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Pettas T, Lachanoudi S, Karageorgos FF, Ziogas IA, Fylaktou A, Papalois V, Katsanos G, Antoniadis N, Tsoulfas G. Immunotherapy and liver transplantation for hepatocellular carcinoma: Current and future challenges. World J Transplant 2025; 15:98509. [DOI: 10.5500/wjt.v15.i2.98509] [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: 06/27/2024] [Revised: 10/03/2024] [Accepted: 11/07/2024] [Indexed: 02/21/2025] Open
Abstract
Despite existing curative options like surgical removal, tissue destruction techniques, and liver transplantation for early-stage hepatocellular carcinoma (HCC), the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies. This review critically assesses the dynamic treatment panorama for HCC, focusing specifically on the burgeoning role of immunotherapy in two key contexts: early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy. It delves into the unique immunobiology of the liver and HCC, highlighting tumor-mediated immune evasion mechanisms. Analyzing the diverse immunotherapeutic approaches including checkpoint inhibitors, cytokine modulators, vaccines, oncolytic viruses, antigen-targeting antibodies, and adoptive cell therapy, this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring. Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC, current research is actively exploring the safety and effectiveness of diverse immunotherapeutic approaches through ongoing clinical trials. The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant, highlighting the need for careful patient selection, meticulous monitoring, and novel strategies to mitigate post-transplant complications. Finally, this review delves into the latest findings from the clinical research landscape and future directions in HCC management, paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.
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Affiliation(s)
- Theodoros Pettas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Sofia Lachanoudi
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Filippos F Karageorgos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Vassilios Papalois
- Department of Transplant Surgery, Imperial College Renal and Transplant Centre, London W12 0HS, United Kingdom
| | - Georgios Katsanos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| | - Nikolaos Antoniadis
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
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Ying S, Liu H, Zhang Y, Mei Y. Harnessing Dendritic Cell Function in Hepatocellular Carcinoma: Advances in Immunotherapy and Therapeutic Strategies. Vaccines (Basel) 2025; 13:496. [PMID: 40432108 PMCID: PMC12115466 DOI: 10.3390/vaccines13050496] [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: 03/21/2025] [Revised: 04/29/2025] [Accepted: 05/01/2025] [Indexed: 05/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Conventional therapies are frequently limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Dendritic cells (DCs), central to orchestrating antitumor immunity, have become key targets for HCC immunotherapy. This review examines the biological functions of DC subsets (cDC1, cDC2, pDC, and moDC) and their roles in initiating and modulating immune responses against HCC. We detail the mechanisms underlying DC impairment within the TME, including suppression by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). Additionally, we discuss novel DC-based therapeutic strategies, such as DC-based vaccines designed to enhance antigen presentation and T cell activation. Combining DC vaccines with immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 and CTLA-4 blockers, demonstrates synergistic effects that can overcome immune evasion and improve clinical outcomes. Despite progress, challenges related to DC subset heterogeneity, TME complexity, and patient variability require the further optimization and personalization of DC-based therapies. Future research should focus on refining these strategies, leveraging advanced technologies like genomic profiling and artificial intelligence, to maximize therapeutic efficacy and revolutionize HCC treatment. By restoring DC function and reprogramming the TME, DC-based immunotherapy holds immense potential to transform the management of HCC and improve patient survival.
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Affiliation(s)
- Shiding Ying
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China;
| | - Haiyan Liu
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore;
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore 117456, Singapore
| | - Yongliang Zhang
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore;
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore 117456, Singapore
| | - Yu Mei
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore;
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore 117456, Singapore
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Maino A, Bourova-Flin E, Decaens T, Khochbin S, Macek Jilkova Z, Rousseaux S, Plumas J, Saas P, Chaperot L, Manches O. Identification of immunogenic HLA-A*02:01 epitopes associated with HCC for immunotherapy development. Hepatol Commun 2025; 9:e0659. [PMID: 40008881 PMCID: PMC11868434 DOI: 10.1097/hc9.0000000000000659] [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: 11/04/2024] [Accepted: 12/16/2024] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND HCC is the most common form of primary liver cancer, and despite recent advances in cancer treatment, it remains associated with poor prognosis and a lack of response to conventional therapies. Immunotherapies have emerged as a promising approach for cancer treatment, especially through the identification of tumor-specific immunogenic epitopes that can trigger a targeted immune response. This study aimed to identify immunogenic epitopes associated with HCC for the development of specific immunotherapies. METHODS We used high-throughput data screening and bioinformatics tools for antigens and epitope selection. The immunogenicity of the selected epitopes was studied after coculture of peripheral blood mononuclear cells obtained from healthy donors or HCC patients with a plasmacytoid dendritic cell line loaded with the selected peptides. Specific CD8+ T cell amplification and functionality were determined by labeling with tetramers and by IFN-γ and CD107a expression (flow cytometry and ELISpot). RESULTS We analyzed the transcriptional gene expression landscape of HCC to screen for a set of 16 ectopically expressed genes in a majority of HCC samples. Epitopes predicted to bind to HLA-A*02:01 with high affinity were further validated for their immunogenicity using the previously described plasmacytoid dendritic cell line in ex vivo CD8+ activation assays using patient immune cells. Three out of the 30 tested epitopes, namely FLWGPRALV (MAGE-A3), FMNKFIYEI (AFP), and KMFHTLDEL (LRRC46), elicited a strong T-cell response, in activation assays, degranulation assays, and IFN-γ secretion assays. CONCLUSIONS These results highlight the potential of these peptides to be considered as targets for immunotherapies. The discovery of such immunogenic epitopes should improve immune-based treatments for liver cancer in combination with the current treatment approach.
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Affiliation(s)
- Anthony Maino
- EFS, R&D Department, Grenoble, France
- Univ. Grenoble Alpes, INSERM U, CNRS UMR, Institute for Advanced Biosciences, Grenoble, France
| | - Ekaterina Bourova-Flin
- Univ. Grenoble Alpes, INSERM U, CNRS UMR, Institute for Advanced Biosciences, Grenoble, France
| | - Thomas Decaens
- Univ. Grenoble Alpes, INSERM U, CNRS UMR, Institute for Advanced Biosciences, Grenoble, France
- Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, Grenoble, France
| | - Saadi Khochbin
- Univ. Grenoble Alpes, INSERM U, CNRS UMR, Institute for Advanced Biosciences, Grenoble, France
| | - Zuzana Macek Jilkova
- Univ. Grenoble Alpes, INSERM U, CNRS UMR, Institute for Advanced Biosciences, Grenoble, France
- Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, Grenoble, France
| | - Sophie Rousseaux
- Univ. Grenoble Alpes, INSERM U, CNRS UMR, Institute for Advanced Biosciences, Grenoble, France
| | - Joel Plumas
- PDC*line Pharma SAS, R&D Department, Grenoble, France
| | - Philippe Saas
- EFS, R&D Department, Grenoble, France
- Univ. Grenoble Alpes, INSERM U, CNRS UMR, Institute for Advanced Biosciences, Grenoble, France
| | - Laurence Chaperot
- EFS, R&D Department, Grenoble, France
- Univ. Grenoble Alpes, INSERM U, CNRS UMR, Institute for Advanced Biosciences, Grenoble, France
| | - Olivier Manches
- EFS, R&D Department, Grenoble, France
- Univ. Grenoble Alpes, INSERM U, CNRS UMR, Institute for Advanced Biosciences, Grenoble, France
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Ren S, Zhang Y, Wang X, Su J, Wang X, Yuan Z, He X, Guo S, Chen Y, Deng S, Wu X, Li M, Du F, Zhao Y, Shen J, Hu W, Li X, Xiao Z. Emerging insights into the gut microbiota as a key regulator of immunity and response to immunotherapy in hepatocellular carcinoma. Front Immunol 2025; 16:1526967. [PMID: 40070843 PMCID: PMC11893557 DOI: 10.3389/fimmu.2025.1526967] [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] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/10/2025] [Indexed: 03/14/2025] Open
Abstract
The gut microbiota, a complex microbial ecosystem closely connected to the liver via the portal vein, has emerged as a critical regulator of liver health and disease. Numerous studies have underscored its role in the onset and progression of liver disorders, including alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). This review provides a comprehensive overview of current insights into the influence of the gut microbiota on HCC progression, particularly its effects on immune cells within the HCC tumor microenvironment (TME). Furthermore, we explore the potential of gut microbiota-targeted interventions, such as antibiotics, probiotics, prebiotics, and fecal microbiota transplantation (FMT), to modulate the immune response and improve outcomes of immunotherapy in HCC. By synthesizing insights from recent studies, this review aims to highlight microbiota-based strategies that may enhance immunotherapy outcomes, advancing personalized approaches in HCC treatment.
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Affiliation(s)
- Siqi Ren
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yinping Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xiang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zijun Yuan
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xinyu He
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Sipeng Guo
- Research and Experiment Center, Sichuan College of Traditional Chinese Medicine, Mianyang, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Wei Hu
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Research and Experiment Center, Sichuan College of Traditional Chinese Medicine, Mianyang, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
- Gulin Traditional Chinese Medicine Hospital, Luzhou, China
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Ascari S, Chen R, Vivaldi C, Stefanini B, De Sinno A, Dalbeni A, Federico P, Tovoli F. Advancements in immunotherapy for hepatocellular carcinoma. Expert Rev Anticancer Ther 2025; 25:151-165. [PMID: 39913170 DOI: 10.1080/14737140.2025.2461631] [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: 11/11/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/07/2025]
Abstract
INTRODUCTION The advent of immune-based combinations, primarily leveraging immune checkpoint inhibitors, has revolutionized the therapeutic landscape of hepatocellular carcinoma (HCC). The current scenario features multiple therapies that have shown superiority over tyrosine kinase inhibitors; however, the absence of direct comparisons and validated prognostic biomarkers complicates therapeutic decision-making. Additionally, a significant proportion of patients still exhibit primary or secondary resistance to existing immunotherapies, underscoring the ongoing need for novel therapeutic strategies. AREAS COVERED This narrative review discusses current strategies aimed at improving the efficacy of immunotherapy for HCC, focusing on the following aspects: available therapeutic options, identification of prognostic biomarkers, approaches to overcoming resistance (including the development of neoantigen vaccines), and the exploration of adjuvant and neoadjuvant strategies. EXPERT OPINION The future of systemic therapies for HCC is likely to be driven by advancements in immunotherapy. Key areas of exploration for the coming years include the discovery of novel checkpoint inhibitors or complementary agents to enhance tumor response when combined with existing treatments, a shift toward neoadjuvant/perioperative trials instead of traditional adjuvant approaches, and the development of personalized neoantigen vaccines.
