponding reduction in both the morbidity and mortality of virus-associated HCC. Nevertheless, rising living standards, coupled with the increasing prevalence of metabolic disorders like diabetes and obesity, have led to a rapid surge in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) incidence. The mechanisms underlying the progression from NAFLD to NAFLD-HCC are multifaceted and remain incompletely understood. Current research suggests that genetic predisposition, metabolic dysregulation, lipotoxicity, oxidative stress, and inflammation are key contributing factors. Given the complexity of these mechanisms and the frequent occurrence of metabolic comorbidities like type 2 diabetes mellitus (T2DM) and cardiovascular disease in NAFLD-HCC patients, there is a pressing need for tailored therapeutic strategies, along with novel prevention, monitoring, and treatment approaches that are personalized to the patient's pathophysiology. Due to the limited depth of research, incomplete understanding of pathogenesis, and insufficient clinical data on NAFLD-HCC treatment, current therapeutic approaches largely rely on tumor staging. In this review, we synthesize current research on the pathogenesis, surveillance, diagnosis, treatment, and prevention of NAFLD-HCC, and offer perspectives for future studies, particularly regarding its underlying mechanisms.
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Affiliation(s)
- Peijun Xu
- Department of Hepatobiliary Pancreatic Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Maoyun Liu
- Department of Hepatobiliary Pancreatic Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Miao Liu
- Department of Gastrointestinal Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Ai Shen
- Department of Hepatobiliary Pancreatic Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
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Meng L, Li H, Ji Y, Yu P, Wang Z, Cao L, Shi B, Shao Y, Yan J, Gao Y, Zhu Z. Efficacy, safety, and biomarker analysis of TACE combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: a real-world study. Cancer Immunol Immunother 2024; 74:13. [PMID: 39499356 PMCID: PMC11538227 DOI: 10.1007/s00262-024-03857-5] [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: 07/21/2024] [Accepted: 10/07/2024] [Indexed: 11/07/2024]
Abstract
BACKGROUND The integration of transarterial chemoembolization (TACE) with systemic therapy has demonstrated improved survival outcomes in patients with unresectable hepatocellular carcinoma (HCC). However, there is limited evidence evaluating the combination of TACE with the systemic regimen of anti-PD-1/L1 inhibitor plus lenvatinib. This study aims to assess the efficacy and safety of TACE combined with lenvatinib and sintilimab in unresectable HCC patients. METHODS Unresectable HCC patients who received TACE in combination with sintilimab plus Lenvatinib as first-line treatment from 1 January 2020 to 31 March 2023 were included for the analysis. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria. Exploratory biomarker analysis was conducted. RESULTS The study included 70 patients with unresectable HCC, predominantly male and infected with Hepatitis B. The median follow-up duration for the whole cohort was 13.8 months (95% CI 11.08-16.7). The ORR was 61.4% (95% CI, 49.0%-72.8%) and the DCR was 68.6% (95%CI, 56.4%-79.2%). The median PFS was 13.2 months (95% CI 11.0-NA), with a corresponding 1-year PFS rate of 50.3% (95% CI 39.7%-65.5%). The median OS was not reached, and the 1-year OS rate was 89.3% (95% CI 81.4%-97.9%). The most common treatment-related adverse events (TRAEs) were fatigue 38.6% (27/70), hypertension 32.9% (23/70), and hand-foot syndrome 31.4% (22/70). Most TRAEs were mild-to-moderate and manageable. In addition, significant predictive value was found in alpha-fetoprotein levels (AFP), with patients showing a level of decrease post-treatment having better PFS. CONCLUSION The combination regimen demonstrated promising efficacy in treating unresectable HCC, accompanied by manageable safety profiles. Furthermore, the results of this investigation suggest that AFP holds promise as predictive biomarkers for this treatment strategy.
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Affiliation(s)
- Lingzhan Meng
- Department of Hepatobiliary Surgery, Hepatobiliary Surgery Center, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Hu Li
- Department of Hepatobiliary Surgery, Hepatobiliary Surgery Center, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Yingjie Ji
- Department of Geriatric Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Peng Yu
- Department of Hepatobiliary Surgery, Hepatobiliary Surgery Center, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Zizheng Wang
- Department of Hepatobiliary Surgery, Hepatobiliary Surgery Center, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Li Cao
- Department of Hepatobiliary Surgery, Hepatobiliary Surgery Center, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Bin Shi
- Department of Hepatobiliary Surgery, The Third Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Yanling Shao
- Department of Hepatobiliary Surgery, Hepatobiliary Surgery Center, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Jin Yan
- Department of Hepatobiliary Surgery, Hepatobiliary Surgery Center, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Yinjie Gao
- Department of Liver Disease, The Fifth Medical Center of PLA General Hospital, No.100 Xi Si Huan Middle Road, Fengtai District, Beijing, 100039, China.
| | - Zhenyu Zhu
- Department of Hepatobiliary Surgery, Hepatobiliary Surgery Center, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China.
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Bitar R, Salem R, Finn R, Greten TF, Goldberg SN, Chapiro J, Atzen S. Interventional Oncology Meets Immuno-oncology: Combination Therapies for Hepatocellular Carcinoma. Radiology 2024; 313:e232875. [PMID: 39560477 PMCID: PMC11605110 DOI: 10.1148/radiol.232875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 08/15/2024] [Accepted: 08/27/2024] [Indexed: 11/20/2024]
Abstract
The management of hepatocellular carcinoma (HCC) is undergoing transformational changes due to the emergence of various novel immunotherapies and their combination with image-guided locoregional therapies. In this setting, immunotherapy is expected to become one of the standards of care in both neoadjuvant and adjuvant settings across all disease stages of HCC. Currently, more than 50 ongoing prospective clinical trials are investigating various end points for the combination of immunotherapy with both percutaneous and catheter-directed therapies. This review will outline essential tumor microenvironment mechanisms responsible for disease evolution and therapy resistance, discuss the rationale for combining locoregional therapy with immunotherapy, summarize ongoing clinical trials, and report on developing imaging end points and novel biomarkers that are relevant to both diagnostic and interventional radiologists participating in the management of HCC.
