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1
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Lyu N, Yi JZ, Zhao M. Immunotherapy in older patients with hepatocellular carcinoma. Eur J Cancer 2021; 162:76-98. [PMID: 34954439 DOI: 10.1016/j.ejca.2021.11.024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/31/2021] [Accepted: 11/21/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer globally and is currently the third leading cause of cancer-related deaths. Recently, immunotherapy using immune checkpoint inhibitors (ICIs) has been shown with encouraging anticancer activity and safety in clinical trials. To reverse the phenomenon of tumours evading immune response, ICIs can be used to stimulate the natural antitumour potential of cancer cells by blocking the relevant checkpoints to activate T cells. However, the components and functions of the immune system may undergo a series of changes with ageing, known as 'immunosenescence,' potentially affecting the antitumour effect and safety of immunotherapy. In the current phase III clinical trials of ICIs including nivolumab, pembrolizumab and atezolizumab, the proportion of patients with HCC older than 65 years in CheckMate 459, KEYNOTE-240 and IMbrave150 is 51%, 58% and 50%, respectively, which is less than 70%-73% of epidemiological investigation. Therefore, the elderly population recruited in clinical trials may not accurately represent the real-world elderly patients with HCC, which affects the extrapolation of the efficacy and safety profile obtained in clinical trials to the elderly population in the real world. This review provides the latest advances in ICIs immuno-treatment available for HCC and relevant information about their therapeutic effects and safety on elderly patients. We discuss the benefits of ICIs for older HCC patients, and relevant recommendations about conducting further clinical trials are proposed for more complete answers to this clinical issue.
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Affiliation(s)
- Ning Lyu
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jun-Zhe Yi
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ming Zhao
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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2
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Ziogas IA, Evangeliou AP, Giannis D, Hayat MH, Mylonas KS, Tohme S, Geller DA, Elias N, Goyal L, Tsoulfas G. The Role of Immunotherapy in Hepatocellular Carcinoma: A Systematic Review and Pooled Analysis of 2,402 Patients. Oncologist 2021; 26:e1036-e1049. [PMID: 33314549 DOI: 10.1002/onco.13638] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 12/03/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Immune checkpoints inhibitors (ICIs) have emerged as a treatment option for several malignancies. Nivolumab, pembrolizumab, nivolumab plus ipilimumab, and atezolizumab plus bevacizumab have been approved for the management of advanced-stage hepatocellular carcinoma (HCC). We aimed to systematically review the literature and summarize the characteristics and outcomes of patients with HCC treated with ICIs. METHODS A systematic literature search of PubMed, the Cochrane Library, and ClinicalTrials.gov was performed according to the PRISMA statement (end of search date: November 7, 2020). Quality of evidence assessment was also performed. RESULTS Sixty-three articles including 2,402 patients were analyzed, 2,376 of whom received ICIs for unresectable HCC. Response to ICIs could be evaluated in 2,116 patients; the overall objective response rate (ORR) and disease control rate (DCR) were 22.7% and 60.7%, respectively, and the mean overall survival (OS) was 15.8 months. The ORR, DCR, and OS for nivolumab (n = 846) were 19.7%, 51.1%, and 18.7 months, respectively; for pembrolizumab (n = 435) they were 20.7%, 64.6% and 13.3 months, respectively. The combination of atezolizumab/bevacizumab (n = 460) demonstrated an ORR and DCR of 30% and 77%, respectively. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence); fatal graft rejection was reported in 40.0% (n = 6/15) and mortality in 80.0% (n = 12/15). CONCLUSION ICIs are safe and effective against unresectable HCC, but caution is warranted regarding their use in the LT setting because of the high graft rejection rate. IMPLICATIONS FOR PRACTICE This systematic review pooled the outcomes from studies reporting on the use of immune checkpoint inhibitors (ICIs) for the management of 2,402 patients with advanced-stage hepatocellular carcinoma (HCC), 2,376 of whom had unresectable HCC. The objective response rate and disease control rate were 22.7% and 60.7%, respectively, and the mean overall survival was 15.8 months. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence). Six of these patients experienced graft rejection (40.0%).