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Affiliation(s)
- Sara Ascari
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Rusi Chen
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Caterina Vivaldi
- Unit of Medical Oncology 2, Azienda Ospedaliero- Universitaria Pisana, Pisa, Italy
| | - Bernardo Stefanini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea De Sinno
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea Dalbeni
- Liver Unit, Medicine Department, University of Verona and University and Hospital Trust (AOUI) of Verona, Verona, Italy
- Unit of General Medicine C, Medicine Department, University of Verona and Hospital Trust (AOUI) of Verona, Verona, Italy
| | | | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Zhang J, Liu J, Ni J, Lin X, Fan L, Sun G. Exosomes Derived from Endoplasmic Reticulum Stressed Hepatocellular Carcinoma Cells Enhance the Antitumor Immunity of Dendritic Cells. Inflammation 2024:10.1007/s10753-024-02214-z. [PMID: 39714721 DOI: 10.1007/s10753-024-02214-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 12/04/2024] [Accepted: 12/09/2024] [Indexed: 12/24/2024]
Abstract
Endoplasmic reticulum stress (ERs) is implicated in antitumor immunity. However, the exact role of ERs in mediating the effects of dendritic cells (DCs) is not unclear. In this study, we explored the role of exosomes derived from ER-stressed hepatocellular carcinoma (HCC) cells in the antitumor effects of DCs and the precise underlying mechanism. We found that ER-stressed HCC cells secreted more exosomes (EXO-TM) than those without ER stress (EXO-CON) and that exosomes were effectively taken up by DCs. EXO-TM significantly promoted DCs maturation, as demonstrated by the increased expression of HLA-ABC, CD83, CD80, CD86, and pro-inflammatory cytokines and the decreased expression of IL-10. Moreover, EXO-TM pulsed DCs (DCEXO-TM) significantly enhanced T lymphocyte-mediated lysis against several types of tumor cells by promoting the proliferation of CD3+CD8+ T cells and increasing the expression of INF-γ both in vitro and in vivo. Mechanistically, we found that heat shock protein (HSP) 90 was more significantly enriched in EXO-TM than in EXO-CON cells, and the knockdown of HSP90 remarkably reversed EXO-TM-mediated DC activation. Our results suggest that exosomes derived from ER-stressed HCC cells could enhance the antitumor effect of DC-mediated T lymphocytes, which may be related to the large amount of HSP90 carried in the exosomes. Therefore, regulating the HSP90 carrying capacity of tumor exosomes may be an effective immunotherapy strategy.
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Affiliation(s)
- Ju Zhang
- Department of Clinical Laboratory, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Jiatao Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jing Ni
- Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Xiao Lin
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Lulu Fan
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Guoping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
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Pourbagheri-Sigaroodi A, Momeny M, Rezaei N, Fallah F, Bashash D. Immune landscape of hepatocellular carcinoma: From dysregulation of the immune responses to the potential immunotherapies. Cell Biochem Funct 2024; 42:e4098. [PMID: 39034646 DOI: 10.1002/cbf.4098] [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: 05/25/2024] [Revised: 07/03/2024] [Accepted: 07/10/2024] [Indexed: 07/23/2024]
Abstract
Hepatocellular carcinoma (HCC) presents a considerable global health burden due to its late diagnosis and high morbidity. The liver's specific anatomical and physiological features expose it to various antigens, requiring precise immune regulation. To the best of our knowledge, this is the first time that a comprehensive overview of the interactions between the immune system and gut microbiota in the development of HCC, as well as the relevant therapeutic approaches are discussed. Dysregulation of immune compartments within the liver microenvironment drives HCC pathogenesis, characterized by elevated regulatory cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells, and M2 macrophages as well as suppressive molecules, alongside reduced number of effector cells like T cells, natural killer cells, and M1 macrophages. Dysbiosis of gut microbiota also contributes to HCC by disrupting intestinal barrier integrity and triggering overactivated immune responses. Immunotherapy approaches, particularly immune checkpoint inhibitors, have exhibited promise in HCC management, yet adoptive cell therapy and cancer vaccination research are in the early steps with relatively less favorable outcomes. Further understanding of immune dysregulation, gut microbiota involvement, and therapeutic combination strategies are essential for advancing precision immunotherapy in HCC.
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Affiliation(s)
- Atieh Pourbagheri-Sigaroodi
- Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Momeny
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Fallah
- Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Zarlashat Y, Mushtaq H, Pham L, Abbas W, Sato K. Advancements in Immunotherapeutic Treatments for Hepatocellular Carcinoma: Potential of Combination Therapies. Int J Mol Sci 2024; 25:6830. [PMID: 38999940 PMCID: PMC11241106 DOI: 10.3390/ijms25136830] [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: 05/25/2024] [Revised: 06/16/2024] [Accepted: 06/17/2024] [Indexed: 07/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a significant global health burden, with increasing incidence rates and limited treatment options. Immunotherapy has become a promising approach due to its ability to affect the immune microenvironment and promote antitumor responses. The immune microenvironment performs an essential role in both the progression and the development of HCC, with different characteristics based on specific immune cells and etiological factors. Immune checkpoint inhibitors, including programmed death-1/programmed death-ligand 1 inhibitors (pembrolizumab, nivolumab, and durvalumab) and cytotoxic T lymphocyte antigen-4 inhibitors (tremelimumab and ipilimumab), have the potential to treat advanced HCC and overcome adverse effects, such as liver failure and chemoresistance. Phase II and phase III clinical trials highlight the efficacy of pembrolizumab and nivolumab, respectively, in advanced HCC patients, as demonstrated by their positive effects on overall survival and progression-free survival. Tremelimumab has exhibited modest response rates, though it does possess antiviral activity. Thus, it is still being investigated in ongoing clinical trials. Combination therapies with multiple drugs have demonstrated potential benefits in terms of survival and tumor response rates, improving patient outcomes compared to monotherapy, especially for advanced-stage HCC. This review addresses the clinical trials of immunotherapies for early-, intermediate-, and advanced-stage HCC. Additionally, it highlights how combination therapy can significantly enhance overall survival, progression-free survival, and objective response rate in advanced-stage HCC, where treatment options are limited.
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Affiliation(s)
- Yusra Zarlashat
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Hassan Mushtaq
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering-C (NIBGE), Faisalabad 38000, Pakistan
- Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 45650, Pakistan
| | - Linh Pham
- Department of Science and Mathematics, Texas A&M University-Central Texas, Killeen, TX 76549, USA
| | - Wasim Abbas
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering-C (NIBGE), Faisalabad 38000, Pakistan
- Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 45650, Pakistan
| | - Keisaku Sato
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Rahman MM, Grice ID, Ulett GC, Wei MQ. Advances in Bacterial Lysate Immunotherapy for Infectious Diseases and Cancer. J Immunol Res 2024; 2024:4312908. [PMID: 38962577 PMCID: PMC11221958 DOI: 10.1155/2024/4312908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 04/22/2024] [Accepted: 04/26/2024] [Indexed: 07/05/2024] Open
Abstract
Antigenic cell fragments, pathogen-associated molecular patterns, and other immunostimulants in bacterial lysates or extracts may induce local and systemic immune responses in specific and nonspecific paradigms. Based on current knowledge, this review aimed to determine whether bacterial lysate has comparable functions in infectious diseases and cancer treatment. In infectious diseases, including respiratory and urinary tract infections, immune system activation by bacterial lysate can identify and combat pathogens. Commercially available bacterial lysates, including OM-85, Ismigen, Lantigen B, and LW 50020, were effective in children and adults in treating respiratory tract infections, chronic obstructive pulmonary disease, rhinitis, and rhinosinusitis with varying degrees of success. Moreover, OM-89, Uromune, Urovac, Urivac, and ExPEC4V showed therapeutic benefits in controlling urinary tract infections in adults, especially women. Bacterial lysate-based therapeutics are safe, well-tolerated, and have few side effects, making them a good alternative for infectious disease management. Furthermore, a nonspecific immunomodulation by bacterial lysates may stimulate innate immunity, benefiting cancer treatment. "Coley's vaccine" has been used to treat sarcomas, carcinomas, lymphomas, melanomas, and myelomas with varying outcomes. Later, several similar bacterial lysate-based therapeutics have been developed to treat cancers, including bladder cancer, non-small cell lung cancer, and myeloma; among them, BCG for in situ bladder cancer is well-known. Proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, may activate bacterial antigen-specific adaptive responses that could restore tumor antigen recognition and response by tumor-specific type 1 helper cells and cytotoxic T cells; therefore, bacterial lysates are worth investigating as a vaccination adjuvants or add-on therapies for several cancers.
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Affiliation(s)
- Md. Mijanur Rahman
- School of Pharmacy and Medical SciencesGriffith University, Gold Coast 4222, QLD, Australia
- Menzies Health Institute QueenslandGriffith University, Gold Coast 4222, QLD, Australia
| | - I. Darren Grice
- School of Pharmacy and Medical SciencesGriffith University, Gold Coast 4222, QLD, Australia
- Institute for GlycomicsGriffith University, Gold Coast 4222, QLD, Australia
| | - Glen C. Ulett
- School of Pharmacy and Medical SciencesGriffith University, Gold Coast 4222, QLD, Australia
- Menzies Health Institute QueenslandGriffith University, Gold Coast 4222, QLD, Australia
| | - Ming Q. Wei
- School of Pharmacy and Medical SciencesGriffith University, Gold Coast 4222, QLD, Australia
- Menzies Health Institute QueenslandGriffith University, Gold Coast 4222, QLD, Australia
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10
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Heumann P, Albert A, Gülow K, Tümen D, Müller M, Kandulski A. Insights in Molecular Therapies for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1831. [PMID: 38791911 PMCID: PMC11120383 DOI: 10.3390/cancers16101831] [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: 04/03/2024] [Revised: 05/03/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
We conducted a comprehensive review of the current literature of published data and clinical trials (MEDLINE), as well as published congress contributions and active recruiting clinical trials on targeted therapies in hepatocellular carcinoma. Combinations of different agents and medical therapy along with radiological interventions were analyzed for the setting of advanced HCC. Those settings were also analyzed in combination with adjuvant situations after resection or radiological treatments. We summarized the current knowledge for each therapeutic setting and combination that currently is or has been under clinical evaluation. We further discuss the results in the background of current treatment guidelines. In addition, we review the pathophysiological mechanisms and pathways for each of these investigated targets and drugs to further elucidate the molecular background and underlying mechanisms of action. Established and recommended targeted treatment options that already exist for patients are considered for systemic treatment: atezolizumab/bevacizumab, durvalumab/tremelimumab, sorafenib, lenvatinib, cabozantinib, regorafenib, and ramucirumab. Combination treatment for systemic treatment and local ablative treatment or transarterial chemoembolization and adjuvant and neoadjuvant treatment strategies are under clinical investigation.
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Affiliation(s)
- Philipp Heumann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
| | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
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11
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Ali FEM, Ibrahim IM, Althagafy HS, Hassanein EHM. Role of immunotherapies and stem cell therapy in the management of liver cancer: A comprehensive review. Int Immunopharmacol 2024; 132:112011. [PMID: 38581991 DOI: 10.1016/j.intimp.2024.112011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/08/2024]
Abstract
Liver cancer (LC) is the sixth most common disease and the third most common cause of cancer-related mortality. The WHO predicts that more than 1 million deaths will occur from LC by 2030. Hepatocellular carcinoma (HCC) is a common form of primary LC. Today, the management of LC involves multiple disciplines, and multimodal therapy is typically selected on an individual basis, considering the intricate interactions between the patient's overall health, the stage of the tumor, and the degree of underlying liver disease. Currently, the treatment of cancers, including LC, has undergone a paradigm shift in the last ten years because of immuno-oncology. To treat HCC, immune therapy approaches have been developed to enhance or cause the body's natural immune response to specifically target tumor cells. In this context, immune checkpoint pathway inhibitors, engineered cytokines, adoptive cell therapy, immune cells modified with chimeric antigen receptors, and therapeutic cancer vaccines have advanced to clinical trials and offered new hope to cancer patients. The outcomes of these treatments are encouraging. Additionally, treatment using stem cells is a new approach for restoring deteriorated tissues because of their strong differentiation potential and capacity to release cytokines that encourage cell division and the formation of blood vessels. Although there is no proof that stem cell therapy works for many types of cancer, preclinical research on stem cells has shown promise in treating HCC. This review provides a recent update regarding the impact of immunotherapy and stem cells in HCC and promising outcomes.