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Affiliation(s)
- Ryan Bitar
- From the Departments of Radiology (R.B., J.C.) and Digestive Diseases
(Hepatology) (J.C.), Yale University School of Medicine, New Haven, Conn;
Department of Radiology, Feinberg School of Medicine, Northwestern University,
Chicago, Ill (R.S.); Department of Medical Oncology, Geffen School of Medicine,
University of California Los Angeles, Los Angeles, Calif (R.F.); Center for
Cancer Research, National Institutes of Health, Bethesda, Md (T.F.G.);
Department of Radiology, Hadassah Hebrew University Medical Center, Hebrew
University, Jerusalem, Israel (S.N.G.); and Department of Biomedical
Engineering, Yale School of Engineering and Applied Sciences, 789 Howard Ave,
Clinic Bldg 363H, New Haven, CT 06520 (J.C.)
| | - Riad Salem
- From the Departments of Radiology (R.B., J.C.) and Digestive Diseases
(Hepatology) (J.C.), Yale University School of Medicine, New Haven, Conn;
Department of Radiology, Feinberg School of Medicine, Northwestern University,
Chicago, Ill (R.S.); Department of Medical Oncology, Geffen School of Medicine,
University of California Los Angeles, Los Angeles, Calif (R.F.); Center for
Cancer Research, National Institutes of Health, Bethesda, Md (T.F.G.);
Department of Radiology, Hadassah Hebrew University Medical Center, Hebrew
University, Jerusalem, Israel (S.N.G.); and Department of Biomedical
Engineering, Yale School of Engineering and Applied Sciences, 789 Howard Ave,
Clinic Bldg 363H, New Haven, CT 06520 (J.C.)
| | - Richard Finn
- From the Departments of Radiology (R.B., J.C.) and Digestive Diseases
(Hepatology) (J.C.), Yale University School of Medicine, New Haven, Conn;
Department of Radiology, Feinberg School of Medicine, Northwestern University,
Chicago, Ill (R.S.); Department of Medical Oncology, Geffen School of Medicine,
University of California Los Angeles, Los Angeles, Calif (R.F.); Center for
Cancer Research, National Institutes of Health, Bethesda, Md (T.F.G.);
Department of Radiology, Hadassah Hebrew University Medical Center, Hebrew
University, Jerusalem, Israel (S.N.G.); and Department of Biomedical
Engineering, Yale School of Engineering and Applied Sciences, 789 Howard Ave,
Clinic Bldg 363H, New Haven, CT 06520 (J.C.)
| | - Tim F. Greten
- From the Departments of Radiology (R.B., J.C.) and Digestive Diseases
(Hepatology) (J.C.), Yale University School of Medicine, New Haven, Conn;
Department of Radiology, Feinberg School of Medicine, Northwestern University,
Chicago, Ill (R.S.); Department of Medical Oncology, Geffen School of Medicine,
University of California Los Angeles, Los Angeles, Calif (R.F.); Center for
Cancer Research, National Institutes of Health, Bethesda, Md (T.F.G.);
Department of Radiology, Hadassah Hebrew University Medical Center, Hebrew
University, Jerusalem, Israel (S.N.G.); and Department of Biomedical
Engineering, Yale School of Engineering and Applied Sciences, 789 Howard Ave,
Clinic Bldg 363H, New Haven, CT 06520 (J.C.)
| | - S. Nahum Goldberg
- From the Departments of Radiology (R.B., J.C.) and Digestive Diseases
(Hepatology) (J.C.), Yale University School of Medicine, New Haven, Conn;
Department of Radiology, Feinberg School of Medicine, Northwestern University,
Chicago, Ill (R.S.); Department of Medical Oncology, Geffen School of Medicine,
University of California Los Angeles, Los Angeles, Calif (R.F.); Center for
Cancer Research, National Institutes of Health, Bethesda, Md (T.F.G.);
Department of Radiology, Hadassah Hebrew University Medical Center, Hebrew
University, Jerusalem, Israel (S.N.G.); and Department of Biomedical
Engineering, Yale School of Engineering and Applied Sciences, 789 Howard Ave,
Clinic Bldg 363H, New Haven, CT 06520 (J.C.)
| | - Julius Chapiro
- From the Departments of Radiology (R.B., J.C.) and Digestive Diseases
(Hepatology) (J.C.), Yale University School of Medicine, New Haven, Conn;
Department of Radiology, Feinberg School of Medicine, Northwestern University,
Chicago, Ill (R.S.); Department of Medical Oncology, Geffen School of Medicine,
University of California Los Angeles, Los Angeles, Calif (R.F.); Center for
Cancer Research, National Institutes of Health, Bethesda, Md (T.F.G.);
Department of Radiology, Hadassah Hebrew University Medical Center, Hebrew
University, Jerusalem, Israel (S.N.G.); and Department of Biomedical
Engineering, Yale School of Engineering and Applied Sciences, 789 Howard Ave,
Clinic Bldg 363H, New Haven, CT 06520 (J.C.)
| | - Sarah Atzen
- From the Departments of Radiology (R.B., J.C.) and Digestive Diseases
(Hepatology) (J.C.), Yale University School of Medicine, New Haven, Conn;
Department of Radiology, Feinberg School of Medicine, Northwestern University,
Chicago, Ill (R.S.); Department of Medical Oncology, Geffen School of Medicine,
University of California Los Angeles, Los Angeles, Calif (R.F.); Center for
Cancer Research, National Institutes of Health, Bethesda, Md (T.F.G.);
Department of Radiology, Hadassah Hebrew University Medical Center, Hebrew
University, Jerusalem, Israel (S.N.G.); and Department of Biomedical
Engineering, Yale School of Engineering and Applied Sciences, 789 Howard Ave,
Clinic Bldg 363H, New Haven, CT 06520 (J.C.)
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Wehrenberg-Klee E, Hampilos P, Austin EE, Ataeinia B, MacPherson A, LaSalle T, Mahmood U. Evaluating the Impact of Adjunctive Partial Cryoablation on Dual Checkpoint Inhibitor Immunotherapy Response in a Murine Model. Radiol Imaging Cancer 2024; 6:e230187. [PMID: 39485112 PMCID: PMC11615628 DOI: 10.1148/rycan.230187] [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: 11/08/2023] [Revised: 08/21/2024] [Accepted: 08/28/2024] [Indexed: 11/03/2024]
Abstract
Purpose To evaluate the impact of adjunctive partial cryoablation on checkpoint inhibitor (CPI) immunotherapy response. Materials and Methods One hundred fifty-six mice (equal number of male and female animals) with dual-implanted tumor models were treated with dual CPI or a vehicle and randomized to treatment of a single tumor with partial cryoablation. Tumors were followed for 60 days following cryoablation for response assessment. In additional groups, the tumor microenvironment was characterized via flow cytometry, cytokine analysis, and immunohistochemistry. Statistical comparison was made between the different treatment groups regarding T-cell infiltration and activation characteristics within the noncryoablated tumor and cytokine levels within the partially ablated tumor. Additionally, qualitative assessment of T-cell activation within the cryoablated and noncryoablated tumors at immunofluorescence was carried out. Results At 60 days following treatment, CPI and adjunctive cryoablation-treated MC-38 mice had a significantly increased survival rate (79%) compared with mice treated with CPI alone (61%; P < .001). CT-26 mice also had an increased survival rate (57% vs 35%, respectively; P = .04). Following cryoablation, increases in inflammatory cytokines and chemokines within the treated tumors were observed. Flow cytometry of noncryoablated tumor showed increased CD8 T-cell activation. Immunofluorescence and histologic evaluation following cryoablation further demonstrated a robust CD8 T-cell and myeloid infiltrate. Conclusion Adjunctive cryoablation significantly increased the response to dual CPI in multiple cancer models at both partially ablated and distant (nonablated) tumor sites. Immune analysis suggests cryoablation promotes a vigorous immune response within the partially cryoablated tumor that increases activation of the adaptive immune system within distant tumor sites. Keywords: Cancer, Cryoablation, Checkpoint Inhibitor Immunotherapy, Tumor Response Supplemental material is available for this article. © RSNA, 2024.