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Affiliation(s)
- Ioannis A Ziogas
- First Department of Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece.,Surgery Working Group, Society of Junior Doctors, Athens, Greece
| | | | - Dimitrios Giannis
- Surgery Working Group, Society of Junior Doctors, Athens, Greece.,Institute of Health Innovations and Outcomes Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA
| | - Muhammad H Hayat
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Konstantinos S Mylonas
- Department of Cardiothoracic Surgery, Yale New Haven Hospital, New Haven, Connecticut, USA
| | - Samer Tohme
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - David A Geller
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Nahel Elias
- Transplantation Unit, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Lipika Goyal
- Department of Medicine, Division of Medical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Georgios Tsoulfas
- First Department of Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece
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3
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Immune Checkpoint Inhibitors as Monotherapy or Within a Combinatorial Strategy in Advanced Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21176302. [PMID: 32878115 PMCID: PMC7504231 DOI: 10.3390/ijms21176302] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/27/2020] [Accepted: 08/28/2020] [Indexed: 12/13/2022] Open
Abstract
In advanced-stage hepatocellular carcinoma (HCC), systemic treatment represents the standard therapy. Target therapy has marked a new era based on a greater knowledge of molecular disease signaling. Nonetheless, survival outcomes and long-term response remain unsatisfactory, mostly because of the onset of primary or acquired resistance. More recently, results from clinical trials with immune targeting agents, such as the immune checkpoint inhibitors (ICIs), have shown a promising role for these drugs in the treatment of advanced HCC. In the context of an intrinsic tolerogenic liver environment, since HCC-induced immune tolerance, it is supported by multiple immunosuppressive mechanisms and several clinical trials are now underway to evaluate ICI-based combinations, including their associations with antiangiogenic agents or multikinase kinase inhibitors and multiple ICIs combinations. In this review, we will first discuss the basic principles of hepatic immunogenic tolerance and the evasive mechanism of antitumor immunity in HCC; furthermore we will elucidate the consistent biological rationale for immunotherapy in HCC even in the presence of an intrinsic tolerogenic environment. Subsequently, we will critically report and discuss current literature on ICIs in the treatment of advanced HCC, including a focus on the currently explored combinatorial strategies and their rationales. Finally, we will consider both challenges and future directions in this field.
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4
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De Mattia E, Cecchin E, Guardascione M, Foltran L, Di Raimo T, Angelini F, D’Andrea M, Toffoli G. Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma. World J Gastroenterol 2019; 25:3870-3896. [PMID: 31413525 PMCID: PMC6689804 DOI: 10.3748/wjg.v25.i29.3870] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/23/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other small-molecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c-MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.
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Affiliation(s)
- Elena De Mattia
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Erika Cecchin
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Michela Guardascione
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Luisa Foltran
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Tania Di Raimo
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
- Medical Oncology and Anatomic Pathology Unit, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Francesco Angelini
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
- Medical Oncology and Anatomic Pathology Unit, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Mario D’Andrea
- Department of Oncology, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Giuseppe Toffoli
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
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5
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Wang L, Wang FS. Clinical immunology and immunotherapy for hepatocellular carcinoma: current progress and challenges. Hepatol Int 2019; 13:521-533. [PMID: 31352593 DOI: 10.1007/s12072-019-09967-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Accepted: 06/27/2019] [Indexed: 12/16/2022]
Abstract
At the time of hepatocellular carcinoma (HCC) diagnosis, patients are most often at an advanced stage; however, the current treatment regimens remain unsatisfactory. Thus, novel and more powerful therapeutic approaches for advanced HCC are urgently required. Exacerbation of immunotolerant signals and/or escaping immunosurveillance leads to the development of HCC, which appears to be a rational reason to use immunotherapy to restore anticancer immunity. Several novel immunotherapeutic methods, including the use of immune checkpoint inhibitors, new types of immune cell adoption [e.g., chimeric antigen receptor T cell (CAR-T), TCR gene-modified T cells and stem cells], and microRNAs have been used in clinical trials for the treatment of HCC. However, some crucial issues remain to be addressed for such novel immunotherapy techniques. Finally, immunotherapy is now standing on the threshold of great advances in the fight against HCC.
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Affiliation(s)
- Lifeng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospital, 100 Western 4th Ring Road, Beijing, 100039, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospital, 100 Western 4th Ring Road, Beijing, 100039, China.
