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Shin SK, Mishima Y, Lee Y, Kwon OS, Kim JH, Kim YS, Kaneko S. Current Landscape of Adoptive Cell Therapy and Challenge to Develop "Off-The-Shelf" Therapy for Hepatocellular Carcinoma. J Gastroenterol Hepatol 2025; 40:791-807. [PMID: 39865534 DOI: 10.1111/jgh.16872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 12/13/2024] [Accepted: 12/26/2024] [Indexed: 01/28/2025]
Abstract
Adoptive cell therapy (ACT) is a type of immunotherapy in which autologous or allogeneic immune cells, such as tumor-infiltrating lymphocytes or engineered lymphocytes, are infused into patients with cancer to eliminate malignant cells. Recently, autologous T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 showed a positive response in clinical studies for hematologic malignancies and have begun to be used in clinical practice. This article discusses the current status and promise of ACT research in hepatocellular carcinoma (HCC), focusing on challenges in off-the-shelf ACT using primary cells or induced pluripotent stem cells (iPSCs) with or without genetic engineering. Early clinical trials of autologous GPC-3-, MUC1-, or CEA-targeted CAR-T cell therapies are underway for HCC. There is a growing demand for the development of off-the-shelf therapies due to the high cost and manufacturing issues associated with autologous CAR-T. The development of ACT from various cell sources, such as NK cells, NKT cells, macrophages, and γδ T cells without MHC restriction other than T cells has been proposed. Advances in genome editing, including HLA gene knockout to avoid GvHD, and strategies to enhance efficacy in overcoming the suppressive tumor microenvironment, are used to create universal 'off-the-shelf' CAR-T cells which can be used immediately as therapeutic products from healthy donors or iPSC-derived immune cells. Despite several limitations, cell-based immunotherapy is expected to become a key cancer treatment modality for both hematologic malignancies and solid tumors including HCC, thanks to technological advancements overcoming these challenges.
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Affiliation(s)
- Seung Kak Shin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea
| | - Yuta Mishima
- Laboratory of Cancer Immunotherapy and Immunology, Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yoonseok Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea
| | - Oh Sang Kwon
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea
| | - Ju Hyun Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea
| | - Yun Soo Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea
| | - Shin Kaneko
- Laboratory of Cancer Immunotherapy and Immunology, Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Laboratory of Regenerative Immunotherapy, Department of Cell Growth and Differentiation, Center for iPS Cell Research, Kyoto University, Kyoto, Sakyo-ku, Japan
- Shinobi Therapeutics Co Ltd, Kyoto, Sakyo-ku, Japan
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Nevola R, Delle Femine A, Rosato V, Kondili LA, Alfano M, Mastrocinque D, Imbriani S, Perillo P, Beccia D, Villani A, Ruocco R, Criscuolo L, La Montagna M, Russo A, Marrone A, Sasso FC, Marfella R, Rinaldi L, Esposito N, Barberis G, Claar E. Neoadjuvant and Adjuvant Systemic Therapies in Loco-Regional Treatments for Hepatocellular Carcinoma: Are We at the Dawn of a New Era? Cancers (Basel) 2023; 15:2950. [PMID: 37296912 PMCID: PMC10251995 DOI: 10.3390/cancers15112950] [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: 04/14/2023] [Revised: 05/20/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Despite maximizing techniques and patient selection, liver resection and ablation for HCC are still associated with high rates of recurrence. To date, HCC is the only cancer with no proven adjuvant or neoadjuvant therapy used in association to potentially curative treatment. Perioperative combination treatments are urgently needed to reduce recurrence rates and improve overall survival. Immunotherapy has demonstrated encouraging results in the setting of adjuvant and neoadjuvant treatments for non-hepatic malignancies. Conclusive data are not yet available in the context of liver neoplasms. However, growing evidence suggests that immunotherapy, and in particular immune checkpoint inhibitors, could represent the cornerstone of an epochal change in the treatment of HCC, improving recurrence rates and overall survival through combination treatments. Furthermore, the identification of predictive biomarkers of treatment response could drive the management of HCC into the era of a precision medicine. The purpose of this review is to analyze the state of the art in the setting of adjuvant and neoadjuvant therapies for HCC in association with loco-regional treatments in patients not eligible for liver transplantation and to hypothesize future scenarios.