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Affiliation(s)
- Eric Wehrenberg-Klee
- From the Department of Radiology, Center for Precision Imaging,
Martinos Center for Biomedical Imaging, Massachusetts General Hospital,
149 13th St, Rm 5.407, Charlestown, MA 02129 (E.W.K., P.H., E.E.A., B.A.,
A.M., T.L., U.M.); and Department of Radiology, Division of Interventional
Radiology, Massachusetts General Hospital, Boston, Mass (E.W.K., P.H.)
| | - Perry Hampilos
- From the Department of Radiology, Center for Precision Imaging,
Martinos Center for Biomedical Imaging, Massachusetts General Hospital,
149 13th St, Rm 5.407, Charlestown, MA 02129 (E.W.K., P.H., E.E.A., B.A.,
A.M., T.L., U.M.); and Department of Radiology, Division of Interventional
Radiology, Massachusetts General Hospital, Boston, Mass (E.W.K., P.H.)
| | - Emily E. Austin
- From the Department of Radiology, Center for Precision Imaging,
Martinos Center for Biomedical Imaging, Massachusetts General Hospital,
149 13th St, Rm 5.407, Charlestown, MA 02129 (E.W.K., P.H., E.E.A., B.A.,
A.M., T.L., U.M.); and Department of Radiology, Division of Interventional
Radiology, Massachusetts General Hospital, Boston, Mass (E.W.K., P.H.)
| | - Bahar Ataeinia
- From the Department of Radiology, Center for Precision Imaging,
Martinos Center for Biomedical Imaging, Massachusetts General Hospital,
149 13th St, Rm 5.407, Charlestown, MA 02129 (E.W.K., P.H., E.E.A., B.A.,
A.M., T.L., U.M.); and Department of Radiology, Division of Interventional
Radiology, Massachusetts General Hospital, Boston, Mass (E.W.K., P.H.)
| | - Abigail MacPherson
- From the Department of Radiology, Center for Precision Imaging,
Martinos Center for Biomedical Imaging, Massachusetts General Hospital,
149 13th St, Rm 5.407, Charlestown, MA 02129 (E.W.K., P.H., E.E.A., B.A.,
A.M., T.L., U.M.); and Department of Radiology, Division of Interventional
Radiology, Massachusetts General Hospital, Boston, Mass (E.W.K., P.H.)
| | - Thomas LaSalle
- From the Department of Radiology, Center for Precision Imaging,
Martinos Center for Biomedical Imaging, Massachusetts General Hospital,
149 13th St, Rm 5.407, Charlestown, MA 02129 (E.W.K., P.H., E.E.A., B.A.,
A.M., T.L., U.M.); and Department of Radiology, Division of Interventional
Radiology, Massachusetts General Hospital, Boston, Mass (E.W.K., P.H.)
| | - Umar Mahmood
- From the Department of Radiology, Center for Precision Imaging,
Martinos Center for Biomedical Imaging, Massachusetts General Hospital,
149 13th St, Rm 5.407, Charlestown, MA 02129 (E.W.K., P.H., E.E.A., B.A.,
A.M., T.L., U.M.); and Department of Radiology, Division of Interventional
Radiology, Massachusetts General Hospital, Boston, Mass (E.W.K., P.H.)
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30
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Rivera Rodríguez DM, Mouli SK. Exploring New Frontiers in Cryoablation and Immunotherapy Synergy. Radiol Imaging Cancer 2024; 6:e240384. [PMID: 39545830 PMCID: PMC11615622 DOI: 10.1148/rycan.240384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 10/18/2024] [Accepted: 10/21/2024] [Indexed: 11/17/2024]
Affiliation(s)
- Delmarie M. Rivera Rodríguez
- From the Department of Interventional Radiology, Northwestern
Memorial Hospital, 676 N St Clair St, Ste 800, Chicago, IL 60611
| | - Samdeep K. Mouli
- From the Department of Interventional Radiology, Northwestern
Memorial Hospital, 676 N St Clair St, Ste 800, Chicago, IL 60611
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31
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Marzi L, Mega A, Turri C, Gitto S, Ferro F, Spizzo G. Immune Checkpoint Inhibitors in the Pre-Transplant Hepatocellular Carcinoma Setting: A Glimpse Beyond the Liver. Int J Mol Sci 2024; 25:11676. [PMID: 39519230 PMCID: PMC11547112 DOI: 10.3390/ijms252111676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/26/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death worldwide. Liver transplantation (LT) is the best therapy for most patients with non-metastatic HCC. In recent years, the management of patients with HCC has considerably changed, thanks to the improvement of molecular biology knowledge and the introduction of immunotherapy. To date, systemic therapy is authorized in the Western world only in patients with advanced HCC. However, this therapy could not only stabilize the tumour disease or improve survival but could display excellent response and lead to downstaging of the tumour that finally permits LT. There are increasing reports of patients that have performed LT after pretreatment with immune checkpoint inhibitors (ICIs). However, due to the intrinsic mechanism of ICIs, graft rejection might be favoured. In addition, chronic adverse effects affecting other organs may also appear after the end of therapy. This review aims to evaluate the readiness and outcomes of LT in patients with advanced HCC who have previously undergone treatment with ICIs. It seeks to identify the challenges, risks, and benefits associated with this conversion therapy. The integration of ICIs into the treatment paradigm for advanced HCC necessitates a nuanced approach to LT. While early evidence supports the feasibility of LT following ICIs therapy, there is an urgent need for standardized guidelines and more extensive longitudinal studies to optimize patient selection, timing, and post-transplant management.
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Affiliation(s)
- Luca Marzi
- Department of Gastroenterology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy; (A.M.); (C.T.)
| | - Andrea Mega
- Department of Gastroenterology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy; (A.M.); (C.T.)
| | - Chiara Turri
- Department of Gastroenterology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy; (A.M.); (C.T.)