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Tighe SP, Iqbal U, Fernandes CT, Ahmed A. Treatment of inoperable hepatocellular carcinoma with immunotherapy. BMJ Case Rep 2019; 12:12/7/e229744. [PMID: 31352386 DOI: 10.1136/bcr-2019-229744] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
In the USA, mortality associated with hepatocellular carcinoma (HCC) continues to rise. Globally, HCC is the third most common cause of cancer-related death. In early stages of HCC, hepatic resection or liver transplantation are the preferred treatment options with a high probability of recurrence-free postoperative course. However, ineffective screening of chronic liver diseases in high-risk populations, poor linkage to care and suboptimal HCC surveillance has led to increasing rates of late-stage HCC at clinical presentation or diagnosis amenable only to palliative and experimental treatment options. Our case is a 66-year-old man with chronic hepatitis C virus infection complicated by cirrhosis and inoperable HCC which was non-responsive to selective intrahepatic trans-arterial chemoembolisation by interventional radiology. Therefore, he was treated with nivolumab immunotherapy and demonstrated normalisation of previously elevated alpha-fetoprotein levels suggestive of at least a partial response to immunotherapy. No adverse events related to nivolumab immunotherapy were encountered.
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Affiliation(s)
- Sean P Tighe
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Umair Iqbal
- Division of Internal Medicine, Geisinger Medical Center, Danville, Pennsylvania, USA
| | - Christopher T Fernandes
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA
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7
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Liu X, Qin S. Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Opportunities and Challenges. Oncologist 2019; 24:S3-S10. [PMID: 30819826 PMCID: PMC6394775 DOI: 10.1634/theoncologist.2019-io-s1-s01] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 11/21/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common malignancy worldwide, and is especially common in China. A total of 70%-80% of patients are diagnosed at an advanced stage and can receive only palliative care. Sorafenib has been the standard of care for a decade, and promising results for regorafenib as a second-line and lenvatinib as a first-line treatment were reported only 1 or 2 years ago. FOLFOX4 was recently recommended as a clinical practice guideline by the China Food and Drug Administration. All approved systemic therapies remain unsatisfactory, with limited objective response rates and poor overall survival. Immune checkpoint inhibitors (CPIs) offer great promise in the treatment of a rapidly expanding spectrum of solid tumors. Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and HCC and in the most important resistance mechanism of sorafenib. The approval of nivolumab by the U.S. Food and Drug Administration on September 23, 2017, for the treatment of patients with HCC, based only on a phase I/II clinical trial, is a strong hint that immunotherapy will introduce a new era of HCC therapy. CPI-based strategies will soon be a main approach in anticancer treatment for HCC, and we will observe the rapid advances in the therapeutic use of CPIs, even in an adjuvant setting, with great interest. How shall we face the opportunities and challenges? Can we dramatically improve the prognosis of patients with HCC? This review may provide some informed guidance. IMPLICATIONS FOR PRACTICE: Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and hepatocellular carcinoma (HCC) and in the most important resistance mechanism of sorafenib. As all approved systemic therapies in HCC remain unsatisfactory, checkpoint inhibitor (CPI)-based strategies will soon be a main approach in anticancer treatment for advanced stage of HCC, even in an adjuvant setting. In virus-related HCC, especially hepatitis B virus-related HCC, whether CPIs can control virus relapse should be further investigated. Combination strategies involving conventional therapies and immunotherapies are needed to increase clinical benefit and minimize adverse toxicities with regard to the underlying liver disease.
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Affiliation(s)
- Xiufeng Liu
- People's Liberation Army Cancer Center, Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, People's Republic of China
| | - Shukui Qin
- People's Liberation Army Cancer Center, Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, People's Republic of China
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8
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Baimas-George M, Baker E, Kamionek M, Salmon JS, Sastry A, Levi D, Vrochides D. A Complete Pathological Response to Pembrolizumab following ex vivo Liver Resection in a Patient with Colorectal Liver Metastases. Chemotherapy 2018; 63:90-94. [PMID: 29621772 DOI: 10.1159/000487814] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 02/16/2018] [Indexed: 02/28/2024]
Abstract
Advances in the systemic treatment of stage IV colorectal cancer with liver metastases has offered improved survival rates for patients who otherwise face a dismal prognosis. However, a pathologically complete response (PCR) to chemotherapy for colorectal liver metastases is still rare, and its significance is not fully understood. In this case report, we describe a patient who achieved PCR after neoadjuvant immunotherapy with pembrolizumab and a left hepatectomy using an ex vivo resection technique.