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Affiliation(s)
- Riccardo Nevola
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Augusto Delle Femine
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Valerio Rosato
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
| | | | - Maria Alfano
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Davide Mastrocinque
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
| | - Simona Imbriani
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Pasquale Perillo
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
| | - Domenico Beccia
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Angela Villani
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Rachele Ruocco
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Livio Criscuolo
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Marco La Montagna
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Antonio Russo
- Department of Mental Health and Public Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Nicolino Esposito
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
| | | | - Ernesto Claar
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
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Zhao M, Huang H, He F, Fu X. Current insights into the hepatic microenvironment and advances in immunotherapy for hepatocellular carcinoma. Front Immunol 2023; 14:1188277. [PMID: 37275909 PMCID: PMC10233045 DOI: 10.3389/fimmu.2023.1188277] [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: 03/20/2023] [Accepted: 05/04/2023] [Indexed: 06/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and shows high global incidence and mortality rates. The liver is an immune-tolerated organ with a specific immune microenvironment that causes traditional therapeutic approaches to HCC, such as chemotherapy, radiotherapy, and molecular targeted therapy, to have limited efficacy. The dramatic advances in immuno-oncology in the past few decades have modified the paradigm of cancer therapy, ushering in the era of immunotherapy. Currently, despite the rapid integration of cancer immunotherapy into clinical practice, some patients still show no response to treatment. Therefore, a rational approach is to target the tumor microenvironment when developing the next generation of immunotherapy. This review aims to provide insights into the hepatic immune microenvironment in HCC and summarize the mechanisms of action and clinical usage of immunotherapeutic options for HCC, including immune checkpoint blockade, adoptive therapy, cytokine therapy, vaccine therapy, and oncolytic virus-based therapy.
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Affiliation(s)
| | | | - Feng He
- *Correspondence: Feng He, ; Xiangsheng Fu,
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2023; 23:1-120. [PMID: 37384024 PMCID: PMC10202234 DOI: 10.17998/jlc.2022.11.07] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/07/2022] [Indexed: 06/30/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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Affiliation(s)
- Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea
- Corresponding author: KLCA-NCC Korea Practice Guideline Revision Committee (KPGRC) (Committee Chair: Joong-Won Park) Center for Liver and Pancreatobiliary Cancer, Division of Gastroenterology, Department of Internal Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel. +82-31-920-1605, Fax: +82-31-920-1520, E-mail:
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5
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Nevola R, Ruocco R, Criscuolo L, Villani A, Alfano M, Beccia D, Imbriani S, Claar E, Cozzolino D, Sasso FC, Marrone A, Adinolfi LE, Rinaldi L. Predictors of early and late hepatocellular carcinoma recurrence. World J Gastroenterol 2023; 29:1243-1260. [PMID: 36925456 PMCID: PMC10011963 DOI: 10.3748/wjg.v29.i8.1243] [Citation(s) in RCA: 87] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/06/2023] [Accepted: 01/30/2023] [Indexed: 02/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent liver neoplasm, and its incidence rates are constantly increasing. Despite the availability of potentially curative treatments (liver transplantation, surgical resection, thermal ablation), long-term outcomes are affected by a high recurrence rate (up to 70% of cases 5 years after treatment). HCC recurrence within 2 years of treatment is defined as "early" and is generally caused by the occult intrahepatic spread of the primary neoplasm and related to the tumor burden. A recurrence that occurs after 2 years of treatment is defined as "late" and is related to de novo HCC, independent of the primary neoplasm. Early HCC recurrence has a significantly poorer prognosis and outcome than late recurrence. Different pathogenesis corresponds to different predictors of the risk of early or late recurrence. An adequate knowledge of predictive factors and recurrence risk stratification guides the therapeutic strategy and post-treatment surveillance. Patients at high risk of HCC recurrence should be referred to treatments with the lowest recurrence rate and when standardized to combined or adjuvant therapy regimens. This review aimed to expose the recurrence predictors and examine the differences between predictors of early and late recurrence.