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy;
| | - Federica Ferro
- Department of Radiology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy;
| | - Gilbert Spizzo
- Department of Internal Medicine, Oncologic Day Hospital, Hospital of Bressanone (SABES-ASDAA), 39042 Bressanone-Brixen, Italy;
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Pan H, Zhou L, Cheng Z, Zhang J, Shen N, Ma H, Li Y, Jin R, Zhou W, Wu D, Sun W, Wang R. Perioperative Tislelizumab plus intensity modulated radiotherapy in resectable hepatocellular carcinoma with macrovascular invasion: a phase II trial. Nat Commun 2024; 15:9350. [PMID: 39472470 PMCID: PMC11522700 DOI: 10.1038/s41467-024-53704-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 10/21/2024] [Indexed: 11/02/2024] Open
Abstract
Hepatocellular carcinoma (HCC) patients with macrovascular invasion (MVI) have dismal prognosis and there are no standard perioperative therapies. This phase 2 trial (ChiCTR2000036385) aimed to investigate the activity and safety of perioperative tislelizumab plus intensity modulated radiotherapy (IMRT) for resectable HCC with MVI. Thirty treatment-naïve patients with MVI received 3 cycles of tislelizumab intravenously (200 mg, every three weeks) and concurrent IMRT (45 Gray in 15 fractions). Primary endpoints were the overall response rate (ORR) and overall survival (OS). Secondary endpoints were the proportion of patients with a complete or major pathological response (pCR or MPR), recurrence-free survival (RFS) and safety. Of patients enrolled, 15 (50%) underwent curative surgery followed by adjuvant tislelizumab. The ORR was 30.0% (90% CI 16.6%-46.5%) and the median OS was 18.7 months. Of the 15 patients underwent surgical resection, 10 (66.7%) achieved pCR or MPR and 8 (53.3%) remained recurrence-free. The median RFS were not reached with a median follow-up of 21.77 months (95% CI 12.50-31.03) post-surgery. 4 (13.3%) patients experienced grade 3 treatment-related adverse events. The most common events were thrombocytopenia, leukopenia, and anemia. The trial has met the pre-specified endpoints, and these results support further studies of perioperative immunotherapy plus radiotherapy in HCC.
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Affiliation(s)
- Hongyu Pan
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Liuyu Zhou
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- University of Shanghai for Science and Technology, Shanghai, China
| | - Zhuo Cheng
- Department of Oncology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jin Zhang
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Ningjia Shen
- The Second Department of Biliary, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hongbin Ma
- Department of Radiation Oncology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yao Li
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Riming Jin
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Weiping Zhou
- The Third Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Dong Wu
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Wen Sun
- National Center for Liver Cancer, Naval Medical University, Shanghai, China.
| | - Ruoyu Wang
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
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Cao WH, Zhang YQ, Li XX, Zhang ZY, Li MH. Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients. World J Hepatol 2024; 16:1158-1168. [PMID: 39474576 PMCID: PMC11514615 DOI: 10.4254/wjh.v16.i10.1158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/28/2024] [Accepted: 09/19/2024] [Indexed: 10/21/2024] Open
Abstract
Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.
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Affiliation(s)
- Wei-Hua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ya-Qin Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xin-Xin Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Zi-Yu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ming-Hui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Peking University Ditan Teaching Hospital, Beijing 100015, China
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Cao WH, Zhang YQ, Li XX, Zhang ZY, Li MH. Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients. World J Hepatol 2024; 16:1338-1348. [DOI: 10.4254/wjh.v16.i10.1338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/28/2024] [Accepted: 09/19/2024] [Indexed: 11/22/2024] Open
Abstract
Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.
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Affiliation(s)
- Wei-Hua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ya-Qin Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xin-Xin Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Zi-Yu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ming-Hui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Peking University Ditan Teaching Hospital, Beijing 100015, China
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Xu XY, Wang Z, Liu CY, Wu HD, Hu ZX, Lin YY, Zhang S, Shen J, Zhong BY, Zhu XL. Immune Indicator Changes in Hepatocellular Carcinoma Undergoing TACE Plus ICIs and Anti-VEGF Antibodies/TKIs: A Prognostic Biomarker Analysis. J Hepatocell Carcinoma 2024; 11:2019-2032. [PMID: 39465041 PMCID: PMC11512558 DOI: 10.2147/jhc.s487472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/18/2024] [Indexed: 10/29/2024] Open
Abstract
Objective To explore changing trends in circulating immune indicators of hepatocellular carcinoma (HCC) undergoing TACE plus immune checkpoint inhibitors (ICIs) and anti-VEGF antibodies/TKIs and to elucidate the relationship between immune response and tumor prognosis. Materials This single-center retrospective study included patients with unresectable HCC undergoing TACE plus ICIs and anti-VEGF antibodies/TKIs from March 11, 2019, to February 15, 2024. Peripheral blood samples were collected at baseline and every cycle, from which blood cell counts and immune indicators were analyzed. The primary outcome was the objective response rate (ORR) at the first evaluation. According to the first evaluation based on mRECIST, patients were classified into PD, SD, and OR groups for analysis. Further subgroup analysis was performed on the OR group based on whether experiencing progression after the first evaluation. Lymphocyte subsets were measured by flow cytometry. Immunoglobulins were measured using the immune turbidimetric method. The neutrophil-to-lymphocyte ratio (NLR) was measured by the complete blood count. Simple linear regression was employed to examine the dynamic trends. Results A total of 63 patients were enrolled, with an ORR of 55.6% and a disease control rate (DCR) of 87.3% at the first evaluation. The median overall survival (mOS) was 27.5 months (95% CI: 22.5-32.5 months). In the OR group (n=35), more active immune responses, expressed in a decrease in CD3-CD19+ (p=0.004), CFB (p=0.027), NLR (p<0.001) and an increase in Ig λ (p=0.010), Ig κ (p=0.037), Ig A (p=0.005), Ig G (p=0.006), were related to better prognosis, while similar patterns seen in the OR-nPD subgroup. Concurrently, no significant differences were noted in the PD group (n=8). Conclusion The combination therapy may modify the tumor microenvironment of HCC. Changing trends in circulating immune indicators and NLR can serve as potential biomarkers for predicting tumor response and guiding clinical treatment.
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Affiliation(s)
- Xiao-Yang Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China
| | - Ze Wang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China
| | - Chen-You Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China
| | - Hao-Dong Wu
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China
| | - Ze-Xin Hu
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China
| | - Yu-Ying Lin
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China
| | - Shuai Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China
| | - Jian Shen
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China
| | - Bin-Yan Zhong
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China
| | - Xiao-Li Zhu
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China
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Yang Y, Sun J, Cai J, Chen M, Dai C, Wen T, Xia J, Ying M, Zhang Z, Zhang X, Fang C, Shen F, An P, Cai Q, Cao J, Zeng Z, Chen G, Chen J, Chen P, Chen Y, Shan Y, Dang S, Guo WX, He J, Hu H, Huang B, Jia W, Jiang K, Jin Y, Jin Y, Jin Y, Li G, Liang Y, Liu E, Liu H, Peng W, Peng Z, Peng Z, Qian Y, Ren W, Shi J, Song Y, Tao M, Tie J, Wan X, Wang B, Wang J, Wang K, Wang K, Wang X, Wei W, Wu FX, Xiang B, Xie L, Xu J, Yan ML, Ye Y, Yue J, Zhang X, Zhang Y, Zhang A, Zhao H, Zhao W, Zheng X, Zhou H, Zhou H, Zhou J, Zhou X, Cheng SQ, Li Q, on behalf of Chinese Association of Liver Cancer and Chinese Medical Doctor Association. Chinese Expert Consensus on the Whole-Course Management of Hepatocellular Carcinoma (2023 Edition). Liver Cancer 2024:1-23. [DOI: 10.1159/000541622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. Most HCC patients have the complications of chronic liver disease and need overall consideration and whole-course management, including diagnosis, treatment, and follow-up. To develop a reasonable, long-term, and complete management plan, multiple factors need to be considered, including the patient’s general condition, basic liver diseases, tumor stage, tumor biological characteristics, treatment requirements, and economic cost. Summary: To better guide the whole-course management of HCC patients, the Chinese Association of Liver Cancer and the Chinese Medical Doctor Association has gathered multidisciplinary experts and scholars in relevant fields to formulate the “Chinese Expert Consensus on The Whole-Course Management of Hepatocellular Carcinoma (2023).” Key Messages: This expert consensus, based on the current clinical evidence and experience, proposes surgical and nonsurgical HCC management pathways and involves 18 recommendations, including perioperative treatment, systematic treatment combined with local treatment, conversion treatment, special population management, symptomatic support treatment, and follow-up management.
