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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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Kar S, Mehrotra S, Prajapati VK. From infection to remedy: Harnessing oncolytic viruses in cancer treatment. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2025; 144:213-257. [PMID: 39978967 DOI: 10.1016/bs.apcsb.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Oncolytic virus (OV) mediated immunotherapy is one of the recent techniques used to treat higher grade cancers where conventional therapies like chemotherapy, radiation fail. OVs as a therapeutic tool show high efficacy and fewer side effects than conventional methods as supported by multiple preclinical and clinical studies since they are engineered to target tumours. In this chapter, we discuss the modifications in viruses to make them oncolytic, types of strains commonly administered, mechanisms employed by viruses to specifically target and eradicate malignancy and progress achieved as reported in case studies (preclinical and clinical trials). OVs also face some unique challenges with respect to the malignancy being treated and the varied pathogen exposure of the patients, which is also highlighted here. Since pathogen exposure varies according to population dynamics worldwide, chances of generating a non-specific recall response to an OV cannot be negated. Lastly, the future perspectives and ongoing practises of combination therapies are discussed as they provide a leading edge over monotherapies in terms of tumour clearance, blocking metastasis and enhancing patient survival. Efforts undertaken to overcome current challenges are also highlighted.
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Affiliation(s)
- Sramona Kar
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
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Tesfay MZ, Zhang Y, Ferdous KU, Taylor MA, Cios A, Shelton RS, Simoes CC, Watters CR, Barro O, Elliott NM, Mustafa B, Chamcheu JC, Graham AL, Washam CL, Alkam D, Gies A, Byrum SD, Giorgakis E, Post SR, Kelly T, Ying J, Moaven O, Chabu CY, Fernandez-Zapico ME, Duda DG, Roberts LR, Govindarajan R, Borad MJ, Cannon MJ, Basnakian AG, Nagalo BM. Enhancing immune response and survival in hepatocellular carcinoma with novel oncolytic Jurona virus and immune checkpoint blockade. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200913. [PMID: 39758249 PMCID: PMC11697550 DOI: 10.1016/j.omton.2024.200913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 10/19/2024] [Accepted: 11/22/2024] [Indexed: 01/07/2025]
Abstract
Members of the Vesiculovirus genus including Jurona virus (JURV) have emerged as promising immunotherapeutic agents, characterized by their tumor selectivity, fast kinetics, low seroprevalence, and minimal toxicity in humans. Here, we demonstrate that the administration of JURV leads to tumor regression in both hepatocellular carcinoma (HCC) xenograft and syngeneic models. Furthermore, our findings indicate that combining JURV and anti-PD-1 therapy reduced tumor burden and improved survival rates over JURV or anti-PD-1 alone in an orthotopic HCC model. Proteogenomic analysis of JURV-treated, murine HCC tumors demonstrates that the therapeutic effects of the combination of JURV and anti-PD-1 are predominantly driven by coordinated activation of immune effectors, which modulate the tumor microenvironment into a state conducive to anti-tumor activity. Our results establish JURV as a potent candidate for immunovirotherapy in HCC, capable of modulating immune response and synergizing with standard of care for HCC to prolong survival in preclinical models. Further, this research deepens our understanding of JURV's anti-tumoral mechanisms and highlights its potential as a novel approach to HCC treatment strategies.
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Affiliation(s)
- Mulu Z. Tesfay
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR, USA
| | - Yuguo Zhang
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
| | - Khandoker U. Ferdous
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
| | - Mika A. Taylor
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
| | - Aleksandra Cios
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
| | | | - Camila C. Simoes
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR, USA
| | | | - Oumar Barro
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Bahaa Mustafa
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
| | - Jean Christopher Chamcheu
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, USA
| | - Alicia L. Graham
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
| | - Charity L. Washam
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR, USA
| | - Duah Alkam
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR, USA
| | - Allen Gies
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR, USA
| | - Stephanie D. Byrum
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR, USA
| | - Emmanouil Giorgakis
- College of Medicine, Surgery Transplant University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
| | - Steven R. Post
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR, USA
| | - Thomas Kelly
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR, USA
| | - Jun Ying
- Department of Biostatistics, UAMS College of Public Health, Little Rock, AR, USA
| | - Omeed Moaven
- Division of Surgical Oncology, Department of Surgery, Louisiana State University (LSU) Health, New Orleans, LA, USA
- Department of Interdisciplinary Oncology, Louisiana Cancer Research Center, Louisiana State University (LSU) Health, New Orleans, LA, USA
- LSU-LCMC Cancer Center, New Orleans, LA, USA
| | - Chiswili Y. Chabu
- Division of Biological Sciences, University of Missouri, Columbia, MO, USA
- Department of Surgery, School of Medicine, University of Missouri, Columbia, MO, USA
- Siteman Cancer Center, Washington University, St. Louis, MO, USA
| | | | - Dan G. Duda
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Lewis R. Roberts
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, USA
| | - Rang Govindarajan
- Medical Oncology Division, Internal Medicine Department, The University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Mitesh J. Borad
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Martin J. Cannon
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR, USA
- Department of Microbiology and Immunology, UAMS, Little Rock, AR, USA
| | - Alexei G. Basnakian
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR, USA
- Department of Pharmacology, UAMS, Little Rock, AR, USA
| | - Bolni M. Nagalo
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR, USA
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Chattopadhyay S, Hazra R, Mallick A, Gayen S, Roy S. A review exploring the fusion of oncolytic viruses and cancer immunotherapy: An innovative strategy in the realm of cancer treatment. Biochim Biophys Acta Rev Cancer 2024; 1879:189110. [PMID: 38754793 DOI: 10.1016/j.bbcan.2024.189110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 05/02/2024] [Accepted: 05/08/2024] [Indexed: 05/18/2024]
Abstract
Oncolytic viruses (OVs) are increasingly recognized as potent tools in cancer therapy, effectively targeting and eradicating oncogenic conditions while sparing healthy cells. They enhance antitumor immunity by triggering various immune responses throughout the cancer cycle. Genetically engineered OVs swiftly destroy cancerous tissues and activate the immune system by releasing soluble antigens like danger signals and interferons. Their ability to stimulate both innate and adaptive immunity makes them particularly attractive in cancer immunotherapy. Recent advancements involve combining OVs with other immune therapies, yielding promising results. Transgenic OVs, designed to enhance immunostimulation and specifically target cancer cells, further improve immune responses. This review highlights the intrinsic mechanisms of OVs and underscores their synergistic potential with other immunotherapies. It also proposes strategies for optimizing armed OVs to bolster immunity against tumors.
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Affiliation(s)
- Soumyadeep Chattopadhyay
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Rudradeep Hazra
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Arijit Mallick
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Sakuntala Gayen
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Souvik Roy
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India.