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Affiliation(s)
- Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
- Internal Medicine and Hepatology Unit, Ospedale Evangelico Betania, Naples 80147, Italy
| | - Rachele Ruocco
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
| | - Livio Criscuolo
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
| | - Angela Villani
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
| | - Maria Alfano
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
| | - Domenico Beccia
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
| | - Simona Imbriani
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
| | - Ernesto Claar
- Internal Medicine and Hepatology Unit, Ospedale Evangelico Betania, Naples 80147, Italy
| | - Domenico Cozzolino
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
| | - Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples 80138, Italy
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6
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Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2023; 29:1054-1075. [PMID: 36844141 PMCID: PMC9950866 DOI: 10.3748/wjg.v29.i6.1054] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/23/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the world’s deadliest and fastest-growing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery (liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying liver condition. Despite promising preclinical and early-phase clinical trials for some drugs, existing systemic therapeutic methods for advanced tumor stages remain limited, underlining an unmet clinical need. In current years, cancer immunotherapy has made significant progress, opening up new treatment options for HCC. HCC, on the other hand, has a variety of causes and can affects the body’s immune system via a variety of mechanisms. With the speedy advancement of synthetic biology and genetic engineering, a range of innovative immunotherapies, such as immune checkpoint inhibitors [anti-programmed cell death-1 (PD-1), anti-cytotoxic T lymphocyte antigen-4, and anti-PD ligand 1 cell death antibodies], therapeutic cancer vaccines, engineered cytokines, and adoptive cell therapy have all been used for the treatment of advanced HCC. In this review, we summarize the present clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent clinical trial outcomes, and address future perspectives in the field of liver cancer.
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Affiliation(s)
- Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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2022 KLCA-NCC Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2022; 23:1126-1240. [PMID: 36447411 PMCID: PMC9747269 DOI: 10.3348/kjr.2022.0822] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol 2022; 28:583-705. [PMID: 36263666 PMCID: PMC9597235 DOI: 10.3350/cmh.2022.0294] [Citation(s) in RCA: 170] [Impact Index Per Article: 56.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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9
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Rallis KS, Makrakis D, Ziogas IA, Tsoulfas G. Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances. World J Clin Oncol 2022; 13:448-472. [PMID: 35949435 PMCID: PMC9244967 DOI: 10.5306/wjco.v13.i6.448] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/27/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. HCC is an inflammation-associated immunogenic cancer that frequently arises in chronically inflamed livers. Advanced HCC is managed with systemic therapies; the tyrosine kinase inhibitor (TKI) sorafenib has been used in 1st-line setting since 2007. Immunotherapies have emerged as promising treatments across solid tumors including HCC for which immune checkpoint inhibitors (ICIs) are licensed in 1st- and 2nd-line treatment setting. The treatment field of advanced HCC is continuously evolving. Several clinical trials are investigating novel ICI candidates as well as new ICI regimens in combination with other therapeutic modalities including systemic agents, such as other ICIs, TKIs, and anti-angiogenics. Novel immunotherapies including adoptive cell transfer, vaccine-based approaches, and virotherapy are also being brought to the fore. Yet, despite advances, several challenges persist. Lack of real-world data on the use of immunotherapy for advanced HCC in patients outside of clinical trials constitutes a main limitation hindering the breadth of application and generalizability of data to this larger and more diverse patient cohort. Consequently, issues encountered in real-world practice include patient ineligibly for immunotherapy because of contraindications, comorbidities, or poor performance status; lack of response, efficacy, and safety data; and cost-effectiveness. Further real-world data from high-quality large prospective cohort studies of immunotherapy in patients with advanced HCC is mandated to aid evidence-based clinical decision-making. This review provides a critical and comprehensive overview of clinical trials and real-world data of immunotherapy for HCC, with a focus on ICIs, as well as novel immunotherapy strategies underway.