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Susman S, Santoso B, Makary MS. Locoregional Therapies for Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease. Biomedicines 2024; 12:2226. [PMID: 39457538 PMCID: PMC11504147 DOI: 10.3390/biomedicines12102226] [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: 09/01/2024] [Revised: 09/17/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide with an average five-year survival rate in the US of 19.6%. With the advent of HBV and HCV treatment and prevention, along with the rising rates of obesity, nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome are set to overtake infectious causes as the most common cause of HCC. While surgical resection and transplantation can be curative when amenable, the disease is most commonly unresectable on presentation, and other treatment approaches are the mainstay of therapy. In these patients, locoregional therapies have evolved as a vital tool in both palliation for advanced disease and as a bridge to surgical resection and transplantation. In this review, we will be exploring the primary locoregional therapies for HCC in patients with NAFLD, including transarterial chemoembolization (TACE), bland transarterial embolization (TAE), transarterial radioembolization (TARE), and percutaneous ablation.
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Affiliation(s)
- Stephen Susman
- Department of Radiology, Yale University Medical Center, New Haven, CT 06510, USA
| | - Breanna Santoso
- Heritage College of Osteopathic Medicine, Ohio University, Dublin, OH 43016, USA
| | - Mina S. Makary
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH 43202, USA
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Chen H, Liu H, Zhang X, Wang S, Liu C, An K, Liu R, Tian X. Diversified applications of hepatocellular carcinoma medications: molecular-targeted, immunotherapeutic, and combined approaches. Front Pharmacol 2024; 15:1422033. [PMID: 39399471 PMCID: PMC11467865 DOI: 10.3389/fphar.2024.1422033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 09/16/2024] [Indexed: 10/15/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the primary forms of liver cancer and is currently the sixth most prevalent malignancy worldwide. In addition to surgical interventions, effective drug treatment is essential for treating HCC. With an increasing number of therapeutic drugs for liver cancer undergoing clinical studies, the therapeutic strategies for advanced HCC are more diverse than ever, leading to improved prospects for HCC patients. Molecular targeted drugs and immunotherapies have become crucial treatment options for HCC. Treatment programs include single-agent molecular-targeted drugs, immunotherapies, combinations of immunotherapies with molecular-targeted drugs, and dual immune checkpoint inhibitors. However, further exploration is necessary to determine the optimal pharmacological treatment regimens, and the development of new effective drugs is urgently needed. This review provides an overview of the current globally approved drugs for liver cancer, as well as the latest advances in ongoing clinical research and drug therapies. Additionally, the review offers an outlook and discussion on the prospects for the development of drug therapy approaches for HCC.
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Affiliation(s)
- Haoyang Chen
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, China
| | - Huihui Liu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, China
| | - Xiaowei Zhang
- School of Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Suhua Wang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, China
| | - Chunxia Liu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, China
| | - Ke An
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, China
| | - Ruijuan Liu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, China
| | - Xin Tian
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, China
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Taherifard E, Tran K, Saeed A, Yasin JA, Saeed A. Biomarkers for Immunotherapy Efficacy in Advanced Hepatocellular Carcinoma: A Comprehensive Review. Diagnostics (Basel) 2024; 14:2054. [PMID: 39335733 PMCID: PMC11431712 DOI: 10.3390/diagnostics14182054] [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: 07/26/2024] [Revised: 09/11/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Hepatocellular carcinoma (HCC), the most common primary liver malignancy and the sixth most common cancer globally, remains fatal for many patients with inappropriate responses to treatment. Recent advancements in immunotherapy have transformed the treatment landscape for advanced HCC. However, variability in patient responses to immunotherapy highlights the need for biomarkers that can predict treatment outcomes. This manuscript comprehensively reviews the evolving role of biomarkers in immunotherapy efficacy, spanning from blood-derived indicators-alpha-fetoprotein, inflammatory markers, cytokines, circulating tumor cells, and their DNA-to tissue-derived indicators-programmed cell death ligand 1 expression, tumor mutational burden, microsatellite instability, and tumor-infiltrating lymphocytes. The current body of evidence suggests that these biomarkers hold promise for improving patient selection and predicting immunotherapy outcomes. Each biomarker offers unique insights into disease biology and the immune landscape of HCC, potentially enhancing the precision of treatment strategies. However, challenges such as methodological variability, high costs, inconsistent findings, and the need for large-scale validation in well-powered two-arm trial studies persist, making them currently unsuitable for integration into standard care. Addressing these challenges through standardized techniques and implementation of further studies will be critical for the future incorporation of these biomarkers into clinical practice for advanced HCC.
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Affiliation(s)
- Erfan Taherifard
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA
| | - Krystal Tran
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA
| | - Ali Saeed
- Department of Medicine, Ochsner Lafayette General Medical Center, Lafayette, LA 70503, USA
| | - Jehad Amer Yasin
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
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Chen S, Duan Y, Zhang Y, Cheng L, Cai L, Hou X, Wang X, Li W. Effect of Low-Dose Aspirin Use After Thermal Ablation in Patients with Hepatocellular Carcinoma: A Retrospective Study. J Hepatocell Carcinoma 2024; 11:1713-1725. [PMID: 39268150 PMCID: PMC11391387 DOI: 10.2147/jhc.s435524] [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: 12/27/2023] [Accepted: 07/01/2024] [Indexed: 09/15/2024] Open
Abstract
Purpose To determine the effect of aspirin on hepatocellular carcinoma (HCC) recurrence and survival after thermal ablation. Methods A retrospective analysis was performed to evaluate the efficacy and safety of aspirin in combination with thermal ablation. The clinical data were collected for the enrolled patients. Progression-free survival (PFS), overall survival (OS), and adverse events were analyzed. Results A total of 174 patients with HCC were enrolled. The median PFS was 11.1 (95% confidence interval [CI]: 8.1-14.0) months for patients who took aspirin and 8.6 (95% CI: 5.5-11.8) months for patients who did not take aspirin. The median OS of patients in the aspirin group was 76.7 (95% CI: 58.1-95.3) months and that in the non-aspirin group was 53.5 (95% CI: 42.7-64.3) months. In patients with non-viral HCC, OS was significantly better for the aspirin group (P = 0.03) after ablation. The PFS of patients who underwent ablation alone in the aspirin group was obviously superior to that of patients in the non-aspirin group (P = 0.002). Stratified Cox regression analysis demonstrated that aspirin use after ablation might be a protective factor in specific HCC patient subgroups. The incidence of major adverse events did not significantly differ between the two groups. Conclusion Low-dose aspirin use was associated with better OS in patients with non-viral HCC after thermal ablation. In patients who received thermal ablation alone, the administration of low-dose aspirin could improve PFS. Aspirin use might be a protective factor in some patients after ablation.