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Abou-Alfa GK, Galle PR, Chao Y, Erinjeri J, Heo J, Borad MJ, Luca A, Burke J, Pelusio A, Agathon D, Lusky M, Breitbach C, Qin S, Gane E. PHOCUS: A Phase 3, Randomized, Open-Label Study of Sequential Treatment with Pexa-Vec (JX-594) and Sorafenib in Patients with Advanced Hepatocellular Carcinoma. Liver Cancer 2024; 13:248-264. [PMID: 38756145 PMCID: PMC11095598 DOI: 10.1159/000533650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 08/09/2023] [Indexed: 05/18/2024] Open
Abstract
Introduction Intratumoral administration of pexa-vec (pexastimogene devacirepvec), an oncolytic and immunotherapeutic vaccinia virus, given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy. Methods This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival, overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥1 dose of study treatment. Results The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib: 234, sorafenib: 225). At the interim analysis, the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to the early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups. Conclusion Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies.
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Affiliation(s)
- Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Medical College, Cornell University, New York, NY, USA
| | - Peter R. Galle
- University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Yee Chao
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Joseph Erinjeri
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Medical College, Cornell University, New York, NY, USA
| | - Jeong Heo
- Pusan National University, Busan, South Korea
| | - Mitesh J. Borad
- Gene and Virus Therapy Program, Mayo Clinic Cancer Center, Scottsdale, AZ, USA
| | - Angelo Luca
- Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo, Italy
| | - James Burke
- Sillajen Biotherapeutics, Inc., San Francisco, CA, USA
| | - Adina Pelusio
- Sillajen Biotherapeutics, Inc., San Francisco, CA, USA
| | | | | | | | - Shukui Qin
- Chinese People’s Liberation Army Bayi Hospital, Nanjing, PR China
| | - Edward Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, University of Auckland, Auckland, New Zealand
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Salem R, Greten TF. Interventional radiology meets immuno-oncology for hepatocellular carcinoma. J Hepatol 2024; 80:967-976. [PMID: 35988688 DOI: 10.1016/j.jhep.2022.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/28/2022] [Accepted: 08/05/2022] [Indexed: 12/04/2022]
Abstract
Locoregional and systemic therapies are the most used treatment options for patients with hepatocellular carcinoma (HCC). Interventional radiologists have improved and developed novel protocols and devices for both intratumoural ablative approaches with curative intent and various transarterial intrahepatic treatment options, which have continuously improved patient outcomes. Two large phase III randomised clinical trials have demonstrated the efficacy of different immune checkpoint inhibitors either as single agents or in combination in the first-line setting and immunotherapy has become the standard first-line treatment option for patients with advanced HCC. Herein, we discuss advances and perspectives in the area of interventional radiology (IR) and immune-oncology (IO). We summarise results from recent studies and provide an overview of ongoing studies in IR and IO. Based on the significant advances in both areas, we propose that IR and IO need to cover the emerging "discipline" of IR-IO, in which we develop and test novel approaches to combine locoregional therapies with immunotherapy, in order to develop sufficient evidence for them to be considered standard of care for patients with HCC in the near future.
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Affiliation(s)
- Riad Salem
- Department of Radiology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
| | - Tim F Greten
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, Bethesda MD, USA; NCI CCR Liver Cancer Program, Center for Cancer Research, NCI, Bethesda MD, USA
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Yu J, Li M, Ren B, Cheng L, Wang X, Ma Z, Yong WP, Chen X, Wang L, Goh BC. Unleashing the efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma: factors, strategies, and ongoing trials. Front Pharmacol 2023; 14:1261575. [PMID: 37719852 PMCID: PMC10501787 DOI: 10.3389/fphar.2023.1261575] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 08/18/2023] [Indexed: 09/19/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer, representing approximately 85% of cases. The diagnosis is often made in the middle and late stages, necessitating systemic treatment as the primary therapeutic option. Despite sorafenib being the established standard of care for advanced HCC in the past decade, the efficacy of systemic therapy remains unsatisfactory, highlighting the need for novel treatment modalities. Recent breakthroughs in immunotherapy have shown promise in HCC treatment, particularly with immune checkpoint inhibitors (ICIs). However, the response rate to ICIs is currently limited to approximately 15%-20% of HCC patients. Recently, ICIs demonstrated greater efficacy in "hot" tumors, highlighting the urgency to devise more effective approaches to transform "cold" tumors into "hot" tumors, thereby enhancing the therapeutic potential of ICIs. This review presented an updated summary of the factors influencing the effectiveness of immunotherapy in HCC treatment, identified potential combination therapies that may improve patient response rates to ICIs, and offered an overview of ongoing clinical trials focusing on ICI-based combination therapy.
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Affiliation(s)
- Jiahui Yu
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Mengnan Li
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Boxu Ren
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Le Cheng
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Xiaoxiao Wang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Zhaowu Ma
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Wei Peng Yong
- Department of Haematology–Oncology, National University Cancer Institute, Singapore, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xiaoguang Chen
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Lingzhi Wang
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Boon Cher Goh
- Department of Haematology–Oncology, National University Cancer Institute, Singapore, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
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Young S, Hannallah J, Goldberg D, Sanghvi T, Arshad J, Scott A, Woodhead G. Friend or Foe? Locoregional Therapies and Immunotherapies in the Current Hepatocellular Treatment Landscape. Int J Mol Sci 2023; 24:11434. [PMID: 37511193 PMCID: PMC10380625 DOI: 10.3390/ijms241411434] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/11/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Over the last several decades, a number of new treatment options for patients with hepatocellular carcinoma (HCC) have been developed. While treatment decisions for some patients remain clear cut, a large numbers of patients have multiple treatment options, and it can be hard for multidisciplinary teams to come to unanimous decisions on which treatment strategy or sequence of treatments is best. This article reviews the available data with regard to two treatment strategies, immunotherapies and locoregional therapies, with a focus on the potential of locoregional therapies to be combined with checkpoint inhibitors to improve outcomes in patients with locally advanced HCC. In this review, the available data on the immunomodulatory effects of locoregional therapies is discussed along with available clinical data on outcomes when the two strategies are combined.