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Affiliation(s)
- Maria Baimas-George
- Department of General Surgery, Carolinas Medical Center, Carolinas Healthcare Systems, Charlotte, North Carolina, USA
| | - Erin Baker
- Department of Hepatopancreatobiliary Surgery, Carolinas Medical Center, Carolinas Healthcare Systems, Charlotte, North Carolina, USA
| | - Michal Kamionek
- Department of Pathology, Carolinas Medical Center, Carolinas Healthcare Systems, Charlotte, North Carolina, USA
| | - J Stuart Salmon
- Department of Medical Oncology, Carolinas Medical Center, Carolinas Healthcare Systems, Charlotte, North Carolina, USA
| | - Amit Sastry
- Department of Hepatopancreatobiliary Surgery, Carolinas Medical Center, Carolinas Healthcare Systems, Charlotte, North Carolina, USA
| | - David Levi
- Department of Transplant Surgery, Carolinas Medical Center, Carolinas Healthcare Systems, Charlotte, North Carolina, USA
| | - Dionisios Vrochides
- Department of Hepatopancreatobiliary Surgery, Carolinas Medical Center, Carolinas Healthcare Systems, Charlotte, North Carolina, USA
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9
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Li N, Wang J, Zhang N, Zhuang M, Zong Z, Zou J, Li G, Wang X, Zhou H, Zhang L, Shi Y. Cross-talk between TNF-α and IFN-γ signaling in induction of B7-H1 expression in hepatocellular carcinoma cells. Cancer Immunol Immunother 2018; 67:271-283. [PMID: 29090321 PMCID: PMC11028210 DOI: 10.1007/s00262-017-2086-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 10/26/2017] [Indexed: 12/11/2022]
Abstract
Clinical benefit from immunotherapy of B7-H1/PD-1 checkpoint blockade indicates that it is important to understand the regulatory mechanism of B7-H1 expression in cancer cells. As an adaptive response to the endogenous antitumor immunity, B7-H1 expression is up-regulated in HCC cells. B7-H1 expression is induced mainly by IFN-γ released from tumor-infiltrating T cells in HCC. In addition, HCC is a prototype of inflammation-related cancer and TNF-α is a critical component of inflammatory microenvironment of HCC. In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors. Furthermore, B7-H1 expression induced synergistically by TNF-α and IFN-γ in murine HCC cells facilitated tumor growth in vivo. Our findings suggest that TNF-α may enhance the adaptive immune resistance mediated by IFN-γ-induced B7-H1 in HCC cells.
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Affiliation(s)
- Na Li
- Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44# Wenhua Xi Road, Jinan, 250012, China
| | - Jianing Wang
- Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44# Wenhua Xi Road, Jinan, 250012, China
| | - Na Zhang
- Yinan People's Hospital, Yinan, China
| | - Mengwei Zhuang
- Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44# Wenhua Xi Road, Jinan, 250012, China
| | - Zhaoyun Zong
- Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44# Wenhua Xi Road, Jinan, 250012, China
| | - Jiahuan Zou
- Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44# Wenhua Xi Road, Jinan, 250012, China
| | - Guosheng Li
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaoyan Wang
- Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44# Wenhua Xi Road, Jinan, 250012, China
| | - Huaiyu Zhou
- Department of Parasitology, School of Medicine, Shandong University, Jinan, China
| | - Lining Zhang
- Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44# Wenhua Xi Road, Jinan, 250012, China
| | - Yongyu Shi
- Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44# Wenhua Xi Road, Jinan, 250012, China.
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Rinninella E, Cerrito L, Spinelli I, Cintoni M, Mele MC, Pompili M, Gasbarrini A. Chemotherapy for Hepatocellular Carcinoma: Current Evidence and Future Perspectives. J Clin Transl Hepatol 2017; 5:235-248. [PMID: 28936405 PMCID: PMC5606970 DOI: 10.14218/jcth.2017.00002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 04/29/2017] [Accepted: 04/29/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocarcinogenesis is a multistep process, heralded by abnormalities in cell differentiation and proliferation and sustained by an aberrant neoangiogenesis. Understanding the underlying molecular pathogenesis leading to hepatocellular carcinoma is a prerequisite to develop new drugs that will hamper or block the steps of these pathways. As hepatocellular carcinoma has higher arterial vascularization than normal liver, this could be a good target for novel molecular therapies. Introduction of the antiangiogenic drug sorafenib into clinical practice since 2008 has led to new perspectives in the management of this tumor. The importance of this drug lies not only in the modest gain of patients' survival, but in having opened a roadmap towards the development of new molecules and targets. Unfortunately, after the introduction of sorafenib, during the last years, a wide number of clinical trials on antiangiogenic therapies failed in achieving significant results. However, many of these trials are still ongoing and promise to improve overall survival and progression-free survival. A recent clinical trial has proven regorafenib effective in patients showing tumor progression under sorafenib, thus opening new interesting therapeutic perspectives. Many other expectations have been borne from the discovery of the immune checkpoint blockade, already known in other solid malignancies. Furthermore, a potential role in hepatocellular carcinoma therapy may derive from the use of branched-chain amino acids and of nutritional support. This review analyses the biomolecular pathways of hepatocellular carcinoma and the ongoing studies, the actual evidence and the future perspectives concerning drug therapy in this open field.