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Affiliation(s)
- Shanshan Chen
- Cancer Center, Beijing Tongren Hospital, Capital Medical University, Beijing, People's Republic of China
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Youjia Duan
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yongchao Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Long Cheng
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Liang Cai
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Xiaopu Hou
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Xiaojun Wang
- Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Wei Li
- Cancer Center, Beijing Tongren Hospital, Capital Medical University, Beijing, People's Republic of China
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
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Gu Q, Yin S, Tong X, Rui F, Zhu Y, Ma X, Huang R, Wu C, Li J. Current research insights into the role of CTLA-4 in hepatitis B virus (HBV) infection. J Viral Hepat 2024; 31:557-564. [PMID: 38771314 DOI: 10.1111/jvh.13958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 04/29/2024] [Accepted: 05/13/2024] [Indexed: 05/22/2024]
Abstract
Chronic hepatitis B virus (HBV) infection is a significant global public health concern, and the clearance of HBV is closely linked to the activity of HBV-specific T cells, which is regulated by various co-suppressor molecules. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is among these co-suppressor molecules which induces T cell exhaustion by competitively inhibiting CD28 and dampening the function of HBV-specific T cells. CTLA-4 also plays a role in the regulation of T helper (Th) cell differentiation and influences cytokine release. In addition, CTLA-4 can impact glucose metabolism in hepatocellular carcinoma through its interaction with T regulatory (Treg) cells. This review aims to provide a comprehensive overview of the existing literature related to the role of CTLA-4 in HBV patients across different subsets of T cells. Additionally, we propose a discussion on the possible mechanisms through which CTLA-4 may contribute to HBV infection, as well as the development of HBV-induced cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Qi Gu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Fajuan Rui
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yixuan Zhu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoyan Ma
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
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Holtermann A, Gislon M, Angele M, Subklewe M, von Bergwelt-Baildon M, Lauber K, Kobold S. Prospects of Synergy: Local Interventions and CAR T Cell Therapy in Solid Tumors. BioDrugs 2024; 38:611-637. [PMID: 39080180 PMCID: PMC11358237 DOI: 10.1007/s40259-024-00669-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2024] [Indexed: 08/30/2024]
Abstract
Chimeric antigen receptor T cell therapy has been established in the treatment of various B cell malignancies. However, translating this therapeutic effect to treat solid tumors has been challenging because of their inter-tumoral as well as intratumoral heterogeneity and immunosuppressive microenvironment. Local interventions, such as surgery, radiotherapy, local ablation, and locoregional drug delivery, can enhance chimeric antigen receptor T cell therapy in solid tumors by improving tumor infiltration and reducing systemic toxicities. Additionally, ablation and radiotherapy have proven to (re-)activate systemic immune responses via abscopal effects and reprogram the tumor microenvironment on a physical, cellular, and chemical level. This review highlights the potential synergy of the combined approaches to overcome barriers of chimeric antigen receptor T cell therapy and summarizes recent studies that may pave the way for new treatment regimens.
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Affiliation(s)
- Anne Holtermann
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Lindwurmstrasse 2a, 80336, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU, Munich, Germany
| | - Mila Gislon
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Lindwurmstrasse 2a, 80336, Munich, Germany
| | - Martin Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Marion Subklewe
- Department of Medicine III, University Hospital, Ludwig Maximilian University (LMU) of Munich, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU, Munich, Germany
| | - Michael von Bergwelt-Baildon
- Department of Medicine III, University Hospital, Ludwig Maximilian University (LMU) of Munich, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU, Munich, Germany
| | - Kirsten Lauber
- Department of Radiation Oncology, LMU University Hospital, LMU Munich, Munich, Germany
| | - Sebastian Kobold
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Lindwurmstrasse 2a, 80336, Munich, Germany.
- German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU, Munich, Germany.
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München-German Research Center for Environmental Health Neuherberg, Munich, Germany.
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Hong C, Liu Y, Shi D, Liu C, Zou S, Guo M, Chen X, Zheng C, Zhao Y, Yang X. Radiofrequency-responsive black phosphorus nanogel crosslinked with cisplatin for precise synergy in multi-modal tumor therapies. J Control Release 2024; 373:853-866. [PMID: 39094632 DOI: 10.1016/j.jconrel.2024.07.075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 08/04/2024]
Abstract
Radiofrequency-responsive nanoparticles (RFNPs) have drawn increasingly attentions as RF energy absorbing antenna to enhance antitumor efficacy of radiofrequency ablation (RFA). However, it remains a huge challenge for inorganic RFNPs to precisely synergize RFA with other antitumor modes in a clinically acceptable way on bio-safety and bio-compatibility. In this work, RF-responsive black phosphorus (BP) nanogel (BP-Pt@PNA) was successfully fabricated by crosslinking coordination of cisplatin with BP and temperature sensitive polymer PNA. BP-Pt@PNA exhibited strong RF-heating effect and RF-induced pulsatile release of cisplatin. Under RF irradiation, BP-Pt@PNA exhibited cytotoxic enhancement on 4T1 cells. By the synergistic effect of BP and cisplatin, BP-Pt@PNA achieved RF-stimulated systemic immune effect, thus induced enhance suppression on tumor growth and metastasis. Moreover, BP-Pt@PNA realized long-term drug retention in tumor and favorable embolization to tumor-feeding arteries. With high drug loading capacity and favorable bio-safety and bio-degradability, BP-Pt@PNA is expected as an ideal RFNP for precisely synergizing RFA with other antitumor modes in clinical application.
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Affiliation(s)
- Can Hong
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, PR China
| | - Yiming Liu
- Hubei Province Key Laboratory of Molecular Imaging, Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Dingwen Shi
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, PR China
| | - Chao Liu
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, PR China
| | - Shidong Zou
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, PR China
| | - Mengqin Guo
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, PR China
| | - Xingyu Chen
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, PR China
| | - Chuansheng Zheng
- Hubei Province Key Laboratory of Molecular Imaging, Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China..
| | - Yanbing Zhao
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, PR China.; School of Biomedical Engineering, Hubei University of Science and Technology, Xianning 437100, PR China.; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, PR China.; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, 430074 Wuhan, PR China.; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, 430074 Wuhan, PR China..