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Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt; Michael Sayegh, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan.
| | - Islam M Ibrahim
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Hanan S Althagafy
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt
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12
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Hsu CY, Mustafa MA, Kumar A, Pramanik A, Sharma R, Mohammed F, Jawad IA, Mohammed IJ, Alshahrani MY, Ali Khalil NAM, Shnishil AT, Abosaoda MK. Exploiting the immune system in hepatic tumor targeting: Unleashing the potential of drugs, natural products, and nanoparticles. Pathol Res Pract 2024; 256:155266. [PMID: 38554489 DOI: 10.1016/j.prp.2024.155266] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/05/2024] [Accepted: 03/15/2024] [Indexed: 04/01/2024]
Abstract
Hepatic tumors present a formidable challenge in cancer therapeutics, necessitating the exploration of novel treatment strategies. In recent years, targeting the immune system has attracted interest to augment existing therapeutic efficacy. The immune system in hepatic tumors includes numerous cells with diverse actions. CD8+ T lymphocytes, T helper 1 (Th1) CD4+ T lymphocytes, alternative M1 macrophages, and natural killer (NK) cells provide the antitumor immunity. However, Foxp3+ regulatory CD4+ T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) are the key immune inhibitor cells. Tumor stroma can also affect these interactions. Targeting these cells and their secreted molecules is intriguing for eliminating malignant cells. The current review provides a synopsis of the immune system components involved in hepatic tumor expansion and highlights the molecular and cellular pathways that can be targeted for therapeutic intervention. It also overviews the diverse range of drugs, natural products, immunotherapy drugs, and nanoparticles that have been investigated to manipulate immune responses and bolster antitumor immunity. The review also addresses the potential advantages and challenges associated with these approaches.
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Affiliation(s)
- Chou-Yi Hsu
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan
| | | | - Ashwani Kumar
- Department of Life Sciences, School of Sciences, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Pharmacy, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Atreyi Pramanik
- Institute of Pharma Sciences and Research, Chandigarh University, Mohali, India
| | - Rajiv Sharma
- Institute of Pharma Sciences and Research, Chandigarh University, Mohali, India
| | - Faraj Mohammed
- Department of Pharmacy, Al-Manara College for Medical Sciences, Maysan, Iraq
| | | | - Imad Jasim Mohammed
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia.
| | | | | | - Munther Kadhim Abosaoda
- College of technical engineering, the Islamic University, Najaf, Iraq; College of technical engineering, the Islamic University of Al Diwaniyah, Iraq; College of technical engineering, the Islamic University of Babylon, Iraq
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13
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Chen Y, Zhang Y, Wang J, Cai X, Chen J, Min X, Xu Y, Qin Q, Wan C. Drug-Loaded Tumor-Derived Microparticles Elicit CD8+ T Cell-Mediated Anti-Tumor Response in Hepatocellular Carcinoma. Int J Nanomedicine 2024; 19:2227-2239. [PMID: 38465206 PMCID: PMC10924763 DOI: 10.2147/ijn.s449694] [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] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 02/14/2024] [Indexed: 03/12/2024] Open
Abstract
Background Hepatocellular Carcinoma (HCC) poses significant challenges due to limited effective treatments and high recurrence rates. Immunotherapy, a promising approach, faces obstacles in HCC patients due to T-cell exhaustion and immunosuppression within the tumor microenvironment. Methods Using doxorubicin-loaded tumor-derived microparticles (Dox-TMPs), the mice with H22 ascites model and subcutaneous tumors model were treated. Following the treatment, mice were re-challenged with H22 cells to compare the therapeutic effects and recurrence among different groups of mice, alongside examining the changes in the proportions of immune cells within the tumor microenvironment. Furthermore, Dox-TMPs were combined with anti-PD-1 to further validate their anti-tumor efficacy. In vitro studies using various liver cancer cell lines were conducted to verify the tumor-killing effects of Dox-TMPs. Additionally, CD8+ T cells from the abdominal cavity of tumor-free mice were co-cultured with H22 cells to confirm their specific tumor-killing abilities. Results Dox-TMPs demonstrate effective anti-tumor effects both in vitro and in vivo. In vivo, their effectiveness primarily involves enhancing CD8+ T cell infiltration, alleviating T cell immunosuppression, and improving the immune microenvironment to combat tumors. When used in combination with anti-PD-1, their anti-tumor effects are further enhanced. Moreover, some mice treated with Dox-TMPs developed anti-tumor immunity, displaying a self-specific T-cell immune response upon re-challenged with tumor cells. This suggests that Dox-TMPs also have the potential to act as a long-term immune response against tumor recurrence, indicating their capability as a tumor vaccine. Conclusion Dox-TMPs exhibit a dual role in liver cancer by regulating T cells within the tumor microenvironment, functioning both as an anti-tumor agent and a potential tumor vaccine.
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Affiliation(s)
- Yulin Chen
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Yi Zhang
- Hubei Engineering Research Center of Tumor-Targeted Biochemotherapy, Wuhan, 430030, People’s Republic of China
| | - Jianjun Wang
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People’s Republic of China
| | - Xiong Cai
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Junzhang Chen
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Xiaobo Min
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Yunjie Xu
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Qi Qin
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Chidan Wan
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
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14
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Zhang C, Qin C, Dewanjee S, Bhattacharya H, Chakraborty P, Jha NK, Gangopadhyay M, Jha SK, Liu Q. Tumor-derived small extracellular vesicles in cancer invasion and metastasis: molecular mechanisms, and clinical significance. Mol Cancer 2024; 23:18. [PMID: 38243280 PMCID: PMC10797874 DOI: 10.1186/s12943-024-01932-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 01/02/2024] [Indexed: 01/21/2024] Open
Abstract
The production and release of tumor-derived small extracellular vesicles (TDSEVs) from cancerous cells play a pivotal role in the propagation of cancer, through genetic and biological communication with healthy cells. TDSEVs are known to orchestrate the invasion-metastasis cascade via diverse pathways. Regulation of early metastasis processes, pre-metastatic niche formation, immune system regulation, angiogenesis initiation, extracellular matrix (ECM) remodeling, immune modulation, and epithelial-mesenchymal transition (EMT) are among the pathways regulated by TDSEVs. MicroRNAs (miRs) carried within TDSEVs play a pivotal role as a double-edged sword and can either promote metastasis or inhibit cancer progression. TDSEVs can serve as excellent markers for early detection of tumors, and tumor metastases. From a therapeutic point of view, the risk of cancer metastasis may be reduced by limiting the production of TDSEVs from tumor cells. On the other hand, TDSEVs represent a promising approach for in vivo delivery of therapeutic cargo to tumor cells. The present review article discusses the recent developments and the current views of TDSEVs in the field of cancer research and clinical applications.
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Affiliation(s)
- Chi Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Institute of Skull Base Surgery and Neuro-Oncology at Hunan Province, Changsha, 410008, China
| | - Chaoying Qin
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Institute of Skull Base Surgery and Neuro-Oncology at Hunan Province, Changsha, 410008, China
| | - Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, West Bengal, India.
| | - Hiranmoy Bhattacharya
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, West Bengal, India
| | - Pratik Chakraborty
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, West Bengal, India
| | - Niraj Kumar Jha
- Centre of Research Impact and Outreach, Chitkara University Institute of Engineering and Technology, Chitkara University, Punjab, India
- Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India
| | - Moumita Gangopadhyay
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Barasat, Kolkata, 700126, West Bengal, India
| | - Saurabh Kumar Jha
- Department of Zoology, Kalindi College, University of Delhi, New Delhi, Delhi, 110008, India.
| | - Qing Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
- The Institute of Skull Base Surgery and Neuro-Oncology at Hunan Province, Changsha, 410008, China.
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15
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Abdelhamed W, El-Kassas M. Hepatocellular carcinoma recurrence: Predictors and management. LIVER RESEARCH (BEIJING, CHINA) 2023; 7:321-332. [PMID: 39958776 PMCID: PMC11791921 DOI: 10.1016/j.livres.2023.11.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 09/14/2023] [Accepted: 11/17/2023] [Indexed: 02/18/2025]
Abstract
Hepatocellular carcinoma (HCC), the sixth most common cancer globally, is associated with high mortality rates and more than 830,000 annual deaths. Despite advances in the available management options including surgical resection and local ablative therapies, recurrence rates after the initial treatment exceed 50%, even among patients who have undergone curative-intent therapy. Moreover, postsurgical HCC recurrence occurs in about 70% of cases five years postoperatively. The management of recurrent HCC remains undefined. This review discusses different predictors for HCC recurrence after each treatment modality and different approaches available to stratify these patients. More specific guidelines for managing HCC recurrence and strict surveillance protocols for such recurrence after initial HCC management are needed.
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Affiliation(s)
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
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16
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Sadeghlar F, Seelemann J, Vogt A, Möhring C, Zhou T, Mahn R, Kornek M, Lukacs-Kornek V, Casares N, Lasarte JJ, Sarobe P, van Beekum C, Matthaei H, Manekeller S, Kalff J, Schmidt-Wolf IGH, Strassburg CP, Gonzalez-Carmona MA. Regulatory T Cell Inhibition by P60 Combined with Adenoviral AFP Transduced Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma. Immunol Invest 2023; 52:966-984. [PMID: 37846958 DOI: 10.1080/08820139.2023.2261980] [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: 10/18/2023]
Abstract
BACKGROUND & AIMS Vaccination with tumor-associated antigen-pulsed dendritic cells leads to specific T-cell response against hepatocellular carcinoma. However, clinical response has been shown to be limited. High regulatory T-cell count is associated with poor prognosis and seems to mediate immune tolerance in hepatocellular carcinoma. Forkhead box P3-peptide inhibitor P60 has been shown to specifically inhibit regulatory T-cell function in murine models. Aim of this study was to investigate whether P60 can improve the immune response induced by vaccination with adenovirus-transduced dendritic cells expressing alpha-fetoprotein in subcutaneous and orthotopic murine models for hepatocellular carcinoma. METHODS Mice developing subcutaneous or orthotopic HCC received daily treatment with P60 starting at different tumor stages. Additionally, mice were vaccinated twice with dendritic cells expressing alpha-fetoprotein. RESULTS In a preventive setting prior to tumor engraftment, vaccination with alpha-fetoprotein-expressing dendritic cells significantly decreased tumor growth in a subcutaneous model (p = .0256), but no further effects were achieved by addition of P60. However, P60 enhanced the antitumoral effect of a vaccination with alpha-fetoprotein-expressing dendritic cells in established subcutaneous and orthotopic hepatocellular carcinoma characterized by high Treg levels (p = .011). CONCLUSION In this study, we showed that vaccination with alpha-fetoprotein-expressing dendritic cells in combination with a specific inhibition of regulatory T-cells by using P60 leads to synergistic tumor inhibition and prolonged survival. This emphasizes the importance of regulatory T-cells inhibition for obtaining an effective antitumoral immune response in hepatocellular carcinoma.
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Affiliation(s)
| | - Julia Seelemann
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Annabelle Vogt
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Christian Möhring
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Taotao Zhou
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Robert Mahn
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Miroslaw Kornek
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Veronika Lukacs-Kornek
- Institute for Molecular Medicine and Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Noelia Casares
- Program of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Juan José Lasarte
- Program of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Pablo Sarobe
- Program of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Cornelius van Beekum
- Program of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Hanno Matthaei
- Department of Visceral Surgery, University Hospital of Bonn, Bonn, Germany
| | - Steffen Manekeller
- Department of Visceral Surgery, University Hospital of Bonn, Bonn, Germany
| | - Jörg Kalff
- Department of Visceral Surgery, University Hospital of Bonn, Bonn, Germany
| | - Ingo G H Schmidt-Wolf
- Department of Medicine I, University Hospital of Bonn, Bonn, Germany
- Department of Integrated Oncology (CIO), University Hospital of Bonn, Bonn, Germany
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17
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Wang L, Piao Y, Guo F, Wei J, Chen Y, Dai X, Zhang X. Current progress of pig models for liver cancer research. Biomed Pharmacother 2023; 165:115256. [PMID: 37536038 DOI: 10.1016/j.biopha.2023.115256] [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: 05/17/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/05/2023] Open
Abstract
Preclinical trials play critical roles in assessing the safety and efficiency of novel therapeutic strategies for human diseases including live cancer. However, most therapeutic strategies that were proved to be effective in preclinical cancer models failed in human clinical trials due to the lack of appropriate disease animal models. Therefore, it is of importance and urgent to develop a precise animal model for preclinical cancer research. Liver cancer is one of the most frequently diagnosed cancers with low 5-year survival rate. Recently, porcine attracted increasing attentions as animal model in biomedical research. Porcine liver cancer model may provide a promising platform for biomedical research due to their similarities to human being in body size, anatomical characteristics, physiology and pathophysiology. In this review, we comprehensively summarized and discussed the advantages and disadvantages, rationale, current status and progress of pig models for liver cancer research.