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Affiliation(s)
- Shamar Young
- Department of Medical Imaging, Division of Interventional Radiology, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724, USA
| | - Jack Hannallah
- Department of Medical Imaging, Division of Interventional Radiology, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724, USA
| | - Dan Goldberg
- Department of Medical Imaging, Division of Interventional Radiology, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724, USA
| | - Tina Sanghvi
- Department of Radiology, Southern Arizona VA, Tucson, AZ 85723, USA
| | - Junaid Arshad
- Department of Medicine, Division of Hematology and Oncology, University of Arizona, Tucson, AZ 85724, USA
| | - Aaron Scott
- Department of Medicine, Division of Hematology and Oncology, University of Arizona, Tucson, AZ 85724, USA
| | - Gregory Woodhead
- Department of Medical Imaging, Division of Interventional Radiology, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724, USA
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Heo J, Liang JD, Kim CW, Woo HY, Shih IL, Su TH, Lin ZZ, Yoo SY, Chang S, Urata Y, Chen PJ. Safety and dose escalation of the targeted oncolytic adenovirus OBP-301 for refractory advanced liver cancer: Phase I clinical trial. Mol Ther 2023; 31:2077-2088. [PMID: 37060176 PMCID: PMC10362399 DOI: 10.1016/j.ymthe.2023.04.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/29/2023] [Accepted: 04/10/2023] [Indexed: 04/16/2023] Open
Abstract
OBP-301 is an oncolytic adenovirus modified to replicate within cancer cells and lyse them. This open-label, non-comparative, phase I dose-escalation trial aimed to assess its safety and optimal dosage in 20 patients with advanced hepatocellular carcinoma. Good tolerance was shown with a maximum tolerated dose of 6 × 1012 viral particles. The most common treatment-emergent adverse events were influenza-like illness, pyrexia, fatigue, decreased platelet count, abdominal distension, and anemia. Cohorts 4 and 5 had approximately 50% higher levels of CD8+ T cells in the peripheral blood after injection. The best target response occurred in 14 patients, 4 of whom had progressive disease. Multiple intratumoral injections of OBP-301 were well tolerated in patients with advanced hepatocellular carcinoma. The stable disease rate for the injected tumors was greater than the overall response rate, even with no obvious tumor response. OBP-301 might have a greater impact on local response as histological examination revealed that the presence of OBP-301 was consistent with the necrotic area at the injection site. Increased infiltration of CD8+ T cells and <1% PD-L1 expression were observed in tumors after injection. Improved antitumor efficacy might be achieved in future studies via viral injection with volume adjustment and in combination with other immuno-therapeutics.
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Affiliation(s)
- Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
| | - Ja-Der Liang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chang Won Kim
- Department of Radiology, College of Medicine, Pusan National University, Busan, Republic of Korea
| | - Hyun Young Woo
- Department of Internal Medicine, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - I-Lun Shih
- Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Zhong-Zhe Lin
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan, Republic of Korea
| | | | | | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
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Zhu L, Lei Y, Huang J, An Y, Ren Y, Chen L, Zhao H, Zheng C. Recent advances in oncolytic virus therapy for hepatocellular carcinoma. Front Oncol 2023; 13:1172292. [PMID: 37182136 PMCID: PMC10169724 DOI: 10.3389/fonc.2023.1172292] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/07/2023] [Indexed: 05/16/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly refractory cancer and the fourth leading cause of cancer-related mortality worldwide. Despite the development of a detailed treatment strategy for HCC, the survival rate remains unsatisfactory. Oncolytic virus has been extensively researched as a new cancer therapeutic agent in the treatment of HCC. Researchers have designed a variety of recombinant viruses based on natural oncolytic diseases, which can increase the targeting of oncolytic viruses to HCC and their survival in tumors, as well as kill tumor cells and inhibit the growth of HCC through a variety of mechanisms. The overall efficacy of oncolytic virus therapy is known to be influenced by anti-tumor immunity, toxic killing effect and inhibition of tumor angiogenesis, etc. Therefore, a comprehensive review of the multiple oncolytic mechanisms of oncolytic viruses in HCC has been conducted. So far, a large number of relevant clinical trials are under way or have been completed, and some encouraging results have been obtained. Studies have shown that oncolytic virus combined with other HCC therapies may be a feasible method, including local therapy, chemotherapy, molecular targeted therapy and immunotherapy. In addition, different delivery routes for oncolytic viruses have been studied so far. These studies make oncolytic virus a new and attractive drug for the treatment of HCC.
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Affiliation(s)
- Licheng Zhu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Lei
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Huang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yahang An
- The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Yanqiao Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huangxuan Zhao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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11
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Ailia MJ, Heo J, Yoo SY. Navigating through the PD-1/PDL-1 Landscape: A Systematic Review and Meta-Analysis of Clinical Outcomes in Hepatocellular Carcinoma and Their Influence on Immunotherapy and Tumor Microenvironment. Int J Mol Sci 2023; 24:ijms24076495. [PMID: 37047482 PMCID: PMC10095164 DOI: 10.3390/ijms24076495] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
This systematic review aimed to assess the prognostic significance of programmed cell death-ligand 1 (PDL-1) and programmed cell death protein 1 (PD-1) in hepatocellular carcinoma (HCC). Medline, EMBASE, and Cochrane Library database searches were conducted, revealing nine relevant cohort studies (seven PDL-1 and three PD-1). Our meta-analysis showed that PD-1/PDL-1 was a marker of poor survival, regardless of the assessment method (PD-1 overall survival (OS): hazard ratio (HR) 2.40; 95% confidence interval (CI), 1.30–4.42; disease-free survival (DFS): HR 2.12; 95% CI, 1.45–3.10; PDL-1: OS: HR 3.61; 95% CI, 2.75–4.75; and DFS: HR 2.74; 95% CI, 2.09–3.59). Additionally, high level of PD-1/PDL-1 expression was associated with aging, multiple tumors, high alpha-fetoprotein levels, and advanced Barcelona Clinic Liver Cancer stage. This high level significantly predicted a poor prognosis for HCC, suggesting that anti-PD-1 therapy is plausible for patients with HCC. Furthermore, HIF-1 induces PD-1 expression, and PD1lowSOCS3high is associated with a better prognosis. Taken together, combination therapy may be the key to effective immunotherapy. Thus, exploring other markers, such as HIF-1 and SOCS3, along with PD-1/PDL-1 immunotherapy, may lead to improved outcomes.
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Affiliation(s)
- Muhammad Joan Ailia
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
| | - So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
- Correspondence: or ; Tel.: +82-51-510-3402
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12
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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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13
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Muthukutty P, Woo HY, Ragothaman M, Yoo SY. Recent Advances in Cancer Immunotherapy Delivery Modalities. Pharmaceutics 2023; 15:pharmaceutics15020504. [PMID: 36839825 PMCID: PMC9967630 DOI: 10.3390/pharmaceutics15020504] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 01/25/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Immunotherapy is crucial in fighting cancer and achieving successful remission. Many novel strategies have recently developed, but there are still some obstacles to overcome before we can effectively attack the cancer cells and decimate the cancer environment by inducing a cascade of immune responses. To successfully demonstrate antitumor activity, immune cells must be delivered to cancer cells and exposed to the immune system. Such cutting-edge technology necessitates meticulously designed delivery methods with no loss or superior homing onto cancer environments, as well as high therapeutic efficacy and fewer adverse events. In this paper, we discuss recent advances in cancer immunotherapy delivery techniques, as well as their future prospects.