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Affiliation(s)
- Kathrine S Rallis
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, United Kingdom
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
| | - Dimitrios Makrakis
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Division of Oncology, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Ioannis A Ziogas
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Aristotle University School of Medicine, Thessaloniki 54622, Greece
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10
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Liu Z, Liu X, Liang J, Liu Y, Hou X, Zhang M, Li Y, Jiang X. Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects. Front Immunol 2021; 12:765101. [PMID: 34675942 PMCID: PMC8524467 DOI: 10.3389/fimmu.2021.765101] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with poor prognosis. Surgery, chemotherapy, and radiofrequency ablation are three conventional therapeutic options that will help only a limited percentage of HCC patients. Cancer immunotherapy has achieved dramatic advances in recent years and provides new opportunities to treat HCC. However, HCC has various etiologies and can evade the immune system through multiple mechanisms. With the rapid development of genetic engineering and synthetic biology, a variety of novel immunotherapies have been employed to treat advanced HCC, including immune checkpoint inhibitors, adoptive cell therapy, engineered cytokines, and therapeutic cancer vaccines. In this review, we summarize the current landscape and research progress of different immunotherapy strategies in the treatment of HCC. The challenges and opportunities of this research field are also discussed.
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Affiliation(s)
- Zhuoyan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xuan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaxin Liang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yixin Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaorui Hou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Meichuan Zhang
- R&D Department, Caleb BioMedical Technology Co. Ltd, Guangzhou, China
| | - Yongyin Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaotao Jiang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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11
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Zhang L, Ding J, Li HY, Wang ZH, Wu J. Immunotherapy for advanced hepatocellular carcinoma, where are we? Biochim Biophys Acta Rev Cancer 2020; 1874:188441. [PMID: 33007432 DOI: 10.1016/j.bbcan.2020.188441] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/10/2020] [Accepted: 09/25/2020] [Indexed: 02/07/2023]
Abstract
A couple of molecular-targeting medications, such as Lenvatinib, are available for the treatment of hepatocellular carcinoma (HCC) in addition to Sorafenib in an advanced stage. Approval for the use of immune check-point inhibitors, such as Nivolumab and Pembrolizumab has shifted the paradigm of current HCC treatment, and the monotherapy or in combination with Lenvatinib or Sorafenib has significantly extended overall survival or progression-free survival in a large portion of patients. A combination of programmed cell death ligand-1 (PD-L1) inhibitor Atezolizumab with a vascular endothelial growth factor (VEGF) inhibitor, Bevacizumab, has recently achieved promising outcome in unresectable HCC patients. Other immunotherapy, such as chimeric antigen receptor T (CAR-T) cell therapy has achieved an evolutional success in hematologic malignancies, and has extended its use in deadly solid tumors, such as HCC. Although there exist various barriers, novel approaches are developed to move potential adoptive T cell therapy strategies, including cytokine-induced killer (CIK) cells, tumor-infiltrating lymphocytes (TIL), T cell receptor (TCR) T cells, CAR-T cells, to clinical application.
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Affiliation(s)
- Li Zhang
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jia Ding
- Department of Gastroenterology, Shanghai Jing'an District Central Hospital, Fudan University, Shanghai 200040, China
| | - Hui-Yan Li
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhong-Hua Wang
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jian Wu
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China.
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12
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Patel K, Lamm R, Altshuler P, Dang H, Shah AP. Hepatocellular Carcinoma-The Influence of Immunoanatomy and the Role of Immunotherapy. Int J Mol Sci 2020; 21:ijms21186757. [PMID: 32942580 PMCID: PMC7555667 DOI: 10.3390/ijms21186757] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality worldwide. Most patients are diagnosed with advanced disease, limiting their options for treatment. While current treatments are adequate for lower staged disease, available systemic treatments are limited, with marginal benefit at best. Chimeric antigen receptor (CAR) T cell therapy, effective in treating liquid tumors such as B-cell lymphoma, presents a potentially promising treatment option for advanced HCC. However, new challenges specific to solid tumors, such as tumor immunoanatomy or the immune cell presence and position anatomically and the tumor microenvironment, need to be defined and overcome. Immunotherapy currently in use must be re-engineered and re-envisioned to treat HCC with the hopes of ushering in an answer to advanced stage solid tumor disease processes. Future therapy options must address the uniqueness of the tumors under the umbrella of HCC. This review strives to summarize HCC, its staging system, current therapy and immunotherapy medications currently being utilized or studied in the treatment of HCC with the hopes of highlighting what is being done and suggesting what needs to be done in the future to champion this therapy as an effective option.