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Affiliation(s)
- Luyao Wang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Yuexian Piao
- Invasive Technology Nursing Platform, First Hospital of Jilin University, Changchun, China
| | - Fucheng Guo
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Jiarui Wei
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Yurong Chen
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Xiangpeng Dai
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China.
| | - Xiaoling Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China.
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18
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Kaczmarek M, Poznańska J, Fechner F, Michalska N, Paszkowska S, Napierała A, Mackiewicz A. Cancer Vaccine Therapeutics: Limitations and Effectiveness-A Literature Review. Cells 2023; 12:2159. [PMID: 37681891 PMCID: PMC10486481 DOI: 10.3390/cells12172159] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/12/2023] [Accepted: 08/18/2023] [Indexed: 09/09/2023] Open
Abstract
In recent years, there has been a surge of interest in tumor microenvironment-associated cancer vaccine therapies. These innovative treatments aim to activate and enhance the body's natural immune response against cancer cells by utilizing specific antigens present in the tumor microenvironment. The goal is to achieve a complete clinical response, where all measurable cancer cells are either eliminated or greatly reduced in size. With their potential to revolutionize cancer treatment, these therapies represent a promising avenue for researchers and clinicians alike. Despite over 100 years of research, the success of therapeutic cancer vaccines has been variable, particularly in advanced cancer patients, with various limitations, including the heterogeneity of the tumor microenvironment, the presence of immunosuppressive cells, and the potential for tumor escape mechanisms. Additionally, the effectiveness of these therapies may be limited by the variability of the patient's immune system response and the difficulty in identifying appropriate antigens for each patient. Despite these challenges, tumor microenvironment-targeted vaccine cancer therapies have shown promising results in preclinical and clinical studies and have the potential to become a valuable addition to current cancer treatment and "curative" options. While chemotherapeutic and monoclonal antibody treatments remain popular, ongoing research is needed to optimize the design and delivery of these therapies and to identify biomarkers that can predict response and guide patient selection. This comprehensive review explores the mechanisms of cancer vaccines, various delivery methods, and the role of adjuvants in improving treatment outcomes. It also discusses the historical background of cancer vaccine research and examines the current state of major cancer vaccination immunotherapies. Furthermore, the limitations and effectiveness of each vaccine type are analyzed, providing insights into the future of cancer vaccine development.
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Affiliation(s)
- Mariusz Kaczmarek
- Department of Medical Biotechnology, Poznan University of Medical Sciences, 61-866 Poznań, Poland
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, 61-866 Poznań, Poland
| | - Justyna Poznańska
- Scientific Society of Cancer Immunology, Poznań University of Medical Sciences, 61-866 Poznań, Poland; (J.P.)
| | - Filip Fechner
- Scientific Society of Cancer Immunology, Poznań University of Medical Sciences, 61-866 Poznań, Poland; (J.P.)
| | - Natasza Michalska
- Scientific Society of Cancer Immunology, Poznań University of Medical Sciences, 61-866 Poznań, Poland; (J.P.)
| | - Sara Paszkowska
- Scientific Society of Cancer Immunology, Poznań University of Medical Sciences, 61-866 Poznań, Poland; (J.P.)
| | - Adrianna Napierała
- Scientific Society of Cancer Immunology, Poznań University of Medical Sciences, 61-866 Poznań, Poland; (J.P.)
| | - Andrzej Mackiewicz
- Department of Medical Biotechnology, Poznan University of Medical Sciences, 61-866 Poznań, Poland
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, 61-866 Poznań, Poland
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19
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Tojjari A, Saeed A, Singh M, Cavalcante L, Sahin IH, Saeed A. A Comprehensive Review on Cancer Vaccines and Vaccine Strategies in Hepatocellular Carcinoma. Vaccines (Basel) 2023; 11:1357. [PMID: 37631925 PMCID: PMC10459477 DOI: 10.3390/vaccines11081357] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/04/2023] [Accepted: 08/09/2023] [Indexed: 08/29/2023] Open
Abstract
HCC, the most prevalent form of primary liver cancer, presents a substantial global health challenge due to its high mortality and limited therapeutic options. This review delves into the potential of cancer vaccines as a novel therapeutic avenue for HCC. We examine the various categories of cancer vaccines, including peptide-based, dendritic cell-based, viral vector-based, DNA, and mRNA vaccines, and their potential application in HCC management. This review also addresses the inherent challenges in vaccine development, such as tumor heterogeneity and the need for identifying tumor-specific antigens. We underscore the role of cancer vaccines in reshaping the immune environment within HCC, fostering durable immune memory, and their potential in combination therapies. The review also evaluates clinical trials and emphasizes the necessity for more extensive research to optimize vaccine design and patient selection criteria. We conclude with future perspectives, highlighting the significance of personalized therapies, innovative antigen delivery platforms, immune modulatory agents, and predictive biomarkers in revolutionizing HCC treatment. Simple Summary: This review explores the potential of cancer vaccines as a promising therapeutic strategy for hepatocellular carcinoma (HCC), a prevalent and deadly liver cancer. The authors discuss various types of cancer vaccines, their challenges, and their role in modulating the immune response within HCC. They also highlight clinical trials and future perspectives, emphasizing the importance of personalized therapies, novel antigen delivery platforms, and predictive biomarkers. The findings from this research could significantly impact the research community by providing a comprehensive understanding of the current state of cancer vaccines for HCC, thereby guiding future research and potentially transforming HCC treatment strategies.
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Affiliation(s)
- Alireza Tojjari
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15213, USA; (A.T.); (M.S.); (I.H.S.)
| | - Ahmed Saeed
- Sarah Cannon Cancer Institute, HCA Midwest Health, Kansas City, MO 64131, USA;
| | - Meghana Singh
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15213, USA; (A.T.); (M.S.); (I.H.S.)
| | | | - Ibrahim Halil Sahin
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15213, USA; (A.T.); (M.S.); (I.H.S.)
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15213, USA; (A.T.); (M.S.); (I.H.S.)
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
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20
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Guerra P, Martini A, Pontisso P, Angeli P. Novel Molecular Targets for Immune Surveillance of Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:3629. [PMID: 37509293 PMCID: PMC10377787 DOI: 10.3390/cancers15143629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/06/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common and aggressive cancer with a high mortality rate. The incidence of HCC is increasing worldwide, and the lack of effective screening programs often results in delayed diagnosis, making it a challenging disease to manage. Immunotherapy has emerged as a promising treatment option for different kinds of cancers, with the potential to stimulate the immune system to target cancer cells. However, the current immunotherapeutic approaches for HCC have shown limited efficacy. Since HCC arises within a complex tumour microenvironment (TME) characterized by the presence of various immune and stromal cell types, the understanding of this interaction is crucial for the identification of effective therapy. In this review, we highlight recent advances in our understanding of the TME of HCC and the immune cells involved in anti-tumour responses, including the identification of new possible targets for immunotherapy. We illustrate a possible classification of HCC based on the tumour immune infiltration and give evidence about the role of SerpinB3, a serine protease inhibitor involved in the regulation of the immune response in different cancers.
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Affiliation(s)
- Pietro Guerra
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Andrea Martini
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Patrizia Pontisso
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
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21
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Shen C, Li M, Duan Y, Jiang X, Hou X, Xue F, Zhang Y, Luo Y. HDAC inhibitors enhance the anti-tumor effect of immunotherapies in hepatocellular carcinoma. Front Immunol 2023; 14:1170207. [PMID: 37304265 PMCID: PMC10250615 DOI: 10.3389/fimmu.2023.1170207] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/18/2023] [Indexed: 06/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common liver malignancy with a poor prognosis and increasing incidence, remains a serious health problem worldwide. Immunotherapy has been described as one of the ideal ways to treat HCC and is transforming patient management. However, the occurrence of immunotherapy resistance still prevents some patients from benefiting from current immunotherapies. Recent studies have shown that histone deacetylase inhibitors (HDACis) can enhance the efficacy of immunotherapy in a variety of tumors, including HCC. In this review, we present current knowledge and recent advances in immunotherapy-based and HDACi-based therapies for HCC. We highlight the fundamental dynamics of synergies between immunotherapies and HDACis, further detailing current efforts to translate this knowledge into clinical benefits. In addition, we explored the possibility of nano-based drug delivery system (NDDS) as a novel strategy to enhance HCC treatment.
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Affiliation(s)
- Chen Shen
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Mei Li
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yujuan Duan
- School of Chemical Science and Engineering, Tongji University, Shanghai, China
- School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xin Jiang
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoming Hou
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Fulai Xue
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yinan Zhang
- School of Chemical Science and Engineering, Tongji University, Shanghai, China
| | - Yao Luo
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
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22
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Donne R, Lujambio A. The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology 2023; 77:1773-1796. [PMID: 35989535 PMCID: PMC9941399 DOI: 10.1002/hep.32740] [Citation(s) in RCA: 297] [Impact Index Per Article: 148.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 07/26/2022] [Accepted: 08/18/2022] [Indexed: 12/19/2022]
Abstract
The liver is the sixth most common site of primary cancer in humans and the fourth leading cause of cancer-related death in the world. Hepatocellular carcinoma (HCC) accounts for 90% of liver cancers. HCC is a prevalent disease with a progression that is modulated by the immune system. Half of the patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib, as a first-line therapy. In the last few years, immune-checkpoint inhibitors (ICIs) have revolutionized cancer therapy and have gained an increased interest in the treatment of HCC. In 2020, the combination of atezolizumab (anti-programmed death-ligand 1) and bevacizumab (anti-vascular endothelial growth factor) improved overall survival over sorafenib, resulting in Food and Drug Administration (FDA) approval as a first-line treatment for patients with advanced HCC. Despite these major advances, a better molecular and cellular characterization of the tumor microenvironment is still needed because it has a crucial role in the development and progression of HCC. Inflamed (hot) and noninflamed (cold) HCC tumors and genomic signatures have been associated with response to ICIs. However, there are no additional biomarkers to guide clinical decision-making. Other immune-targeting strategies, such as adoptive T-cell transfer, vaccination, and virotherapy, are currently under development. This review provides an overview on the HCC immune microenvironment, different cellular players, current available immunotherapies, and potential immunotherapy modalities.
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Affiliation(s)
- Romain Donne
- Department of Oncological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai , Tisch Cancer Institute , New York , New York , USA
- Icahn School of Medicine at Mount Sinai , The Precision Immunology Institute , New York , New York , USA
| | - Amaia Lujambio
- Department of Oncological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai , Tisch Cancer Institute , New York , New York , USA
- Icahn School of Medicine at Mount Sinai , The Precision Immunology Institute , New York , New York , USA
- Graduate School of Biomedical Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
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23
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Luo YZ, Zhu H. Immunotherapy for advanced or recurrent hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:405-424. [PMID: 37009314 PMCID: PMC10052663 DOI: 10.4251/wjgo.v15.i3.405] [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: 09/18/2022] [Revised: 02/11/2023] [Accepted: 02/28/2023] [Indexed: 03/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is associated with high morbidity and mortality, and is prone to intra- and extrahepatic metastasis due to the anatomical and functional characteristics of the liver. Due to the complexity and high relapse rate associated with radical surgery or radiofrequency ablation, immune checkpoint inhibitors (ICIs) are increasingly being used to treat HCC. Several immunotherapeutic agents, along with their combinations, have been clinically approved to treat advanced or recurrent HCC. This review discusses the leading ICIs in practice and those currently undergoing randomized phase 1–3 trials as monotherapy or combination therapy. Furthermore, we summarize the rapidly developing alternative strategies such as chimeric antigen receptor-engineered T cell therapy and tumor vaccines. Combination therapy is a promising potential treatment option. These immunotherapies are also summarized in this review, which provides insights into the advantages, limitations, and novel angles for future research in establishing viable and alternative therapies against HCC.