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Affiliation(s)
- Palaniyandi Muthukutty
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
| | - Hyun Young Woo
- Department of Internal Medicine and Medical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
| | - Murali Ragothaman
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
| | - So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
- Correspondence: or ; Tel.: +82-51-510-3402
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14
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Wang J, Wu R, Sun JY, Lei F, Tan H, Lu X. An overview: Management of patients with advanced hepatocellular carcinoma. Biosci Trends 2022; 16:405-425. [PMID: 36476621 DOI: 10.5582/bst.2022.01109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) has constituted a significant health burden worldwide, and patients with advanced HCC, which is stage C as defined by the Barcelona Clinic Liver Cancer staging system, have a poor overall survival of 6-8 months. Studies have indicated the significant survival benefit of treatment based on sorafenib, lenvatinib, or atezolizumab-bevacizumab with reliable safety. In addition, the combination of two or more molecularly targeted therapies (first- plus second-line) has become a hot topic recently and is now being extensively investigated in patients with advanced HCC. In addition, a few biomarkers have been investigated and found to predict drug susceptibility and prognosis, which provides an opportunity to evaluate the clinical benefits of current therapies. In addition, many therapies other than tyrosine kinase inhibitors that might have additional survival benefits when combined with other therapeutic modalities, including immunotherapy, transarterial chemoembolization, radiofrequency ablation, hepatectomy, and chemotherapy, have also been examined. This review provides an overview on the current understanding of disease management and summarizes current challenges with and future perspectives on advanced HCC.
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Affiliation(s)
- Jincheng Wang
- The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China.,Graduate School of Biomedical Science and Engineering, Hokkaido University, Sapporo, Japan
| | - Rui Wu
- The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jin-Yu Sun
- The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Feifei Lei
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Xiaojie Lu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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15
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Sarantis P, Trifylli EM, Koustas E, Papavassiliou KA, Karamouzis MV, Papavassiliou AG. Immune Microenvironment and Immunotherapeutic Management in Virus-Associated Digestive System Tumors. Int J Mol Sci 2022; 23:13612. [PMID: 36362398 PMCID: PMC9655697 DOI: 10.3390/ijms232113612] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/31/2022] [Accepted: 11/04/2022] [Indexed: 08/29/2023] Open
Abstract
The development of cancer is a multifactorial phenomenon, while it constitutes a major global health problem. Viruses are an important factor that is involved in tumorigenesis and is associated with 12.1% of all cancer cases. Major examples of oncogenic viruses which are closely associated with the digestive system are HBV, HCV, EBV, HPV, JCV, and CMV. EBV, HPV, JCV, and CMV directly cause oncogenesis by expressing oncogenic proteins that are encoded in their genome. In contrast, HBV and HCV are correlated indirectly with carcinogenesis by causing chronic inflammation in the infected organs. In addition, the tumor microenvironment contains various immune cells, endothelial cells, and fibroblasts, as well as several growth factors, cytokines, and other tumor-secreted molecules that play a key role in tumor growth, progression, and migration, while they are closely interrelated with the virus. The presence of T-regulatory and B-regulatory cells in the tumor microenvironment plays an important role in the anti-tumor immune reaction. The tumor immune microenvironments differ in each type of cancer and depend on viral infection. The alterations in the immune microenvironment caused by viruses are also reflected in the effectiveness of immunotherapy. The present review aims at shedding light on the association between viruses and digestive system malignancies, the characteristics of the tumor immune microenvironment that develop, and the possible treatments that can be administered.
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Affiliation(s)
- Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eleni-Myrto Trifylli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Evangelos Koustas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Kostas A. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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16
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Ailia MJ, Yoo SY. In Vivo Oncolytic Virotherapy in Murine Models of Hepatocellular Carcinoma: A Systematic Review. Vaccines (Basel) 2022; 10:vaccines10091541. [PMID: 36146619 PMCID: PMC9505175 DOI: 10.3390/vaccines10091541] [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: 08/15/2022] [Revised: 09/07/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Current therapies often provide marginal survival benefits at the expense of undesirable side effects. Oncolytic viruses represent a novel strategy for the treatment of HCC due to their inherent ability to cause direct tumor cell lysis while sparing normal tissue and their capacity to stimulate potent immune responses directed against uninfected tumor cells and distant metastases. Oncolytic virotherapy (OVT) is a promising cancer treatment, but before it can become a standard option in practice, several challenges-systemic viral delivery optimization/enhancement, inter-tumoral virus dispersion, anti-cancer immunity cross-priming, and lack of artificial model systems-need to be addressed. Addressing these will require an in vivo model that accurately mimics the tumor microenvironment and allows the scientific community to design a more precise and accurate OVT. Due to their close physiologic resemblance to humans, murine cancer models are the likely preferred candidates. To provide an accurate assessment of the current state of in vivo OVT in HCC, we have reviewed a comprehensively searched body of work using murine in vivo HCC models for OVT.
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17
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Chen S, Chen H, Zhang Y, Li W. Efficacy and Safety of Cellular Immunotherapy by Local Infusion for Liver Tumor: A Systematic Review and Meta-Analysis. Front Oncol 2022; 12:772509. [PMID: 35296019 PMCID: PMC8918675 DOI: 10.3389/fonc.2022.772509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 02/01/2022] [Indexed: 01/30/2023] Open
Abstract
Background Cellular immunotherapy has become a new and promising treatment for patients with liver tumor. However, as most immune cells are delivered by intravenous injection, the effect is limited and is likely to produce systemic toxicity. Here, the objective was to investigate the efficacy and safety of cellular immunotherapy by local infusion, which seems to be a promising approach and has not been well-studied. Methods The PubMed, Web of Science, Embase, and Cochrane Library databases were searched to obtain literature. The overall response rate (ORR), overall survival (OS) rates, and adverse events were investigated to evaluate the effectiveness and safety of locoregional therapy. The methodological quality of the articles was assessed using the methodological index for non-randomized studies (MINORS) score. The meta-analysis was performed using Stata 15.0. Results The eligible 17 studies involved a total of 318 patients. The random-effects model demonstrated that the ORR of local cell infusion therapy was 48% (95% confidence interval [CI]: 26%–70%). The pooled OS rate was 94% (95% CI: 83%–100%) at 6 months, 87% (95% CI: 74%–96%) at 12 months, and 42% (95% CI: 16%–70%) at 24 months. Subgroup analyses suggested that minimally invasive treatment and absence of metastasis were significantly associated with better ORR. Fourteen studies reported a variety of adverse events related to cell therapy by local perfusion. The most common complications after regional infusion of immune cells were myelosuppression (66%), fever (50%), gastrointestinal toxicity (22%), hepatic dysfunction (15%), and pleural effusion and/or ascites (14%). Conclusions Immune cell therapy through local perfusion is effective for patients with liver cancer, with manageable toxicity. It demonstrates better prognosis when combined with minimally invasive therapy. Considering the potential limitations, more randomized controlled trials are needed to provide solid evidence for our findings.