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Affiliation(s)
- Keyur Patel
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Ryan Lamm
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Peter Altshuler
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Hien Dang
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
- Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA
- Correspondence: (H.D.); (A.P.S.)
| | - Ashesh P. Shah
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
- Correspondence: (H.D.); (A.P.S.)
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13
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Piñero F, Tanno M, Aballay Soteras G, Tisi Baña M, Dirchwolf M, Fassio E, Ruf A, Mengarelli S, Borzi S, Fernández N, Ridruejo E, Descalzi V, Anders M, Mazzolini G, Reggiardo V, Marciano S, Perazzo F, Spina JC, McCormack L, Maraschio M, Lagues C, Gadano A, Villamil F, Silva M, Cairo F, Ameigeiras B. Argentinian clinical practice guideline for surveillance, diagnosis, staging and treatment of hepatocellular carcinoma. Ann Hepatol 2020; 19:546-569. [PMID: 32593747 DOI: 10.1016/j.aohep.2020.06.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/05/2020] [Accepted: 06/10/2020] [Indexed: 02/08/2023]
Abstract
The A.A.E.E.H has developed this guideline for the best care of patients with hepatocellular carcinoma (HCC) from Argentina. It was done from May 2018 to March 2020. Specific clinical research questions were systematically searched. The quality of evidence and level of recommendations were organized according to GRADE. HCC surveillance is strongly recommended with abdominal ultrasound (US) every six months in the population at risk for HCC (cirrhosis, hepatitis B or hepatitis C); it is suggested to add alpha-feto protein (AFP) levels in case of inexeperienced sonographers. Imaging diagnosis in patients at risk for HCC has high specificity and tumor biopsy is not mandatory. The Barcelona Clinic Liver Cancer algorithm is strongly recommended for HCC staging and treatment-decision processes. Liver resection is strongly recommended for patients without portal hypertension and preserved liver function. Composite models are suggested for liver transplant selection criteria. Therapies for HCC with robust clinical evidence include transarterial chemoembolization (TACE) and first to second line systemic treatment options (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). Immunotherapy with nivolumab and pembrolizumab has failed to show statistical benefit but the novel combination of atezolizumab plus bevacizumab has recently shown survival benefit over sorafenib in frontline.
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Affiliation(s)
- Federico Piñero
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina.
| | - Mario Tanno
- Hospital Centenario de Rosario, Santa Fe, Argentina
| | | | - Matías Tisi Baña
- Internal Medicine and Epidemiology Department, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | - Andrés Ruf
- Hospital Privado de Rosario, Santa Fe, Argentina
| | | | - Silvia Borzi
- Instituto Rossi, La Plata, Buenos Aires, Argentina
| | | | - Ezequiel Ridruejo
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina; Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Ciudad de Buenos Aires, Argentina
| | | | | | - Guillermo Mazzolini
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | | | | | | | | | - Cecilia Lagues
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | - Marcelo Silva
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
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14
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Park R, Eshrat F, Al-Jumayli M, Saeed A, Saeed A. Immuno-Oncotherapeutic Approaches in Advanced Hepatocellular Carcinoma. Vaccines (Basel) 2020; 8:E447. [PMID: 32784389 PMCID: PMC7563532 DOI: 10.3390/vaccines8030447] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/01/2020] [Accepted: 08/05/2020] [Indexed: 12/13/2022] Open
Abstract
Advanced hepatocellular carcinoma has limited treatment options, but there has been extensive growth recently with cabozantinib, regorafenib, lenvatinib, nivolumab, atezolizumab, and bevacizumab, which are some of the treatments that have received FDA approval just over the last three years. Because HCC tumor microenvironment is potentially immunogenic and typically characterized by inflammation, immunotherapy has been proposed as a potential novel therapeutic approach, which has prompted studies in advanced HCC patients investigating various immune-therapeutic strategies such as CAR-T cell therapy, checkpoint inhibitors, and onco-vaccines. The anti-PD-1 checkpoint inhibitors nivolumab and pembrolizumab have been FDA approved as a second line treatment in patients who progressed or are intolerant to Sorafenib. To build up on the success of PD-1 monotherapy, combinatorial regimens with PD-1/PD-L1 inhibitors plus VEGF targeted agents have shown positive results in various malignancies including HCC. The combination of atezolizumab plus bevacizumab is the new addition to the HCC treatment armamentarium following a pivotal study that demonstrated an improvement in OS over frontline sorafenib. Other novel immune-based approaches and oncolytic viruses are in the early phases of clinical evaluation. These innovative approaches enhance the intensity of cancer-directed immune responses and will potentially impact the outlook of this aggressive disease.