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Affiliation(s)
- Ying-Zhe Luo
- Department of Medical Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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24
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Hu X, Zhu H, He X, Chen J, Xiong L, Shen Y, Li J, Xu Y, Chen W, Liu X, Cao D, Xu X. The application of nanoparticles in immunotherapy for hepatocellular carcinoma. J Control Release 2023; 355:85-108. [PMID: 36708880 DOI: 10.1016/j.jconrel.2023.01.051] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 01/30/2023]
Abstract
Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths worldwide, however, current clinical diagnostic and treatment approaches remain relatively limited, creating an urgent need for the development of effective technologies. Immunotherapy has emerged as a powerful treatment strategy for advanced cancer. The number of clinically approved drugs for HCC immunotherapy has been increasing. However, it remains challenging to improve their transport and therapeutic efficiency, control their targeting and release, and mitigate their adverse effects. Nanotechnology has recently gained attention for improving the effectiveness of precision therapy for HCC. We summarize the key features of HCC associated with nanoparticle (NPs) targeting, release, and uptake, the roles and limitations of several major immunotherapies in HCC, the use of NPs in immunotherapy, the properties of NPs that influence their design and application, and current clinical trials of NPs in HCC, with the aim of informing the design of delivery platforms that have the potential to improve the safety and efficacy of HCC immunotherapy，and thus, ultimately improve the prognosis of HCC patients.
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Affiliation(s)
- Xinyao Hu
- Cancer center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Hua Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Xiaoqin He
- Cancer center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jiayu Chen
- Cancer center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Lin Xiong
- Cancer center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yang Shen
- Cancer center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jiayi Li
- Cancer center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yangtao Xu
- Cancer center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Wenliang Chen
- Cancer center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Xin Liu
- Cancer center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Dedong Cao
- Cancer center, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Ximing Xu
- Cancer center, Renmin Hospital of Wuhan University, Wuhan 430060, China.
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25
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Minaei N, Ramezankhani R, Tamimi A, Piryaei A, Zarrabi A, Aref AR, Mostafavi E, Vosough M. Immunotherapeutic approaches in Hepatocellular carcinoma: Building blocks of hope in near future. Eur J Cell Biol 2023; 102:151284. [PMID: 36584598 DOI: 10.1016/j.ejcb.2022.151284] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/30/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary hepatic cancer and is among the major causes of mortality due to cancer. Due to the lack of efficient conventional therapeutic options for this cancer, particularly in advanced cases, novel treatments including immunotherapy have been considered. However, despite the encouraging clinical outcomes after implementing these innovative approaches, such as oncolytic viruses (OVs), adoptive cell therapies (ACT), immune checkpoint blockades (ICBs), and cancer vaccines, several factors have restricted their therapeutic effect. The main concern is the existence of an immunosuppressive tumor microenvironment (TME). Combination of different ICBs or ICBs plus tyrosine kinase inhibitors have shown promising results in overcoming these limiting factors to some extent. Combination of programmed cell death ligand-1 (PD-L1) antibody Atezolizumab and vascular endothelial growth factor (VEGF) antibody Bevacizumab has become the standard of care in the first-line therapy for untestable HCC, approved by regulatory agencies. This paper highlighted a wide overview of the direct and indirect immunotherapeutic strategies proposed for the treatment of HCC patients and the common challenges that have hindered their further clinical applications.
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Affiliation(s)
- Neda Minaei
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Roya Ramezankhani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Development and Regeneration, KU Leuven Stem Cell Institute, Leuven, Belgium
| | - Atena Tamimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital-Huddinge, Sweden.
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26
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Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2023; 29:1054-1075. [PMID: 36844141 PMCID: PMC9950866 DOI: 10.3748/wjg.v29.i6.1054] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/23/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the world’s deadliest and fastest-growing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery (liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying liver condition. Despite promising preclinical and early-phase clinical trials for some drugs, existing systemic therapeutic methods for advanced tumor stages remain limited, underlining an unmet clinical need. In current years, cancer immunotherapy has made significant progress, opening up new treatment options for HCC. HCC, on the other hand, has a variety of causes and can affects the body’s immune system via a variety of mechanisms. With the speedy advancement of synthetic biology and genetic engineering, a range of innovative immunotherapies, such as immune checkpoint inhibitors [anti-programmed cell death-1 (PD-1), anti-cytotoxic T lymphocyte antigen-4, and anti-PD ligand 1 cell death antibodies], therapeutic cancer vaccines, engineered cytokines, and adoptive cell therapy have all been used for the treatment of advanced HCC. In this review, we summarize the present clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent clinical trial outcomes, and address future perspectives in the field of liver cancer.
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Affiliation(s)
- Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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27
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Laface C, Ranieri G, Maselli FM, Ambrogio F, Foti C, Ammendola M, Laterza M, Cazzato G, Memeo R, Mastrandrea G, Lioce M, Fedele P. Immunotherapy and the Combination with Targeted Therapies for Advanced Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:654. [PMID: 36765612 PMCID: PMC9913568 DOI: 10.3390/cancers15030654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/11/2023] [Accepted: 01/17/2023] [Indexed: 01/24/2023] Open
Abstract
One of the most important abilities of a tumor is to establish a state of immunosuppression inside the tumor microenvironment. This is made possible through numerous mechanisms of tumor immune escape that have been identified in experimental studies during the last decades. In addition, the hepatic microenvironment is commonly oriented towards a state of immune tolerance because the liver receives blood from the hepatic arteries and portal veins containing a variety of endogenous antigens. Therefore, the hepatic microenvironment establishes an autoimmune tolerance, preventing an autoimmune reaction in the liver. On this basis, hepatic tumor cells may escape the immune system, avoiding being recognized and destroyed by immune cells. Moreover, since the etiology of Hepatocellular Carcinoma (HCC) is often related to cirrhosis, and hepatitis B or C, this tumor develops in the context of chronic inflammation. Thus, the HCC microenvironment is characterized by important immune cell infiltration. Given these data and the poor prognosis of advanced HCC, different immunotherapeutic strategies have been developed and evaluated for these patients. In this review, we describe all the clinical applications of immunotherapy for advanced HCC, from the drugs that have already been approved to the ongoing clinical trials.
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Affiliation(s)
- Carmelo Laface
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | | | | | - Francesca Ambrogio
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Caterina Foti
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Michele Ammendola
- Department of Health Science, General Surgery, Medicine School of Germaneto, Magna Graecia University, 88100 Catanzaro, Italy
| | - Marigia Laterza
- Division of Cardiac Surgery, University of Bari, 70124 Bari, Italy
| | - Gerardo Cazzato
- Department of Emergency and Organ Transplantation, Pathology Section, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Riccardo Memeo
- Unit of Hepato-Pancreatic-Biliary Surgery, “F. Miulli” General Regional Hospital, 70021 Acquaviva Delle Fonti, Italy
| | | | - Marco Lioce
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
| | - Palma Fedele
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
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28
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Basak M, Chaudhary DK, Takahashi RU, Yamamoto Y, Tiwari S, Tahara H, Mittal A. Immunocyte Derived Exosomes: Insight into the Potential Chemo-immunotherapeutic Nanocarrier Targeting the Tumor Microenvironment. ACS Biomater Sci Eng 2023; 9:20-39. [PMID: 36524837 DOI: 10.1021/acsbiomaterials.2c00893] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
"Cancer" is a dreadful immune-pathological condition that is characterized by anti-inflammatory and tumorigenic responses, elicited by the infiltrating immune cells in the vicinity of an uncontrollably proliferative tumor in the tumor microenvironment (TME). The TME offers a conducive microenvironment that supports cancer cell survival by modulating the host immune defense. Recent advancement in exosomal research has shown exosomes, originating from immune cells as well as the cancer cells, have immense potential for suppressing cancer progression and survival in the TME. Additionally, exosomes, irrespective of their diverse sources, have been reported to be efficient nanocarriers for cancer therapeutics with the ability for targeted delivery due to their biogenic nature, ease of cellular uptake, and scope for functionalization with biomolecules like peptides, aptamers, targeting ligands, etc. Immune cell-derived exosomes per se have been found efficacious against cancer owing to their immune-stimulant properties (in either naive or antigen primed form) even without loading any of cancer therapeutics or targeting ligand conjugation. Nevertheless, exosomes are being primarily explored as nanovesicular carriers for therapeutic molecules with different loading and targeting strategies, and the synergism between immunotherapeutic behavior of exosomes and the anticancer effect of the therapeutic molecules is yet to be explored. Hence, this review focuses specifically on the possible strategies to modulate the immunological nature of the source immune cells to obtain immune stimulant exosomes and bring these into the spotlight as chemo-immunotherapeutic nanovesicles, that can easily target and modulate the TME.
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Affiliation(s)
- Moumita Basak
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333031, India
| | - Dharmendra Kumar Chaudhary
- Molecular Medicine and Biotechnology Division, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India
| | - Ryou-U Takahashi
- Department of Cellular and Molecular Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Yuki Yamamoto
- Department of Cellular and Molecular Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Swasti Tiwari
- Molecular Medicine and Biotechnology Division, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India
| | - Hidetoshi Tahara
- Department of Cellular and Molecular Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Anupama Mittal
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333031, India.,Department of Cellular and Molecular Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
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29
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Makandar AI, Jain M, Yuba E, Sethi G, Gupta RK. Canvassing Prospects of Glyco-Nanovaccines for Developing Cross-Presentation Mediated Anti-Tumor Immunotherapy. Vaccines (Basel) 2022; 10:vaccines10122049. [PMID: 36560459 PMCID: PMC9784904 DOI: 10.3390/vaccines10122049] [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: 09/28/2022] [Revised: 11/18/2022] [Accepted: 11/22/2022] [Indexed: 12/02/2022] Open
Abstract
In view of the severe downsides of conventional cancer therapies, the quest of developing alternative strategies still remains of critical importance. In this regard, antigen cross-presentation, usually employed by dendritic cells (DCs), has been recognized as a potential solution to overcome the present impasse in anti-cancer therapeutic strategies. It has been established that an elevated cytotoxic T lymphocyte (CTL) response against cancer cells can be achieved by targeting receptors expressed on DCs with specific ligands. Glycans are known to serve as ligands for C-type lectin receptors (CLRs) expressed on DCs, and are also known to act as a tumor-associated antigen (TAA), and, thus, can be harnessed as a potential immunotherapeutic target. In this scenario, integrating the knowledge of cross-presentation and glycan-conjugated nanovaccines can help us to develop so called 'glyco-nanovaccines' (GNVs) for targeting DCs. Here, we briefly review and analyze the potential of GNVs as the next-generation anti-tumor immunotherapy. We have compared different antigen-presenting cells (APCs) for their ability to cross-present antigens and described the potential nanocarriers for tumor antigen cross-presentation. Further, we discuss the role of glycans in targeting of DCs, the immune response due to pathogens, and imitative approaches, along with parameters, strategies, and challenges involved in cross-presentation-based GNVs for cancer immunotherapy. It is known that the effectiveness of GNVs in eradicating tumors by inducing strong CTL response in the tumor microenvironment (TME) has been largely hindered by tumor glycosylation and the expression of different lectin receptors (such as galectins) by cancer cells. Tumor glycan signatures can be sensed by a variety of lectins expressed on immune cells and mediate the immune suppression which, in turn, facilitates immune evasion. Therefore, a sound understanding of the glycan language of cancer cells, and glycan-lectin interaction between the cancer cells and immune cells, would help in strategically designing the next-generation GNVs for anti-tumor immunotherapy.