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18
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Truong CS, Yoo SY. Oncolytic Vaccinia Virus in Lung Cancer Vaccines. Vaccines (Basel) 2022; 10:240. [PMID: 35214699 PMCID: PMC8875327 DOI: 10.3390/vaccines10020240] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 11/26/2022] Open
Abstract
Therapeutic cancer vaccines represent a promising therapeutic modality via the induction of long-term immune response and reduction in adverse effects by specifically targeting tumor-associated antigens. Oncolytic virus, especially vaccinia virus (VV) is a promising cancer treatment option for effective cancer immunotherapy and thus can also be utilized in cancer vaccines. Non-small cell lung cancer (NSCLC) is likely to respond to immunotherapy, such as immune checkpoint inhibitors or cancer vaccines, since it has a high tumor mutational burden. In this review, we will summarize recent applications of VV in lung cancer treatment and discuss the potential and direction of VV-based therapeutic vaccines.
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Affiliation(s)
| | - So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Korea;
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19
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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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20
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Sparchez Z, Radu P, Bartos A, Nenu I, Craciun R, Mocan T, Horhat A, Spârchez M, Dufour JF. Combined treatments in hepatocellular carcinoma: Time to put them in the guidelines? World J Gastrointest Oncol 2021; 13:1896-1918. [PMID: 35070032 PMCID: PMC8713312 DOI: 10.4251/wjgo.v13.i12.1896] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 05/03/2021] [Accepted: 11/05/2021] [Indexed: 02/06/2023] Open
Abstract
The time for battling cancer has never been more suitable than nowadays and fortunately against hepatocellular carcinoma (HCC) we do have a far-reaching arsenal. Moreover, because liver cancer comprises a plethora of stages-from very early to advanced disease and with many treatment options-from surgery to immunotherapy trials-it leaves the clinician a wide range of options. The scope of our review is to throw light on combination treatments that seem to be beyond guidelines and to highlight these using evidence-based analysis of the most frequently used combination therapies, discussing their advantages and flaws in comparison to the current standard of care. One particular combination therapy seems to be in the forefront: Transarterial chemoembolization plus ablation for medium-size non-resectable HCC (3-5 cm), which is currently at the frontier between Barcelona Clinic Liver Cancer classification A and B. Not only does it improve the outcome in contrast to each individual therapy, but it also seems to have similar results to surgery. Also, the abundance of immune checkpoint inhibitors that have appeared lately in clinical trials are bringing promising results against HCC. Although the path of combination therapies in HCC is still filled with uncertainty and caveats, in the following years the hepatology and oncology fields could witness an HCC guideline revolution.
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Affiliation(s)
- Zeno Sparchez
- 3rd Medical Department, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Pompilia Radu
- Department of Visceral Surgery and Medicine, Hepatology, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland
| | - Adrian Bartos
- Department of Surgery, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Iuliana Nenu
- 3rd Medical Department, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Rares Craciun
- 3rd Medical Department, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Tudor Mocan
- 3rd Medical Department, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Adelina Horhat
- 3rd Medical Department, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Mihaela Spârchez
- Department of Mother and Child, 2nd Paediatric Clinic, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400177, Romania
| | - Jean-François Dufour
- Department for BioMedical Research, Hepatology, University of Bern, Bern 3008, Switzerland
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Gupta S, Khan S, Kawka M, Gujjuri R, Chau I, Starling N, Cunningham D, Jiao LR, Gall T. Clinical utility of clonal origin determination in managing recurrent hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:1159-1167. [PMID: 34402366 DOI: 10.1080/17474124.2021.1967144] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Recurrence is the driving factor for reduced long-term survival in patients following resected hepatocellular carcinoma (HCC). Extensive research efforts have been conducted to understand the molecular processes precipitating disease recurrence. Modern genomic techniques have identified two distinct mechanisms for recurrent HCC (RHCC): Intrahepatic metastasis (IM-HCC); and multicentric origin (MO-HCC). Medline, EMBASE and Cochrane library were methodically searched for primary research articles in English with the aim of appraising existing literature on the identification of clonal origin of RHCC and its potential clinical utility. AREAS COVERED Molecular and next-generation sequencing techniques, when applied to clonal origin identification, yield superior accuracy than traditional clinicopathological criteria. Despite various treatment modalities, no optimal therapy has yet been identified for treating clonally differentiated RHCC. Patients with MO-HCC appear to experience improved long-term survival following re-treatment compared to their IM-HCC counterparts (91.7% vs 22.9% 5-year survival, p < 0.001). However, cautious interpretation is advised as heterogeneous classification criteria and small sample sizes restrict the generalizability of such findings. EXPERT OPINION Improved identification of clonal origin in RHCC may facilitate further research on RHCC treatment strategies and enable the development of novel therapeutic targets, potentially leading to individualized treatment approaches in the future.
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Affiliation(s)
- Shubham Gupta
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Sikandar Khan
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Michal Kawka
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Rohan Gujjuri
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Ian Chau
- Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - Naureen Starling
- Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - David Cunningham
- Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - Long R Jiao
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK.,Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - Tamara Gall
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK.,Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
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22
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Santos Apolonio J, Lima de Souza Gonçalves V, Cordeiro Santos ML, Silva Luz M, Silva Souza JV, Rocha Pinheiro SL, de Souza WR, Sande Loureiro M, de Melo FF. Oncolytic virus therapy in cancer: A current review. World J Virol 2021; 10:229-255. [PMID: 34631474 PMCID: PMC8474975 DOI: 10.5501/wjv.v10.i5.229] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/19/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
In view of the advancement in the understanding about the most diverse types of cancer and consequently a relentless search for a cure and increased survival rates of cancer patients, finding a therapy that is able to combat the mechanism of aggression of this disease is extremely important. Thus, oncolytic viruses (OVs) have demonstrated great benefits in the treatment of cancer because it mediates antitumor effects in several ways. Viruses can be used to infect cancer cells, especially over normal cells, to present tumor-associated antigens, to activate "danger signals" that generate a less immune-tolerant tumor microenvironment, and to serve transduction vehicles for expression of inflammatory and immunomodulatory cytokines. The success of therapies using OVs was initially demonstrated by the use of the genetically modified herpes virus, talimogene laherparepvec, for the treatment of melanoma. At this time, several OVs are being studied as a potential treatment for cancer in clinical trials. However, it is necessary to be aware of the safety and possible adverse effects of this therapy; after all, an effective treatment for cancer should promote regression, attack the tumor, and in the meantime induce minimal systemic repercussions. In this manuscript, we will present a current review of the mechanism of action of OVs, main clinical uses, updates, and future perspectives on this treatment.