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Affiliation(s)
- Robin Park
- MetroWest Medical Center, Tufts University School of Medicine, Framingham, MA 01702, USA;
| | - Fariha Eshrat
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS 66160, USA; (F.E.); (M.A.-J.)
| | - Mohammed Al-Jumayli
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS 66160, USA; (F.E.); (M.A.-J.)
| | - Azhar Saeed
- Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS 66160, USA;
| | - Anwaar Saeed
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS 66160, USA; (F.E.); (M.A.-J.)
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15
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Sahara K, Farooq SA, Tsilimigras DI, Merath K, Paredes AZ, Wu L, Mehta R, Hyer JM, Endo I, Pawlik TM. Immunotherapy utilization for hepatobiliary cancer in the United States: disparities among patients with different socioeconomic status. Hepatobiliary Surg Nutr 2020; 9:13-24. [PMID: 32140475 DOI: 10.21037/hbsn.2019.07.01] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Patients with advanced hepatobiliary cancer (HBC) have a dismal prognosis and limited treatment options. Immunotherapy has been considered as a promising treatment, especially for cancers not amenable to surgery. Methods Between 2004, and 2015, patients diagnosed with hepatocellular carcinoma (HCC), intra- and extrahepatic cholangiocarcinoma and gallbladder cancer (GBC) were identified in the National Cancer Database. Results Among 249,913 patients with HBC, only 585 (0.2%) patients received immunotherapy. Among patients who received immunotherapy, most patients were diagnosed between 2012 and 2015, had private insurance, as well as an income ≥$46,000 and were treated at an academic facility. The use of immunotherapy among HBC patients varied by diagnosis (HCC, 67.7%; bile duct cancer, 14%). On multivariable analysis, a more recent period of diagnosis (OR 1.80, 95% CI: 1.44-2.25), median income >$46,000 (OR 1.43, 95% CI: 1.11-1.87), and higher tumor stage (stage III, OR 2.22, 95% CI: 1.65-3.01; stage IV, OR 3.24, 95% CI: 2.41-4.34) were associated with greater odds of receiving immunotherapy. Conclusions Overall utilization of immunotherapy in the US among patients with HBC was very low, yet has increased over time. Certain socioeconomic factors were associated with an increased likely of receiving immunotherapy, suggesting disparities in access of patients with lower socioeconomic status.