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Affiliation(s)
- Amina I. Makandar
- Protein Biochemistry Research Centre, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, Maharashtra, India
| | - Mannat Jain
- Protein Biochemistry Research Centre, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, Maharashtra, India
| | - Eiji Yuba
- Department of Applied Chemistry, Graduate School of Engineering, Osaka Metropolitan University, 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Osaka, Japan
- Correspondence: (E.Y.); (G.S.); or (R.K.G.)
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- Correspondence: (E.Y.); (G.S.); or (R.K.G.)
| | - Rajesh Kumar Gupta
- Protein Biochemistry Research Centre, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, Maharashtra, India
- Correspondence: (E.Y.); (G.S.); or (R.K.G.)
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30
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Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W, Wang C. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2022; 20:203-222. [PMID: 36369487 DOI: 10.1038/s41575-022-00704-9] [Citation(s) in RCA: 362] [Impact Index Per Article: 120.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/13/2022] [Indexed: 11/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common solid malignancies worldwide. A large proportion of patients with HCC are diagnosed at advanced stages and are only amenable to systemic therapies. We have witnessed the evolution of systemic therapies from single-agent targeted therapy (sorafenib and lenvatinib) to the combination of a checkpoint inhibitor plus targeted therapy (atezolizumab plus bevacizumab therapy). Despite remarkable advances, only a small subset of patients can obtain durable clinical benefit, and therefore substantial therapeutic challenges remain. In the past few years, emerging systemic therapies, including new molecular-targeted monotherapies (for example, donafenib), new immuno-oncology monotherapies (for example, durvalumab) and new combination therapies (for example, durvalumab plus tremelimumab), have shown encouraging results in clinical trials. In addition, many novel therapeutic approaches with the potential to offer improved treatment effects in patients with advanced HCC, such as sequential combination targeted therapy and next-generation adoptive cell therapy, have also been proposed and developed. In this Review, we summarize the latest clinical advances in the treatment of advanced HCC and discuss future perspectives that might inform the development of more effective therapeutics for advanced HCC.
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Affiliation(s)
- Chen Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hailin Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Linmeng Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Boston, MA, USA. .,Jiahui International Cancer Center, Jiahui Health, Shanghai, China.
| | - René Bernards
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands.
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Cun Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Harkus U, Wankell M, Palamuthusingam P, McFarlane C, Hebbard L. Immune checkpoint inhibitors in HCC: Cellular, molecular and systemic data. Semin Cancer Biol 2022; 86:799-815. [PMID: 35065242 DOI: 10.1016/j.semcancer.2022.01.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/12/2022] [Accepted: 01/17/2022] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths in the world, and for patients with advanced disease there are few therapeutic options available. The complex immunological microenvironment of HCC and the success of immunotherapy in several types of tumours, has raised the prospect of potential benefit for immune based therapies, such as immune checkpoint inhibitors (ICIs), in HCC. This has led to significant breakthrough research, numerous clinical trials and the rapid approval of multiple systemic drugs for HCC by regulatory bodies worldwide. Although some patients responded well to ICIs, many have failed to achieve significant benefit, while others showed unexpected and paradoxical deterioration. The aim of this review is to discuss the pathophysiology of HCC, the tumour microenvironment, key clinical trials evaluating ICIs in HCC, various resistance mechanisms to ICIs, and possible ways to overcome these impediments to improve patient outcomes.
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Affiliation(s)
- Uasim Harkus
- Townsville University Hospital, Townsville, Queensland 4811, Australia
| | - Miriam Wankell
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia
| | - Pranavan Palamuthusingam
- College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia; Townsville University Hospital, Townsville, Queensland 4811, Australia; Mater Hospital, Townsville, Queensland 4811, Australia
| | - Craig McFarlane
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia
| | - Lionel Hebbard
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales 2145, Australia.
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Motamedi Dehbarez F, Mahmoodi S. Production of a Novel Multi-Epitope Peptide Vaccine against Hepatocellular Carcinoma. IRANIAN JOURNAL OF MEDICAL SCIENCES 2022; 47:558-565. [PMID: 36380977 PMCID: PMC9652490 DOI: 10.30476/ijms.2021.90916.2199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/11/2021] [Accepted: 08/28/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the prevalent cancers in the world with a high recurrence rate. In recent years, different researches have focused on designing efficient multi-epitope peptide vaccines against HCC. In designing these vaccines, over-expressed antigens in HCC patients, such as α- fetoprotein (AFP) and glypican-3 (GPC-3), have been employed. In our previous study, a multi-epitope peptide vaccine for HCC was designed by in-silico methods. The designed vaccine construct included the AFP, GPC-3, and aspartyl-β-hydroxylase (ASPH) as CytoLoxic T cell Lymphocytes (CTL), one epitope from Tetanus Toxin Fragment C (TTFrC) as Helper T cell Lymphocytes (HTL), and a segment of microbial heat shock protein (HSP70) peptide407-426 as an adjuvant. All the mentioned parts were connected by appropriate linkers. The aim of this study is the production of the designed vaccine. METHODS This research is experimental and was carried out in Fasa, Iran, in 2017. The designed vaccine construct gene was transformed to the Escherchia coli BL21 (DE3) strain and expressed in different isopropyl β-D-1-thiogalactopyranoside (IPTG) concentrations (0.6 and 1 mM), times (4, 6, 8, 16 hours), and temperatures (25 and 37 °C). Then, the expressed protein was analyzed by Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and the Western blot methods. RESULTS The best conditions for protein expression were obtained in the Super Optimal Broth (SOB) medium at 37 °C after the induction of expression by 1 mM IPTG for six hour. CONCLUSION The recombinant HCC vaccine was produced with a proper concentration.
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Affiliation(s)
- Fatemeh Motamedi Dehbarez
- Department of Medical Biotechnology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Shirin Mahmoodi
- Department of Medical Biotechnology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
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Jeng LB, Liao LY, Shih FY, Teng CF. Dendritic-Cell-Vaccine-Based Immunotherapy for Hepatocellular Carcinoma: Clinical Trials and Recent Preclinical Studies. Cancers (Basel) 2022; 14:cancers14184380. [PMID: 36139542 PMCID: PMC9497058 DOI: 10.3390/cancers14184380] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/06/2022] [Accepted: 09/06/2022] [Indexed: 11/16/2022] Open
Abstract
Although many surgical and nonsurgical therapeutic options have been well-established, hepatocellular carcinoma (HCC) remains the third most common cause of cancer-related death worldwide. Therefore, the discovery of novel potential therapeutic strategies is still urgently required for improving survival and prognosis of HCC patients. As the most potent antigen-presenting cells in the human immune system, dendritic cells (DCs) play an important role in activating not only innate but also adaptive immune responses to specifically destroy tumor cells. As a result, DC-based vaccines, which are prepared by different tumor-antigen-pulsing strategies or maturation-stimulating reagents, either alone or in combination with various anticancer therapies and/or immune effector cells, have been developed as a promising personalized cancer immunotherapy. This review provides a comprehensive summary of the evidence from clinical trials evaluating the safety, feasibility, and efficacy of DC-based vaccines in treating HCC patients and highlights the data from recent preclinical studies regarding the development of promising strategies for optimizing the efficacy of DC-vaccine-based immunotherapy for HCC.
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Affiliation(s)
- Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan
- Cell Therapy Center, China Medical University Hospital, Taichung 404, Taiwan
| | - Li-Ying Liao
- Development of Plastic and Reconstructive Surgery, China Medical University Hospital, Taichung 404, Taiwan
| | - Fu-Ying Shih
- Ph.D. Program for Biotech Pharmaceutical Industry, School of Pharmacy, China Medical University, Taichung 404, Taiwan
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- Program for Cancer Biology and Drug Development, China Medical University, Taichung 404, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung 404, Taiwan
- Correspondence: ; Tel.: +886-4-2205-2121
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Immunotherapy for hepatocellular carcinoma. Clin Exp Med 2022:10.1007/s10238-022-00874-5. [PMID: 36001163 DOI: 10.1007/s10238-022-00874-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/08/2022] [Indexed: 11/03/2022]
Abstract
Hepatocellular carcinoma (HCC), a primary malignancy of the liver, is a threat to the health of all humans as a prevalent malignancy and is the sixth most common cancer worldwide. It is difficult to diagnose because symptoms do not show up until late in the disease, and patients often progress to the point where transplantation, resection, or even local treatment cannot be performed. The progression of HCC is regulated by the immune system, and immunotherapy enables the body's immune system's defenses to target liver cancer cells; therefore, immunotherapy has brought a new hope for the treatment of HCC. Currently, the main types of immunotherapies for liver cancer are: immune checkpoint inhibitors, liver cancer vaccines and cellular therapies. In this review, the progress of immunotherapy for the treatment of HCC is summarized.
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Intercellular communication in the tumour microecosystem: Mediators and therapeutic approaches for hepatocellular carcinoma. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166528. [PMID: 36007784 DOI: 10.1016/j.bbadis.2022.166528] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/10/2022] [Accepted: 08/18/2022] [Indexed: 11/24/2022]
Abstract
Hepatocellular carcinoma (HCC), one of the most common tumours worldwide, is one of the main causes of mortality in cancer patients. There are still numerous problems hindering its early diagnosis, which lead to late patients receiving treatment, and these problems need to be solved urgently. The tumour microecosystem is a complex network system comprising seven parts: the hypoxia niche, immune microenvironment, metabolic microenvironment, acidic niche, innervated niche, mechanical microenvironment, and microbial microenvironment. Intercellular communication is divided into direct contact and indirect communication. Direct contact communication includes gap junctions, tunneling nanotubes, and receptor-ligand interactions, whereas indirect communication includes exosomes, apoptotic vesicles, and soluble factors. Mechanical communication and cytoplasmic exchange are further means of intercellular communication. Intercellular communication mediates the crosstalk between the tumour microecosystem and the host as well as that between cells and cell-free components in the tumour microecosystem, causing changes in the tumour hallmarks of the HCC microecosystem such as changes in tumour proliferation, invasion, apoptosis, angiogenesis, metastasis, inflammatory response, gene mutation, immune escape, metabolic reprogramming, and therapeutic resistance. Here, we review the role of the above-mentioned intercellular communication in the HCC microecosystem and discuss the advantages of targeted intercellular communication in the clinical diagnosis and treatment of HCC. Finally, the current problems and prospects are discussed.
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Abushukair HM, Saeed A. Hepatocellular carcinoma and immunotherapy: Beyond immune checkpoint inhibitors. World J Gastrointest Oncol 2022; 14:1210-1212. [PMID: 35949209 PMCID: PMC9244992 DOI: 10.4251/wjgo.v14.i6.1210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/29/2021] [Accepted: 05/13/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest and most common malignancies of the liver. Considering the rich immune background of carcinogenesis in HCC, efforts have been focused on further understanding the role of the immune system in tumor suppression and promotion. The utilization of immunotherapy in HCC has led to encouraging results that has translated to longer survival and better quality of life among patients. The development of novel HCC-tailored regimens such as vaccine therapy and adoptive cellular therapy coupled with a deeper understanding of biomarkers predictive of the response to immunotherapy will lead to better treatment outcomes.