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Affiliation(s)
- Jonathan Santos Apolonio
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Maria Luísa Cordeiro Santos
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - João Victor Silva Souza
- Universidade Estadual do Sudoeste da Bahia, Campus Vitória da Conquista, Vitória da Conquista 45083-900, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Wedja Rafaela de Souza
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Matheus Sande Loureiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
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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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Gallage S, García-Beccaria M, Szydlowska M, Rahbari M, Mohr R, Tacke F, Heikenwalder M. The therapeutic landscape of hepatocellular carcinoma. MED 2021; 2:505-552. [PMID: 35590232 DOI: 10.1016/j.medj.2021.03.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/23/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023]
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Lai E, Astara G, Ziranu P, Pretta A, Migliari M, Dubois M, Donisi C, Mariani S, Liscia N, Impera V, Persano M, Tolu S, Balconi F, Pinna G, Spanu D, Pireddu A, Saba G, Camera S, Musio F, Puzzoni M, Pusceddu V, Madeddu C, Casadei Gardini A, Scartozzi M. Introducing immunotherapy for advanced hepatocellular carcinoma patients: Too early or too fast? Crit Rev Oncol Hematol 2020; 157:103167. [PMID: 33271389 DOI: 10.1016/j.critrevonc.2020.103167] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 11/02/2020] [Accepted: 11/05/2020] [Indexed: 02/06/2023] Open
Abstract
Advanced hepatocellular carcinoma (HCC) is the most frequent liver cancer. Immunotherapy has been explored in this disease in order to improve survival outcomes. Nowadays, scientific research is focusing especially on immune checkpoint inhibitors, in particular anti-PD1, anti-PD-L1 and anti-CTLA4 monoclonal antibodies (mAbs), as single-agent or in combination with other immunotherapy agents, target therapies, anti-vascular endothelial growth factor (VEGF) and other agents targeting specific molecular pathways. Other immunotherapy strategies have been assessed or are under investigation in advanced HCC, namely cytokines, adoptive cell therapy, oncolytic virus, cancer vaccines. Each treatment presents specific efficacy and toxicity profiles, strictly related to their mechanism of action and to advanced HCC tumour microenvironment (TME). The aim of this review is to outline the state-of-the-art of immunotherapy in advanced HCC treatment, highlighting data on already investigated treatment strategies, safety and toxicity (including HBV/HCV-related HCC), and ongoing clinical trials focusing on new promising therapeutic weapons.
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Affiliation(s)
- Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Simona Tolu
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Francesca Balconi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Giovanna Pinna
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Annagrazia Pireddu
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Silvia Camera
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, 20019, Milan, Italy. Dipartimento di Oncologia, IRCCS Ospedale San Raffaele, via Olgettina 60, Milan, Italy.
| | - Francesca Musio
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Clelia Madeddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Andrea Casadei Gardini
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, 20019, Milan, Italy. Dipartimento di Oncologia, IRCCS Ospedale San Raffaele, via Olgettina 60, Milan, Italy.
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
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Heinrich S, Castven D, Galle PR, Marquardt JU. Translational Considerations to Improve Response and Overcome Therapy Resistance in Immunotherapy for Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:E2495. [PMID: 32899197 PMCID: PMC7563159 DOI: 10.3390/cancers12092495] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/26/2020] [Accepted: 08/31/2020] [Indexed: 12/24/2022] Open
Abstract
Over the last decade, progress in systemic therapies significantly improved the outcome of primary liver cancer. More recently, precision oncological and immunotherapeutic approaches became the focus of intense scientific and clinical research. Herein, preclinical studies showed promising results with high response rates and improvement of overall survival. However, results of phase III clinical trials revealed that only a subfraction of hepatocellular carcinoma (HCC) patients respond to therapy and display only moderate objective response rates. Further, predictive molecular characteristics are largely missing. In consequence, suitable trial design has emerged as a crucial factor for the success of a novel compound. In addition, increasing knowledge from translational studies indicate the importance of targeting the tumor immune environment to overcome resistance to immunotherapy. Thus, combination of different immunotherapies with other treatment modalities including antibodies, tyrosine kinase inhibitors, or local therapies is highly promising. However, the mechanisms of failure to respond to immunotherapy in liver cancer are still not fully understood and the modulation of the immune system and cellular tumor composition is particularly relevant in this context. Altogether, it is increasingly clear that tailoring of immunotherapy and individualized approaches are required to improve efficacy and patient outcome in liver cancer. This review provides an overview of the current knowledge as well as translational considerations to overcome therapy resistance in immunotherapy of primary liver cancer.
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Affiliation(s)
- Sophia Heinrich
- Laboratory of Human Carcinogenesis, Liver Carcinogenesis Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
- Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center, 55131 Mainz, Germany;
| | - Darko Castven
- Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center, 55131 Mainz, Germany;
- Lichtenberg Research Group for Molecular Hepatocarcinogenesis, Department of Medicine I, University Medical Center Schleswig Holstein, 23538 Luebeck, Germany
| | - Peter R. Galle
- Department of Medicine I, University Medical Center, 55131 Mainz, Germany
| | - Jens U. Marquardt
- Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center, 55131 Mainz, Germany;
- Lichtenberg Research Group for Molecular Hepatocarcinogenesis, Department of Medicine I, University Medical Center Schleswig Holstein, 23538 Luebeck, Germany
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Ghavimi S, Apfel T, Azimi H, Persaud A, Pyrsopoulos NT. Management and Treatment of Hepatocellular Carcinoma with Immunotherapy: A Review of Current and Future Options. J Clin Transl Hepatol 2020; 8:168-176. [PMID: 32832397 PMCID: PMC7438354 DOI: 10.14218/jcth.2020.00001] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 05/13/2020] [Accepted: 05/16/2020] [Indexed: 02/06/2023] Open
Abstract
With mortality rates of liver cancer doubling in the last 20 years, this disease is on the rise and has become the fifth most common cancer in men and the seventh most common cancer in women. Hepatocellular carcinoma (HCC) represents approximately 90% of all primary liver cancers and is a major global health concern. Patients with HCC can be managed curatively with surgical resection or with liver transplantation, if they are diagnosed at an early stage. Unfortunately, most patients with HCC present with advanced stages of the disease and have underlying liver dysfunction, which allows only 15% of patients to be eligible for curative treatment. Several different treatment modalities are available, including locoregional therapy radiofrequency ablation, microwave ablation, percutaneous ethanol injection, trans-arterial chemoembolization, transarterial radio-embolization, cryoablation, radiation therapy, stereotactic radiotherapy, systemic chemotherapy, molecularly targeted therapies, and immunotherapy. Immunotherapy has recently become a promising method for inhibiting HCC tumor progression, recurrence, and metastasis. The term "Immunotherapy" is a catch-all, encompassing a wide range of applications and targets, including HCC vaccines, adoptive cell therapy, immune checkpoint inhibitors, and use of oncolytic viruses to treat HCC. Immunotherapy in HCC is a relatively safe option for treating patients with advanced disease in the USA who are either unable to receive or failed sorafenib/lenvatinib therapy and thus may offer an additional survival benefit for these patients. The purpose of this review is to elaborate on some of the most recent advancements in immunotherapy.