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, PR China.; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, PR China.; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, 430074 Wuhan, PR China.; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, 430074 Wuhan, PR China..
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Miura R, Ono A, Yano S, Amioka K, Naruto K, Yamaoka K, Fujii Y, Uchikawa S, Fujino H, Nakahara T, Murakami E, Kawaoka T, Miki D, Tsuge M, Hayes CN, Oka S. Real-world efficacy and safety of durvalumab-tremelimumab as second-line systemic therapy after atezolizumab-bevacizumab in unresectable hepatocellular carcinoma. Medicine (Baltimore) 2024; 103:e39289. [PMID: 39288227 PMCID: PMC11346847 DOI: 10.1097/md.0000000000039289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/23/2024] [Indexed: 09/19/2024] Open
Abstract
The efficacy and safety of immune-checkpoint inhibitors (ICI) for the treatment of unresectable hepatocellular carcinoma are known. We explored ICI rechallenges with direct switching from 1 ICI regimen to another. This retrospective study included 16 patients who received atezolizumab-bevacizumab (Atezo+Bev) and durvalumab-tremelimumab (Dur+Tre) as the first-line and second-line combination therapy, respectively, at Hiroshima University Hospital. The radiological response and adverse event were evaluated in all patients. Of the 16 patients, 12 were male, and the median age at Atezo+Bev induction was 71 years. The reasons for medication changes were disease progression in 11 patients and adverse events in 5 patients. With Atezo+Bev and Dur+Tre initiation, the Barcelona-Clinic Liver-Cancer stage (A/B/C) progressed in 9/6/3 and 3/4/9 patients and the Child-Pugh classification (A/B/C) progressed in 12/4/0 and 9/6/3 patients, respectively. The disease control rate and overall response rate of Atezo+Bev were 87.5% and 58.3%, respectively, and of Dur+Tre were 62.5% and 0%, respectively. The most common immune-related adverse event in both the Atezo+Bev and Dur+Tre groups was colitis; 3 of the 5 patients with colitis on Atezo+Bev treatment had colitis with Dur+Tre, and 2 had exacerbations. Regarding liver function, ALBI score significantly decreased during Atezo+Bev, but not Dur+Tre, treatment. In patients with colitis following Atezo+Bev, subsequent Dur+Tre treatment may induce colitis recurrence or exacerbation. For immune-related adverse events other than colitis, Dur+Tre could provide relatively safe disease control while maintaining liver function.
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MESH Headings
- Humans
- Male
- Liver Neoplasms/drug therapy
- Carcinoma, Hepatocellular/drug therapy
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Female
- Aged
- Retrospective Studies
- Bevacizumab/therapeutic use
- Bevacizumab/administration & dosage
- Bevacizumab/adverse effects
- Middle Aged
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal/adverse effects
- Antibodies, Monoclonal/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Aged, 80 and over
- Immune Checkpoint Inhibitors/adverse effects
- Immune Checkpoint Inhibitors/therapeutic use
- Immune Checkpoint Inhibitors/administration & dosage
- Treatment Outcome
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/administration & dosage
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Affiliation(s)
- Ryoichi Miura
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Shigeki Yano
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Kei Amioka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Kensuke Naruto
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Kenji Yamaoka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Yasutoshi Fujii
- Department of Clinical Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - C. Nelson Hayes
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
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Wang X, Sun X, Lei Y, Fang L, Wang Y, Feng K, Xia F. The efficacy and safety of Radiofrequency ablation combined with Lenvatinib plus Sintilimab in Unresectable Hepatocellular Carcinoma: a real-world study. BMC Cancer 2024; 24:1036. [PMID: 39174912 PMCID: PMC11340044 DOI: 10.1186/s12885-024-12779-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 08/07/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND The combination of targeted therapy and immunotherapy has improved the clinical outcomes of unresectable hepatocellular Carcinoma (HCC). However, the overall prognosis remains suboptimal. This study aims to evaluate the efficacy and safety of a novel combination of radiofrequency ablation (RFA) with lenvatinib plus sintilimab in unresectable HCC. METHODS In this retrospective study, patients diagnosed with unresectable HCC were included and divided into two cohorts: RFA combined with lenvatinib plus sintilimab (R-L-S group) and lenvatinib plus sintilimab (L-S group). The primary efficacy endpoints were objective response rate (ORR) and progression free survival (PFS). Adverse events were analyzed to assess the safety profiles. RESULTS The median follow-up periods for the entire cohort were 14.0 months. The R-L-S group (n = 60) had a significantly higher ORR than those with L-S alone (n = 62) (40.0% vs. 20.9%; p = 0.022). Moreover, patients in the R-L-S group had improved median PFS (12 vs. 8 months; p = 0.013) and median overall survival (24 vs. 18 months; p = 0.037), as compared with lenvatinib and sintilimab alone. No significant difference in treatment related adverse event (TRAE) of any grade between the two groups. The most common TRAEs of grade ≥ 3 were fatigue 10.0% (6/60) and hand-foot skin reaction 10.0% (6/60) in the R-L-S group and hand-foot skin reaction 11.3% (7/62) in the L-S group. CONCLUSION In unresectable HCC patients, the incorporation of RFA to lenvatinib plus sintilimab demonstrated improved efficacy without compromising safety compared with lenvatinib plus sintilimab alone.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/therapy
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/surgery
- Quinolines/therapeutic use
- Quinolines/administration & dosage
- Quinolines/adverse effects
- Liver Neoplasms/drug therapy
- Liver Neoplasms/therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/surgery
- Liver Neoplasms/mortality
- Male
- Female
- Phenylurea Compounds/administration & dosage
- Phenylurea Compounds/therapeutic use
- Phenylurea Compounds/adverse effects
- Middle Aged
- Aged
- Retrospective Studies
- Radiofrequency Ablation/methods
- Radiofrequency Ablation/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Combined Modality Therapy
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Adult
- Treatment Outcome
- Aged, 80 and over
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Affiliation(s)
- Xishu Wang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Ximin Sun
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Yongrong Lei
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Lingyan Fang
- Department of Surgical Anesthesiology, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Yuedi Wang
- Outpatient Department, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Kai Feng
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Feng Xia
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, China.