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Affiliation(s)
| | - Anwaar Saeed
- Division of Medical Oncology, Department of Medicine, The University of Kansas Cancer Center, Kansas City, KS 66205, United States
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37
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Löffler MW, Gori S, Izzo F, Mayer-Mokler A, Ascierto P, Königsrainer A, Ma YT, Sangro B, Francque S, Vonghia L, Inno A, Avallone A, Ludwig J, Alcoba DD, Flohr C, Aslan K, Mendrzyk R, Schuster H, Borrelli M, Valmori D, Chaumette T, Heidenreich R, Gouttefangeas C, Forlani G, Tagliamonte M, Fusco C, Penta R, Iñarrairaegui M, Gnad-Vogt U, Reinhardt C, Weinschenk T, Accolla RS, Singh H, Rammensee HG, Buonaguro L. Phase I/II multicenter trial of a novel therapeutic cancer vaccine, HepaVac-101, for hepatocellular carcinoma. Clin Cancer Res 2022; 28:2555-2566. [PMID: 35421231 DOI: 10.1158/1078-0432.ccr-21-4424] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/25/2022] [Accepted: 04/12/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-man Phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multi-peptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102. IMA970A includes 5 HLA-A*24 and 7 HLA-A*02 as well as 4 HLA-DR restricted peptides selected after mass spectrometric identification in human HCC tissues or cell lines. CV8102 is an RNA-based immunostimulator inducing a balanced Th1/Th2 immune response. EXPERIMENTAL DESIGN 82 patients with very early to intermediate stage HCCs were enrolled and screened for suitable HLA haplotypes and 22 put on study treatment. This consisted in a single infusion of low-dose cyclophosphamide followed by 9 intradermal coadministrations of IMA970A and CV8102. Only patients with no disease relapse after standard of care treatments were vaccinated. Primary endpoints of HepaVac-101 clinical trial were safety, tolerability and antigen-specific T-cell responses. Secondary or exploratory endpoints included additional immunological parameters and survival endpoints. RESULTS The vaccination showed a good safety profile. Transient mild-to-moderate injection-site reactions were the most frequent IMA970A/CV8102-related side effects. Immune responses against {greater than or equal to}1 vaccinated HLA class I tumor-associated peptide (TAA) and {greater than or equal to}1 vaccinated HLA class II TAA were respectively induced in 37% and 53% of the vaccinees. CONCLUSION Immunotherapy may provide a great improvement in treatment options for HCC. HepaVac-101 is a first-in-man clinical vaccine trial with multiple novel HLA class I- and class II-restricted TAAs against HCC. The results are initial evidence for safety and immunogenicity of the vaccine. Further clinical evaluations are warranted.
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Affiliation(s)
| | - Stefania Gori
- IRCCS Sacro Cuore Don Calabria, Negrar di Valpolicella, Italy
| | - Francesco Izzo
- Istituto Nazionale per lo Studio e la Cura dei Tumori, Napoli, Italy
| | | | - Paolo Ascierto
- Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
| | | | - Yuk Ting Ma
- University of Birmingham, Birmingham, United Kingdom
| | - Bruno Sangro
- Clínica Universidad de Navarra and CIBEREHD, Pamplona, Navarra, Spain
| | | | | | - Alessandro Inno
- IRCCS Ospedale Sacro Cuore Don Calabria, Negrar di Valpolicella, Verona, Italy
| | | | - Jörg Ludwig
- Immatics Biotechnologies (Germany), Tuebingen, Germany
| | | | | | | | | | | | - Marco Borrelli
- ISTITUTO NAZIONALE TUMORI IRCCS - Fondazione Pascale, napoli, napoli, Italy
| | - Danila Valmori
- Institut National de la Sante et de la Recherche Medicale, Nantes-Saint Herblain, France
| | | | | | | | | | | | | | - Roberta Penta
- AORN Santobono-Pausilipon Children's Hospital, Naples, Italy
| | | | | | | | | | | | | | | | - Luigi Buonaguro
- ISTITUTO NAZIONALE TUMORI IRCCS - Fondazione Pascale, NAPLES, Italy
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Fan Y, Xue H, Zheng H. Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook. J Hepatocell Carcinoma 2022; 9:233-263. [PMID: 35388357 PMCID: PMC8977221 DOI: 10.2147/jhc.s358082] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has emerged the culprit of cancer-related mortality worldwide with its dismal prognosis climbing. In recent years, ground-breaking progress has been made in systemic therapy for HCC. Targeted therapy based on specific signaling molecules, including sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab, has been widely used for advanced HCC (aHCC). Immunotherapies such as pembrolizumab and nivolumab greatly improve the survival of aHCC patients. More recently, synergistic combination therapy has boosted first-line (atezolizumab in combination with bevacizumab) and second-line (ipilimumab in combination with nivolumab) therapeutic modalities for aHCC. This review aims to summarize recent updates of systemic therapy relying on the biological mechanisms of HCC, particularly highlighting the approved agents for aHCC. Adjuvant and neoadjuvant therapy, as well as a combination with locoregional therapies (LRTs), are also discussed. Additionally, we describe the promising effect of traditional Chinese medicine (TCM) as systemic therapy on HCC. In this setting, the challenges and future directions of systemic therapy for HCC are also explored.
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Affiliation(s)
- Yinjie Fan
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, People’s Republic of China
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Hang Xue
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Huachuan Zheng
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
- Correspondence: Huachuan Zheng, Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China, Tel +86-0314-2279458, Fax +86-0314-2279458, Email
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Abstract
Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib, resulting in FDA approval of this regimen. More recently, durvalumab plus tremelimumab yielded superior overall survival versus sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have received FDA Accelerated Approval in the second-line setting based on early efficacy data. Despite these major advances, the molecular underpinnings governing immune responses and evasion remain unclear. The immune microenvironment has crucial roles in the development and progression of HCC and distinct aetiology-dependent immune features have been defined. Inflamed and non-inflamed classes of HCC and genomic signatures have been associated with response to immune-checkpoint inhibitors, yet no validated biomarker is available to guide clinical decision-making. This Review provides information on the immune microenvironments underlying the response or resistance of HCC to immunotherapies. In addition, current evidence from phase III trials on the efficacy, immune-related adverse events and aetiology-dependent mechanisms of response are described. Finally, we discuss emerging trials assessing immunotherapies across all stages of HCC that might change the management of this disease in the near future.
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Therapeutic Vaccines against Hepatocellular Carcinoma in the Immune Checkpoint Inhibitor Era: Time for Neoantigens? Int J Mol Sci 2022; 23:ijms23042022. [PMID: 35216137 PMCID: PMC8875127 DOI: 10.3390/ijms23042022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/07/2022] [Accepted: 02/10/2022] [Indexed: 02/01/2023] Open
Abstract
Immune checkpoint inhibitors (ICI) have been used as immunotherapy for hepatocellular carcinoma (HCC) with promising but still limited results. Identification of immune elements in the tumor microenvironment of individual HCC patients may help to understand the correlations of responses, as well as to design personalized therapies for non-responder patients. Immune-enhancing strategies, such as vaccination, would complement ICI in those individuals with poorly infiltrated tumors. The prominent role of responses against mutated tumor antigens (neoAgs) in ICI-based therapies suggests that boosting responses against these epitopes may specifically target tumor cells. In this review we summarize clinical vaccination trials carried out in HCC, the available information on potentially immunogenic neoAgs in HCC patients, and the most recent results of neoAg-based vaccines in other tumors. Despite the low/intermediate mutational burden observed in HCC, data obtained from neoAg-based vaccines in other tumors indicate that vaccines directed against these tumor-specific antigens would complement ICI in a subset of HCC patients.
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41
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Liu JKH, Irvine AF, Jones RL, Samson A. Immunotherapies for hepatocellular carcinoma. Cancer Med 2022; 11:571-591. [PMID: 34953051 PMCID: PMC8817091 DOI: 10.1002/cam4.4468] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/21/2022] Open
Abstract
Cases of hepatocellular carcinoma (HCC) are rapidly rising. This is particularly the case in the Western world, as a result of increasing rates of chronic liver disease, secondary to lifestyle-associated risk factors and the lack of an established screening programme for the general population. Traditionally, radical/curative treatment options for HCC, including liver transplantation and surgical resection are reserved for the minority of patients, presenting with an early stage cancer. For patients with advanced disease, Sorafenib and Lenvatinib were, until recently, the only licensed systemic treatments, and provided only limited survival benefits at the cost of a multitude of potential side effects. Recent scientific advances in the field of cancer immunotherapy have renewed significant interest in advanced HCC, in order to fulfil this apparent area of unmet clinical need. This has led to the success and recent regulatory approval of an Atezolizumab/Bevacizumab combination for the first-line treatment of advanced HCC following results from the IMbrave150 clinical trial in 2019, with further immune checkpoint inhibitors currently undergoing testing in advanced clinical trials. Furthermore, other cancer immunotherapies, including chimeric antigen receptor T-cells, dendritic cell vaccines and oncolytic viruses are also in early stage clinical trials, for the treatment of advanced HCC. This review will summarise the major approaches that have been and are currently in development for the systemic treatment of advanced HCC, their advantages, drawbacks, and predictions of where this revolutionary treatment field will continue to travel for the foreseeable future.
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Affiliation(s)
- Justin K. H. Liu
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
| | - Andrew F. Irvine
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
| | - Rebecca L. Jones
- Leeds Liver UnitSt James's University HospitalLeeds Teaching Hospitals NHS TrustLeedsUK
| | - Adel Samson
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
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Rai V, Mukherjee S. Targets of immunotherapy for hepatocellular carcinoma: An update. World J Hepatol 2022; 14:140-157. [PMID: 35126844 PMCID: PMC8790386 DOI: 10.4254/wjh.v14.i1.140] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/20/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma, the most common primary liver cancer, in an immunogenic tumor with a poor prognosis because these tumors are diagnosed at late stages. Although, surgical resection, ablation, liver transplant, and locoregional therapies are available for early stages; however, there are yet no effective treatment for advanced and recurrent tumors. Immune checkpoint inhibitor therapy and adoptive cell transfer therapy has gained the popularity with some positive results because these therapies overcome anergy and systemic immune suppression. However, still there is a lack of an effective treatment and thus there is an unmet need of a novel treatment. At present, the focus of the research is on oncolytic viral therapy and combination therapy where therapies including radiotherapy, immune checkpoint therapy, adoptive cell transfer therapy, and vaccines are combined to get an additive or synergistic effect enhancing the immune response of the liver with a cytotoxic effect on tumor cells. This review discusses the recent key development, the basis of drug resistance, immune evasion, immune tolerance, the available therapies based on stage of the tumor, and the ongoing clinical trials on immune checkpoint inhibitor therapy, adoptive cell transfer therapy, oncolytic viral vaccine therapy, and combination therapy.
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Affiliation(s)
- Vikrant Rai
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, United States
| | - Sandeep Mukherjee
- Department of Medicine, Creighton University School of Medicine, Omaha, NE 68124, United States.
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Lei W, Yang C, Wu Y, Ru G, He X, Tong X, Wang S. Nanocarriers surface engineered with cell membranes for cancer targeted chemotherapy. J Nanobiotechnology 2022; 20:45. [PMID: 35062958 PMCID: PMC8781141 DOI: 10.1186/s12951-022-01251-w] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 01/07/2022] [Indexed: 02/08/2023] Open
Abstract
Abstract
Background
Inspired by nature, the biomimetic approach has been incorporated into drug nanocarriers for cancer targeted chemotherapy. The nanocarriers are cloaked in cell membranes, which enables them to incorporate the functions of natural cells.