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Affiliation(s)
- Shima Ghavimi
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Tehila Apfel
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Hamed Azimi
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Alana Persaud
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Nikolaos T. Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
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Novel Oncolytic Virus Armed with Cancer Suicide Gene and Normal Vasculogenic Gene for Improved Anti-Tumor Activity. Cancers (Basel) 2020; 12:cancers12051070. [PMID: 32344903 PMCID: PMC7281019 DOI: 10.3390/cancers12051070] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 04/24/2020] [Indexed: 12/22/2022] Open
Abstract
Here, we developed a novel oncolytic vaccinia virus (NOV) with the dual advantages of cancer selectivity and normal vessel reconstructive activity by replacing the viral thymidine kinase (vTk) and vaccinia growth factor (VGF) genes with genes encoding TNF-related apoptosis-inducing ligand (TRAIL) and angiopoietin 1 (Ang1), respectively. The pan-cancer-specific oncolytic potency of NOV was confirmed in various human and mouse cancer cell lines (colon, liver, pancreas, cholangiocarcinoma, cervical cancer, osteosarcoma, and melanoma). Vaccinia virus (VV) treatment directly induced early apoptosis in tumors within 24 h, and this effect was enhanced with further engineering; VGF and Tk deletion with Ang1 and TRAIL insertion. Meanwhile, treatment with the conventional anti-cancer drug cisplatin did not induce apoptosis. A virus-treated CT26 mouse colon cancer syngeneic model showed attenuated tumor growth, which was in accordance with the results of percent survival measurement, CD8 expression analysis, and TUNEL staining with advanced genetic engineering (vAng1 < vTRAIL < NOV). Taken together, our results indicate that NOV induces cancer tissue apoptosis and anti-tumor immunity and may constitute a highly advantageous therapeutic agent for next-generation solid tumor virotherapy with pan-cancer-specific oncolytic activity and high biosafety.
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Abstract
Liver cancer is a particularly aggressive group of malignancies with historically low survival rates. Despite advancements in cancer treatments in general in the last few decades, incidence and mortality have not changed. Even though some phase 1 and 2 studies have shown promising results, many medication have failed to reach a sustainable level of efficacy to move into the clinical setting. Immunotherapy drugs have shown impressive results in the treatment of specific immunogenic cancers, prompting the possibility of their use in liver cancers. Immunotherapy medications approved for other cancers have received FDA accelerated approval for treatment of hepatocellular carcinoma. But, these approvals are contingent upon verification and description of clinical benefit in confirmatory trials. With more treatments in development involving cancer vaccines and natural killer cell-mediated therapy, liver cancer treatment is being reinvigorated with a broad array of new treatment angles. In this review article, we discuss these treatments, focusing on mechanism of action and clinical trials. Much needed advancements in treating late- and early-stage liver cancers will require new and innovative immunotherapeutic treatments.
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Affiliation(s)
- Christoffer Briggs Lambring
- Graduate School of Biomedical Sciences, The University of North Texas Health Science Center, Fort Worth, Texas
| | | | | | - Riyaz Basha
- Graduate School of Biomedical Sciences, The University of North Texas Health Science Center, Fort Worth, Texas
- Department of Pediatrics and Women’s Health, Texas College of Osteopathic Medicine, The University of North Texas Health Science Center, Fort Worth, Texas
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Hilmi M, Vienot A, Rousseau B, Neuzillet C. Immune Therapy for Liver Cancers. Cancers (Basel) 2019; 12:E77. [PMID: 31892230 PMCID: PMC7016834 DOI: 10.3390/cancers12010077] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 12/24/2019] [Accepted: 12/25/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) display a poor prognosis with 5-year overall survival rates around 15%, all stages taken together. These primary liver malignancies are often diagnosed at advanced stages where therapeutic options are limited. Recently, immune therapy has opened new opportunities in oncology. Based on their high programmed death-ligand 1 expression and tumor-infiltrating lymphocytes, HCC and BTC are theoretically good candidates for immune checkpoint blockade. However, clinical activity of single agent immunotherapy appears limited to a subset of patients, which is still ill-defined, and combinations are under investigation. In this review, we provide an overview of (i) the biological rationale for immunotherapies in HCC and BTC, (ii) the current state of their clinical development, and (iii) the predictive value of immune signatures for both clinical outcome and response to these therapies.
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Affiliation(s)
- Marc Hilmi
- Department of Medical Oncology, Curie Institute, University of Versailles Saint-Quentin, 35 rue Dailly, 92210 Saint-Cloud, France;
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (A.V.); (B.R.)
| | - Angélique Vienot
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (A.V.); (B.R.)
- Department of Medical Oncology, Besançon University Hospital, 3 Boulevard Alexandre Fleming, 25030 Besançon, France
| | - Benoît Rousseau
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (A.V.); (B.R.)
- Department of Medicine, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Cindy Neuzillet
- Department of Medical Oncology, Curie Institute, University of Versailles Saint-Quentin, 35 rue Dailly, 92210 Saint-Cloud, France;
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (A.V.); (B.R.)
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Tai D, Choo SP, Chew V. Rationale of Immunotherapy in Hepatocellular Carcinoma and Its Potential Biomarkers. Cancers (Basel) 2019; 11:E1926. [PMID: 31816940 PMCID: PMC6966558 DOI: 10.3390/cancers11121926] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/27/2019] [Accepted: 11/29/2019] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of liver cancer, is derived mostly from a background of chronic inflammation. Multiple immunotherapeutic strategies have been evaluated in HCC, with some degree of success, particularly with immune checkpoint blockade (ICB). Despite the initial enthusiasm, treatment benefit is only appreciated in a modest proportion of patients (response rate to single agent ~20%). Therapy-induced immune-related adverse events (irAEs) and economic impact are pertinent considerations with ICB. It is imperative that a deeper understanding of its mechanisms of action either as monotherapy or in combination with other therapeutic agents is needed. We herein discuss the latest developments in the immunotherapeutic approaches for HCC, the potential predictive biomarkers., and the rationale for combination therapies. We also outline promising future immunotherapeutic strategies for HCC patients.