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Affiliation(s)
- Kota Sahara
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.,Gastroenterological Surgery Division, Yokohama City University School of Medicine, Yokohama, Japan
| | - S Ayesha Farooq
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Katiuscha Merath
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Anghela Z Paredes
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Lu Wu
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Rittal Mehta
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - J Madison Hyer
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Itaru Endo
- Gastroenterological Surgery Division, Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
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16
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Torabi-Rahvar M, Aghayan HR, Ahmadbeigi N. Antigen-independent killer cells prepared for adoptive immunotherapy: One source, divergent protocols, diverse nomenclature. J Immunol Methods 2019; 477:112690. [PMID: 31678265 DOI: 10.1016/j.jim.2019.112690] [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] [Received: 02/22/2019] [Revised: 06/15/2019] [Accepted: 10/25/2019] [Indexed: 12/30/2022]
Abstract
Adoptive cell therapy (ACT) using tumor antigen-independent killer cells has been widely used in clinical trials of cancer treatment. Circumventing the need for identification of a particular tumor-associated antigen on tumor cells, the approach has opened possibilities for the extension of ACT immunotherapy to patients with a wide variety of cancer types. Namely, Natural Killer (NK), Lymphokine-activated Killer (LAK) cells and Cytokine-induced killer (CIK) cells are the most commonly used cell types in antigen-independent adoptive immunotherapy of cancer. They all originate from peripheral blood mononuclear cells and share several common features in their killing mechanisms. However, despite broad application in clinical settings, the boundaries between these cell types are not very clearly defined. The current study aims to review different aspects of these cell populations in terms of phenotypical characteristic and preparation media, to clarify how the boundaries are set.
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Affiliation(s)
| | - Hamid-Reza Aghayan
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Naser Ahmadbeigi
- Cell-Based Therapies Research Center, Digestive Disease Research Institute,Shariati Hospital, Tehran University of Medical Sciences, North Kargar Ave, 14117 Tehran, Iran.
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17
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Lu SD, Li L, Liang XM, Chen W, Chen FL, Fan LL, Ahir BK, Zhang WG, Zhong JH. Updates and advancements in the management of hepatocellular carcinoma patients after hepatectomy. Expert Rev Gastroenterol Hepatol 2019; 13:1077-1088. [PMID: 31648568 DOI: 10.1080/17474124.2019.1684898] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023]
Abstract
Introduction: The 5-year recurrence rate of hepatocellular carcinoma (HCC) after hepatic resection or local ablation is up to 70%. Adjuvant therapies to prevent HCC recurrence have been reported but are not currently recommended by EASL or AASLD guidelines. This review examined evidence from randomized controlled trials, meta-analyses and systematic reviews on the safety and efficacy of adjuvant therapies and chemotherapies in HCC patients after resection or local ablation.Areas covered: PubMed was searched through 15 June 2019. Available evidence was assessed based on the GRADE system.Expert commentary: Transarterial chemoembolization is the best adjuvant therapy for HCC patients at high risk of recurrence, antiviral therapy with nucleoside analogs is effective for preventing recurrence of HBV-related HCC, and interferon-α is effective for preventing recurrence of HCV-related HCC. Further studies are needed to clarify the efficacy of adjuvant immune checkpoint inhibitors. Adjuvant sorafenib appears to offer negligible clinical benefit and high risk of adverse effects.
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Affiliation(s)
- Shi-Dong Lu
- Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lin Li
- Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xin-Min Liang
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Wu Chen
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Fu-Li Chen
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Lang-Lin Fan
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Bhavesh K Ahir
- Section of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Wan-Guang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
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18
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Wang J, Shen T, Wang Q, Zhang T, Li L, Wang Y, Fang Y. The long-term efficacy of cytokine-induced killer cellular therapy for hepatocellular carcinoma: a meta-analysis. Immunotherapy 2019; 11:1325-1335. [PMID: 31578914 DOI: 10.2217/imt-2019-0079] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Aim: The long-term efficacy of cytokine-induced killer cellular therapy for hepatocellular carcinoma patients after curative treatments remains controversial. Methods: A meta-analysis was conducted, and the outcomes were the recurrence rate and overall survival. Results: Eight randomized clinical trials with 1038 participants were included. Compared with the control group, cytokine-induced killer cellular therapy group could reduce 1-year, 3-year recurrence rates, as well as improve 1-5 years overall survival for hepatocellular carcinoma patients (p < 0.05). However, it failed to affect the 5-year recurrence rate and 6-year overall survival (p > 0.05). Conclusion: Cytokine-induced killer cellular adjuvant therapy exerted a favorable role in improving early and long-term efficacy for hepatocellular carcinoma patients.