Key scientific concepts of review
Nanocarriers surface engineered with cell membranes have emerged as a fascinating source of materials for cancer targeted chemotherapy. A distinctive characteristic of cell membrane-coated nanocarriers (CMCNs) is that they include carbohydrates, proteins, and lipids, in addition to being biocompatible. CMCNs are capable of interacting with the complicated biological milieu of the tumor because they contain the signaling networks and intrinsic functions of their parent cells. Numerous cell membranes have been investigated for the purpose of masking nanocarriers with membranes, and various tumor-targeting methods have been devised to improve cancer targeted chemotherapy. Moreover, the diverse structure of the membrane from different cell sources broadens the spectrum of CMCNs and offers an entirely new class of drug-delivery systems.
Aim of review
This review will describe the manufacturing processes for CMCNs and the therapeutic uses for different kinds of cell membrane-coated nanocarrier-based drug delivery systems, as well as addressing obstacles and future prospects.
Graphical Abstract
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Wang K, Wang C, Jiang H, Zhang Y, Lin W, Mo J, Jin C. Combination of Ablation and Immunotherapy for Hepatocellular Carcinoma: Where We Are and Where to Go. Front Immunol 2022; 12:792781. [PMID: 34975896 PMCID: PMC8714655 DOI: 10.3389/fimmu.2021.792781] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and is increasing in incidence. Local ablative therapy plays a leading role in HCC treatment. Radiofrequency (RFA) is one of the first-line therapies for early local ablation. Other local ablation techniques (e.g., microwave ablation, cryoablation, irreversible electroporation, phototherapy.) have been extensively explored in clinical trials or cell/animal studies but have not yet been established as a standard treatment or applied clinically. On the one hand, single treatment may not meet the needs. On the other hand, ablative therapy can stimulate local and systemic immune effects. The combination strategy of immunotherapy and ablation is reasonable. In this review, we briefly summarized the current status and progress of ablation and immunotherapy for HCC. The immune effects of local ablation and the strategies of combination therapy, especially synergistic strategies based on biomedical materials, were discussed. This review is hoped to provide references for future researches on ablative immunotherapy to arrive to a promising new era of HCC treatment.
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Affiliation(s)
- Kunpeng Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Cong Wang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, China
| | - Hao Jiang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Yaqiong Zhang
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Weidong Lin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jinggang Mo
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Chong Jin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
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Immunotherapy for Hepatocellular Carcinoma: New Prospects for the Cancer Therapy. Life (Basel) 2021; 11:life11121355. [PMID: 34947886 PMCID: PMC8704694 DOI: 10.3390/life11121355] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/29/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. HCC patients may benefit from liver transplantation, hepatic resection, radiofrequency ablation, transcatheter arterial chemoembolization, and targeted therapies. The increased infiltration of immunosuppressive immune cells and the elevated expression of immunosuppressive factors in the HCC microenvironment are the main culprits of the immunosuppressive nature of the HCC milieu. The immunosuppressive tumor microenvironment can substantially attenuate antitumoral immune responses and facilitate the immune evasion of tumoral cells. Immunotherapy is an innovative treatment method that has been promising in treating HCC. Immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), and cell-based (primarily dendritic cells) and non-cell-based vaccines are the most common immunotherapeutic approaches for HCC treatment. However, these therapeutic approaches have not generally induced robust antitumoral responses in clinical settings. To answer to this, growing evidence has characterized immune cell populations and delineated intercellular cross-talk using single-cell RNA sequencing (scRNA-seq) technologies. This review aims to discuss the various types of tumor-infiltrating immune cells and highlight their roles in HCC development. Besides, we discuss the recent advances in immunotherapeutic approaches for treating HCC, e.g., ICIs, dendritic cell (DC)-based vaccines, non-cell-based vaccines, oncolytic viruses (OVs), and ACT. Finally, we discuss the potentiality of scRNA-seq to improve the response rate of HCC patients to immunotherapeutic approaches.
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Liu Z, Liu X, Liang J, Liu Y, Hou X, Zhang M, Li Y, Jiang X. Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects. Front Immunol 2021; 12:765101. [PMID: 34675942 PMCID: PMC8524467 DOI: 10.3389/fimmu.2021.765101] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with poor prognosis. Surgery, chemotherapy, and radiofrequency ablation are three conventional therapeutic options that will help only a limited percentage of HCC patients. Cancer immunotherapy has achieved dramatic advances in recent years and provides new opportunities to treat HCC. However, HCC has various etiologies and can evade the immune system through multiple mechanisms. With the rapid development of genetic engineering and synthetic biology, a variety of novel immunotherapies have been employed to treat advanced HCC, including immune checkpoint inhibitors, adoptive cell therapy, engineered cytokines, and therapeutic cancer vaccines. In this review, we summarize the current landscape and research progress of different immunotherapy strategies in the treatment of HCC. The challenges and opportunities of this research field are also discussed.
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Affiliation(s)
- Zhuoyan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xuan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaxin Liang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yixin Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaorui Hou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Meichuan Zhang
- R&D Department, Caleb BioMedical Technology Co. Ltd, Guangzhou, China
| | - Yongyin Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaotao Jiang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Bo XW, Sun LP, Yu SY, Xu HX. Thermal ablation and immunotherapy for hepatocellular carcinoma: Recent advances and future directions. World J Gastrointest Oncol 2021; 13:1397-1411. [PMID: 34721773 PMCID: PMC8529921 DOI: 10.4251/wjgo.v13.i10.1397] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/20/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of most common cancers that cause death in the world. Thermal ablation (TA) is an important alternative treatment method for HCC patients who are not appropriate for surgery or liver transplantation. Particularly for small and early HCCs, TA can be considered as the first-line curative treatment. However, local and distant recurrence rates are still high even though the TA equipment and technology develop rapidly. Immunotherapy is a novel systemic treatment method to enhance the anti-tumor immune response of HCC patients, which has the potential to reduce the tumor recurrence and metastasis. The combination of local TA and systemic immunotherapy for HCCs may be an ideal treatment for enhancing the efficacy of TA and controlling the recurrence. Herein we summarize the latest progress in TA, immunotherapy, and their combination for the treatment of patients with HCC and discuss the limitations and future research directions of the combined therapy.
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Affiliation(s)
- Xiao-Wan Bo
- Center of Minimally Invasive Treatment for Tumor, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital; Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, School of Medicine, Tongji University, Shanghai 200072, China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment; National Clinical Research Center for Interventional Medicine, Shanghai 200072, China
| | - Li-Ping Sun
- Center of Minimally Invasive Treatment for Tumor, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital; Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, School of Medicine, Tongji University, Shanghai 200072, China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment; National Clinical Research Center for Interventional Medicine, Shanghai 200072, China
| | - Song-Yuan Yu
- Center of Minimally Invasive Treatment for Tumor, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital; Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, School of Medicine, Tongji University, Shanghai 200072, China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment; National Clinical Research Center for Interventional Medicine, Shanghai 200072, China
| | - Hui-Xiong Xu
- Center of Minimally Invasive Treatment for Tumor, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital; Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, School of Medicine, Tongji University, Shanghai 200072, China
- Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment; National Clinical Research Center for Interventional Medicine, Shanghai 200072, China
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Martini G, Ciardiello D, Paragliola F, Nacca V, Santaniello W, Urraro F, Stanzione M, Niosi M, Dallio M, Federico A, Selvaggi F, Della Corte CM, Napolitano S, Ciardiello F, Martinelli E. How Immunotherapy Has Changed the Continuum of Care in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13184719. [PMID: 34572944 PMCID: PMC8466991 DOI: 10.3390/cancers13184719] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/08/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment of patients with metastatic disease was limited to the use of the multikinase inhibitor (MKI) sorafenib with a marginal effect on survival outcome. New target approaches, such as the oral MKI lenvatinib in first-line treatment and regorafenib, ramucirumab, and cabozantinib in later lines of therapy, have demonstrated efficacy in patients with preserved liver function (Child-Pugh class A) and good performance status. On the other hand, the implementation of immune checkpoint inhibitors directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab), and anti-CTLA4 (ipilimumab) in the management of advanced HCC has strongly changed the continuum of care of HCC. Future research should include the evaluation of molecular biomarkers that can help patient selection and provide new insight on potential combined approaches. In this review, we provide an overview of the clinical evidence of the use of immune checkpoint inhibitors in HCC, and discuss how immunotherapy has been implemented into the continuum of HCC care.
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Affiliation(s)
- Giulia Martini
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Davide Ciardiello
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Fernando Paragliola
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Valeria Nacca
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Walter Santaniello
- Chirurgia Epatobiliare e Trapianto di Fegato, A.O.R.N. Antonio Cardarelli, 80100 Naples, Italy;
| | - Fabrizio Urraro
- Radiologia, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy;
| | - Maria Stanzione
- Malattie Infettive, Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy;
| | - Marco Niosi
- Epato-Gastroenterologia, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (M.N.); (M.D.); (A.F.)
| | - Marcello Dallio
- Epato-Gastroenterologia, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (M.N.); (M.D.); (A.F.)
| | - Alessandro Federico
- Epato-Gastroenterologia, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (M.N.); (M.D.); (A.F.)
| | - Francesco Selvaggi
- Dipartimento di Scienze Mediche e Chirurgiche Avanzate, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy;
| | - Carminia Maria Della Corte
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Stefania Napolitano
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Fortunato Ciardiello
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Erika Martinelli
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
- Correspondence:
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Miao L, Zhang Z, Ren Z, Li Y. Application of Immunotherapy in Hepatocellular Carcinoma. Front Oncol 2021; 11:699060. [PMID: 34513678 PMCID: PMC8426571 DOI: 10.3389/fonc.2021.699060] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma is one of the most common malignancies globally. It not only has a hidden onset but also progresses rapidly. Most HCC patients are already in the advanced stage of cancer when they are diagnosed, and have even lost the opportunity for surgical treatment. As an inflammation-related tumor, the immunosuppressive microenvironment of HCC can promote immune tolerance through a variety of mechanisms. Immunotherapy can activate tumor-specific immune responses, which brings a new hope for the treatment of HCC. At the present time, main immunotherapy strategies of HCC include immune checkpoint inhibitors, tumor vaccines, adoptive cell therapy, and so on. This article reviews the application and research progress of immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapy in the treatment of HCC.
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Affiliation(s)
- Lele Miao
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhengchao Zhang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhijian Ren
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
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Charneau J, Suzuki T, Shimomura M, Fujinami N, Nakatsura T. Peptide-Based Vaccines for Hepatocellular Carcinoma: A Review of Recent Advances. J Hepatocell Carcinoma 2021; 8:1035-1054. [PMID: 34513746 PMCID: PMC8424432 DOI: 10.2147/jhc.s291558] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/10/2021] [Indexed: 12/14/2022] Open
Abstract
Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide. After surgery, up to 70% of patients experience relapses. The current first-line therapy for advanced cases of hepatocellular carcinoma (HCC) comprises sorafenib and lenvatinib administered as single-drug therapies. Regorafenib, cabozantinib, and ramucirumab are administered as second-line therapies. Recently, it has been reported that using the immune checkpoint inhibitors atezolizumab (anti-PDL1 antibody) and bevacizumab (anti-VEGF antibody) leads to longer overall survival of unresectable cases, when compared with the use of sorafenib. The role of cancer immunity against HCC has attracted the attention of clinicians. In this review, we describe our phase I/II clinical trials of peptide vaccines targeting GPC3 in HCC and discuss the potential of peptide vaccines targeting common cancer antigens that are highly expressed in HCC, such as WT-I, AFP, ROBO1, and FOXM1. Further, we introduce recent cancer vaccines targeting neoantigens, which have attracted attention in recent times, as well as present our preclinical studies, the results of which might aid to initiate a neoantigen vaccine clinical trial, which would be the first of its kind in Japan.
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Affiliation(s)
- Jimmy Charneau
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
| | - Toshihiro Suzuki
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan.,Department of Pharmacology, School of Medicine, Teikyo University, Tokyo, Japan
| | - Manami Shimomura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
| | - Norihiro Fujinami
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
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