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Affiliation(s)
- Emanuele Rinninella
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
- Clinical Nutrition Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Lucia Cerrito
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Irene Spinelli
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Marco Cintoni
- Clinical Nutrition Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Maria Cristina Mele
- Clinical Nutrition Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
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11
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Gosalia AJ, Martin P, Jones PD. Advances and Future Directions in the Treatment of Hepatocellular Carcinoma. Gastroenterol Hepatol (N Y) 2017; 13:398-410. [PMID: 28867968 PMCID: PMC5572970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Liver transplant is considered the gold standard for curative therapy for HCC when patients are not candidates for surgical resection or ablation. Because a subset of patients with HCC have a survival rate with liver transplantation that is comparable to that of cirrhotic patients without tumors, the organ allocation system allows for increased priority for transplant in potential recipients within the Milan criteria. With the recent change in the Model for End-Stage Liver Disease exception point allocation, patients with HCC will now need to wait at least 6 months before being awarded extra points. This extension leads to increased time on the transplant waiting list and underscores the importance of locoregional therapy to contain the tumor burden. Fortunately, there has been significant progress in therapy for HCC in the past few decades, namely due to advances in interventional radiology, radiotherapy, and expanded surgical and transplant criteria. Recent advances in immunotherapy also provide promising options for patients who are not candidates for other therapies. This article highlights the major therapeutic options for HCC, including surgical resection, liver transplant, thermal and nonthermal ablation, chemoembolization, radiotherapy, and systemic chemotherapy, as well as discusses the evidence supporting these approaches.
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Affiliation(s)
- Ashil J Gosalia
- Dr Gosalia is a gastroenterology fellow in the Department of Medicine at the University of Miami Miller School of Medicine in Miami, Florida. Dr Martin is a professor and Dr Jones is an assistant professor in the Division of Hepatology at the University of Miami Miller School of Medicine. Dr Martin and Dr Jones are also affiliated with the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine
| | - Paul Martin
- Dr Gosalia is a gastroenterology fellow in the Department of Medicine at the University of Miami Miller School of Medicine in Miami, Florida. Dr Martin is a professor and Dr Jones is an assistant professor in the Division of Hepatology at the University of Miami Miller School of Medicine. Dr Martin and Dr Jones are also affiliated with the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine
| | - Patricia D Jones
- Dr Gosalia is a gastroenterology fellow in the Department of Medicine at the University of Miami Miller School of Medicine in Miami, Florida. Dr Martin is a professor and Dr Jones is an assistant professor in the Division of Hepatology at the University of Miami Miller School of Medicine. Dr Martin and Dr Jones are also affiliated with the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine
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Hoseini SS, Cheung NKV. Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies. Cancer Lett 2017; 399:44-52. [PMID: 28428075 DOI: 10.1016/j.canlet.2017.04.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 04/05/2017] [Accepted: 04/09/2017] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide with an overall survival rate of less than 15% in developed countries. Despite attempts at new therapeutic strategies, the majority of patients succumb to this cancer. Buttressed by the highly successful clinical impact in melanoma, immunotherapy is gaining momentum as the next treatment modality for many human cancers. Chimeric antigen receptors (CAR) contain the antigen binding moieties of a monoclonal antibody and the co-stimulatory and signaling domains associated with effector receptor signaling. Bispecific antibodies (BsAb) combine the binding specificities of two different monoclonal antibodies, one activating a receptor on a killer effector cell, while the other engaging a tumor-associated antigen to initiate tumor cytotoxicity. In this review, we survey the HCC targets for which CARs and bispecific antibodies have been generated. The pros and cons of these targets for T-cell and Natural Killer cell based immunotherapy will be discussed.
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Affiliation(s)
| | - Nai-Kong V Cheung
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, United States.
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