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Liu T, Meng G, Ma S, You J, Yu L, He R, Zhao X, Cui Y. Progress of immune checkpoint inhibitors in the treatment of advanced hepatocellular carcinoma. Front Immunol 2024; 15:1455716. [PMID: 39185414 PMCID: PMC11341420 DOI: 10.3389/fimmu.2024.1455716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 07/30/2024] [Indexed: 08/27/2024] Open
Abstract
Among primary liver cancers, hepatocellular carcinoma is the most common pathological type. Its onset is insidious, and most patients have no obvious discomfort in the early stage, so it is found late, and the opportunity for surgical radical treatment is lost, resulting in a poor prognosis. With the introduction of molecular-targeted drugs represented by sorafenib, patients with middle- and late-stage liver cancer have regained the light of day. However, their therapeutic efficacy is relatively low due to the limited target of drug action, toxic side effects, and other reasons. At this time, the emergence of immunotherapy represented by immune checkpoint inhibitors (ICIs) well breaks this embarrassing situation, which mainly achieves the anti-tumor purpose by improving the tumor immune microenvironment. Currently, ICI monotherapy, as well as combination therapy, has been widely used in the clinic, further prolonging the survival of patients with advanced hepatocellular carcinoma. This article reviews the development of monotherapy and combination therapy for ICIs in advanced hepatocellular carcinoma and the latest research progress.
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Affiliation(s)
| | | | | | | | | | | | | | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Su X, Li J, Xu X, Ye Y, Wang C, Pang G, Liu W, Liu A, Zhao C, Hao X. Strategies to enhance the therapeutic efficacy of anti-PD-1 antibody, anti-PD-L1 antibody and anti-CTLA-4 antibody in cancer therapy. J Transl Med 2024; 22:751. [PMID: 39123227 PMCID: PMC11316358 DOI: 10.1186/s12967-024-05552-6] [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: 05/10/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
Although immune checkpoint inhibitors (anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA-4 antibody) have displayed considerable success in the treatment of malignant tumors, the therapeutic effect is still unsatisfactory for a portion of patients. Therefore, it is imperative to develop strategies to enhance the effect of these ICIs. Increasing evidence strongly suggests that the key to this issue is to transform the tumor immune microenvironment from a state of no or low immune infiltration to a state of high immune infiltration and enhance the tumor cell-killing effect of T cells. Therefore, some combination strategies have been proposed and this review appraise a summary of 39 strategies aiming at enhancing the effectiveness of ICIs, which comprise combining 10 clinical approaches and 29 foundational research strategies. Moreover, this review improves the comprehensive understanding of combination therapy with ICIs and inspires novel ideas for tumor immunotherapy.
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Affiliation(s)
- Xin Su
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Jian Li
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Xiao Xu
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Youbao Ye
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Cailiu Wang
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Guanglong Pang
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Wenxiu Liu
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Ang Liu
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Changchun Zhao
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, 730000, China
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China
| | - Xiangyong Hao
- Department of General Surgery, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, China.
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Abstract
ABSTRACT Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Its high recurrence rate and lack of effective control drugs result in a 5-year survival rate of only about 10%. HCC is a tumor regulated by the immune system. Significant breakthroughs have occurred in treating solid tumors with immunotherapy in recent years. Various immunotherapies, such as immune checkpoint inhibitors (ICIs), including combination therapies, have demonstrated promising therapeutic effects in both clinical applications and research. Other immunotherapies, such as adoptive cell therapies and oncolytic viruses, are also emerging, offering hope for addressing long-term survival issues in HCC. This article reviews current commonly used immunotherapy strategies and the latest research findings for reference.
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Affiliation(s)
- Xiaoxia Wang
- Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Laboratory for Clinical Medicine, Capital Medical University
| | - Jun Lu
- Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Laboratory for Clinical Medicine, Capital Medical University
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He P, Ma L, Xu B, Wang Y, Li X, Chen H, Li Y. Research progress and future directions of immune checkpoint inhibitor combination therapy in advanced gastric cancer. Ther Adv Med Oncol 2024; 16:17588359241266156. [PMID: 39091604 PMCID: PMC11292724 DOI: 10.1177/17588359241266156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 06/18/2024] [Indexed: 08/04/2024] Open
Abstract
In recent years, with the continuous development of molecular immunology, immune checkpoint inhibitors (ICIs) have also been widely used in the treatment of gastric cancer, but they still face some challenges: The first is that only some people can benefit, the second is the treatment-related adverse events (TRAEs) that occur during treatment, and the third is the emergence of varying degrees of drug resistance with long-term use. How to overcome these challenges, combined therapy based on ICIs has become one of the important strategies. This article summarizes the clinical application of ICIs combined with chemotherapy, targeted therapy, radiotherapy, photodynamic therapy, thermotherapy, immune adjuvant, and dual immunotherapy and discusses the mechanism, and also summarizes the advantages and disadvantages of the current combination modalities and the potential research value. The aim of this study is to provide more and more optimized combination regimen for ICI combined therapy in patients with advanced gastric cancer and to provide reference for clinical and scientific research.
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Affiliation(s)
- Puyi He
- The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Key Laboratory of Environmental Oncology, China
| | - Long Ma
- The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Key Laboratory of Environmental Oncology, China
| | - Bo Xu
- The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Key Laboratory of Environmental Oncology, China
| | - Yunpeng Wang
- The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Key Laboratory of Environmental Oncology, China
| | - Xiaomei Li
- The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Key Laboratory of Environmental Oncology, China
| | - Hao Chen
- The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Key Laboratory of Environmental Oncology, Lanzhou, China
- No. 82, Cuiyingmen, Chengguan, Lanzhou 730030, China
| | - Yumin Li
- The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Key Laboratory of Environmental Oncology, Lanzhou, China
- No. 82, Cuiyingmen, Chengguan, Lanzhou 730030, China
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50
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Tong LW, Hu YS, Yu SJ, Li CL, Shao JW. Current application and future perspective of CRISPR/cas9 gene editing system mediated immune checkpoint for liver cancer treatment. NANOTECHNOLOGY 2024; 35:402002. [PMID: 38964289 DOI: 10.1088/1361-6528/ad5f33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 07/04/2024] [Indexed: 07/06/2024]
Abstract
Liver cancer, which is well-known to us as one of human most prevalent malignancies across the globe, poses a significant risk to live condition and life safety of individuals in every region of the planet. It has been shown that immune checkpoint treatment may enhance survival benefits and make a significant contribution to patient prognosis, which makes it a promising and popular therapeutic option for treating liver cancer at the current time. However, there are only a very few numbers of patients who can benefit from the treatment and there also exist adverse events such as toxic effects and so on, which is still required further research and discussion. Fortunately, the clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9) provides a potential strategy for immunotherapy and immune checkpoint therapy of liver cancer. In this review, we focus on elucidating the fundamentals of the recently developed CRISPR/Cas9 technology as well as the present-day landscape of immune checkpoint treatment which pertains to liver cancer. What's more, we aim to explore the molecular mechanism of immune checkpoint treatment in liver cancer based on CRISPR/Cas9 technology. At last, its encouraging and powerful potential in the future application of the clinic is discussed, along with the issues that already exist and the difficulties that must be overcome. To sum up, our ultimate goal is to create a fresh knowledge that we can utilize this new CRISPR/Cas9 technology for the current popular immune checkpoint therapy to overcome the treatment issues of liver cancer.
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Affiliation(s)
- Ling-Wu Tong
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Yong-Shan Hu
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Shi-Jing Yu
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Cheng-Lei Li
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Jing-Wei Shao
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
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