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Affiliation(s)
- David Tai
- National Cancer Centre, Singapore 169610, (NCCS), Singapore; (D.T.); (S.P.C.)
| | - Su Pin Choo
- National Cancer Centre, Singapore 169610, (NCCS), Singapore; (D.T.); (S.P.C.)
- Curie Oncology, Mount Elizabeth Novena Specialist Centre, Singapore 329563, Singapore
| | - Valerie Chew
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore 169856, Singapore
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Yoo SY, Badrinath N, Lee HL, Heo J, Kang DH. A Cancer-Favoring, Engineered Vaccinia Virus for Cholangiocarcinoma. Cancers (Basel) 2019; 11:E1667. [PMID: 31717883 PMCID: PMC6896061 DOI: 10.3390/cancers11111667] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 10/23/2019] [Accepted: 10/24/2019] [Indexed: 12/22/2022] Open
Abstract
While oncolytic vaccinia virus-based therapy has shown promising results for uncured patients with cancer, its effects on cholangiocarcinoma (CCA) remain unclear. Here, we evaluated the anti-cancer activity of the cancer-favoring oncolytic vaccinia virus (CVV), which was recognized as a promising therapy for stem cell-like colon cancer cells (SCCs) and metastatic hepatocellular carcinoma (HCC) in previous studies. CCA presents major challenges, such as clinical complexity, stem cell cancer characteristics, a high refractory rate, resistance to conventional therapy, and a dismal prognosis. In the present study, we confirmed the oncolytic activity of the CVV in CCA with a slightly alkaline microenvironment (pH 7-8), in which the CVV was stable and highly effective at infecting CCA. Taken together, our findings suggest that CVV-based therapy is highly suitable for the treatment of CCA.
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Affiliation(s)
- So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Korea; (H.L.L.); (D.-H.K.)
| | - Narayanasamy Badrinath
- Biomedical Sciences, School of Medicine, Pusan National University, Yangsan 50612, Korea; (N.B.); (J.H.)
| | - Hye Lim Lee
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Korea; (H.L.L.); (D.-H.K.)
| | - Jeong Heo
- Biomedical Sciences, School of Medicine, Pusan National University, Yangsan 50612, Korea; (N.B.); (J.H.)
| | - Dae-Hwan Kang
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Korea; (H.L.L.); (D.-H.K.)
- Biomedical Sciences, School of Medicine, Pusan National University, Yangsan 50612, Korea; (N.B.); (J.H.)
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Dendy MS, Ludwig JM, Stein SM, Kim HS. Locoregional Therapy, Immunotherapy and the Combination in Hepatocellular Carcinoma: Future Directions. Liver Cancer 2019; 8:326-340. [PMID: 31768343 PMCID: PMC6873025 DOI: 10.1159/000494843] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 10/23/2018] [Indexed: 02/04/2023] Open
Abstract
Image-guided locoregional therapies (LRTs) have long been a vital part of treatment regimens for hepatocellular carcinoma (HCC). Ablation, chemoembolization, and radioembolization are examples of commonly used treatment techniques for HCC. This review describes the various methods utilized to treat HCC in the field of interventional oncology and also focuses on new and novel treatment concepts being developed in the field including the use of novel immunotherapy agents and combination therapy of LRTs with immunotherapy.
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Affiliation(s)
- Meaghan S. Dendy
- Division of Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut, USA
| | - Johannes M. Ludwig
- Division of Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut, USA,Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Stacey M. Stein
- Division of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA,Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA
| | - Hyun S. Kim
- Division of Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut, USA,Division of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA,Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA,*Hyun S. Kim, MD, Yale Cancer Center, Yale School of Medicine, 330 Cedar Street, TE 2-224, New Haven, CT 06510 (USA), E-Mail
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Treatment Strategies for Hepatocellular Carcinoma ⁻ a Multidisciplinary Approach. Int J Mol Sci 2019; 20:ijms20061465. [PMID: 30909504 PMCID: PMC6470895 DOI: 10.3390/ijms20061465] [Citation(s) in RCA: 166] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 03/20/2019] [Accepted: 03/21/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and its mortality is third among all solid tumors, behind carcinomas of the lung and the colon. Despite continuous advancements in the management of this disease, the prognosis for HCC remains inferior compared to other tumor entities. While orthotopic liver transplantation (OLT) and surgical resection are the only two curative treatment options, OLT remains the best treatment strategy as it not only removes the tumor but cures the underlying liver disease. As the applicability of OLT is nowadays limited by organ shortage, major liver resections—even in patients with underlying chronic liver disease—are adopted increasingly into clinical practice. Against the background of the oftentimes present chronical liver disease, locoregional therapies have also gained increasing significance. These strategies range from radiofrequency ablation and trans-arterial chemoembolization to selective internal radiation therapy and are employed in both curative and palliative intent, individually, as a bridging to transplant or in combination with liver resection. The choice of the appropriate treatment, or combination of treatments, should consider the tumor stage, the function of the remaining liver parenchyma, the future liver remnant volume and the patient’s general condition. This review aims to address the topic of multimodal treatment strategies in HCC, highlighting a multidisciplinary treatment approach to further improve outcome in these patients.
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Bahreyni A, Ghorbani E, Fuji H, Ryzhikov M, Khazaei M, Erfani M, Avan A, Hassanian SM, Azadmanesh K. Therapeutic potency of oncolytic virotherapy-induced cancer stem cells targeting in brain tumors, current status, and perspectives. J Cell Biochem 2018; 120:2766-2773. [PMID: 30321455 DOI: 10.1002/jcb.27661] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 08/21/2018] [Indexed: 12/11/2022]
Abstract
Brain tumors are the most common form of solid tumors in children and is presently a serious therapeutic challenge worldwide. Traditional treatment with chemotherapy and radiotherapy was shown to be unsuccessful in targeting brain tumor cancer stem cells (CSCs), leading to recurrent, treatment-resistant secondary malignancies. Oncolytic virotherapy (OV) is an effective antitumor therapeutic strategy which offers a novel, targeted approach for eradicating pediatric brain tumor CSCs by utilizing mechanisms of cell killing that differ from conventional therapies. A number of studies and some clinical trials have therefore investigated the effects of combined therapy of radiations or chemotherapies with oncolytic viruses which provide new insights regarding the effectiveness and improvement of treatment responses for brain cancer patients. This review summarizes the current knowledge of the therapeutic potency of OVs-induced CSCs targeting in the treatment of brain tumors for a better understanding and hence a better management of this disease.
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Affiliation(s)
- Amirhossein Bahreyni
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elnaz Ghorbani
- Department of Microbiology, Al-Zahra University, Tehran, Iran
| | - Hamid Fuji
- Department of Biochemistry, Payame-Noor University, Mashhad, Iran
| | - Mikhail Ryzhikov
- Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, Missouri
| | - Majid Khazaei
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Marjan Erfani
- Department of Neurology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed M Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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