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Affiliation(s)
- Jiaxue Wang
- Department of Pharmacy, Peking University People's Hospital, Beijing, China.,Department of Pharmacy Administration & Clinical Pharmacy, School of Pharmaceutical, Peking University, Beijing, China
| | - Tiantian Shen
- Department of Pharmacy, Peking University People's Hospital, Beijing, China.,School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Qi Wang
- Department of Pharmacy, Peking University People's Hospital, Beijing, China.,Department of Pharmacy Administration & Clinical Pharmacy, School of Pharmaceutical, Peking University, Beijing, China
| | - Tan Zhang
- Department of Pharmacy, Peking University People's Hospital, Beijing, China.,Department of Pharmacy Administration & Clinical Pharmacy, School of Pharmaceutical, Peking University, Beijing, China
| | - Lujin Li
- The Center for Drug Clinical Research of Shanghai University of TCM, Shanghai, China
| | - Yu Wang
- Immunotech Applied Science Limited, Beijing, China
| | - Yi Fang
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
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19
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Clinical Trials with Combination of Cytokine-Induced Killer Cells and Dendritic Cells for Cancer Therapy. Int J Mol Sci 2019; 20:ijms20174307. [PMID: 31484350 PMCID: PMC6747410 DOI: 10.3390/ijms20174307] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/23/2019] [Accepted: 08/30/2019] [Indexed: 02/06/2023] Open
Abstract
Adoptive cellular immunotherapy (ACI) is a promising treatment for a number of cancers. Cytokine-induced killer cells (CIKs) are considered to be major cytotoxic immunologic effector cells. Usually cancer cells are able to suppress antitumor responses by secreting immunosuppressive factors. CIKs have significant antitumor activity and are capable of eradicating tumors with few side effects. They are a very encouraging cell population used against hematological and solid tumors, with an inexpensive expansion protocol which could yield to superior clinical outcome in clinical trials employing adoptive cellular therapy combination. In the last decade, clinical protocols have been modified by enriching lymphocytes with CIK cells. They are a subpopulation of lymphocytes characterized by the expression of CD3+ and CD56+ wich are surface markers common to T lymphocytes and natural killer NK cells. CIK cells are mainly used in two diseases: in hematological patients who suffer relapse after allogeneic transplantation and in patients with hepatic carcinoma after surgical ablation to eliminate residual tumor cells. Dendritic cells DCs could play a pivotal role in enhancing the antitumor efficacy of CIKs.
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20
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2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2019; 20:1042-1113. [PMID: 31270974 PMCID: PMC6609431 DOI: 10.3348/kjr.2019.0140] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 02/24/2019] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology, and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions.
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21
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Tian M, Shi Y, Liu W, Fan J. Immunotherapy of hepatocellular carcinoma: strategies for combinatorial intervention. SCIENCE CHINA-LIFE SCIENCES 2019; 62:1138-1143. [PMID: 31119560 DOI: 10.1007/s11427-018-9446-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 03/20/2019] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, leading to 74.6 thousand deaths annually. The prognosis of HCC over the last few decades has remained unsatisfactory, and over half of patients with early-stage HCC develop recurrence by the time of follow-up. Immunotherapeutic intervention has emerged as a novel, effective treatment to delay the progression of aggressive tumors and suppress tumor recurrence and metastasis. However, few clinical immunotherapy trials have been conducted in HCC patients, and there is an unmet need for novel therapeutic strategies. The combination of conventional treatments with specific immunotherapeutic approaches may dramatically improve the efficacy of HCC treatment and the clinical outcome of HCC patients. In this review, we briefly summarize immunotherapy strategies and discuss new advances in combined immunotherapeutic approaches for the treatment of patients with liver cancer.
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Affiliation(s)
- Mengxin Tian
- Department of Liver Surgery & Transplantation Center, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, 200032, China
| | - Yinghong Shi
- Department of Liver Surgery & Transplantation Center, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, 200032, China
| | - Weiren Liu
- Department of Liver Surgery & Transplantation Center, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, 200032, China
| | - Jia Fan
- Department of Liver Surgery & Transplantation Center, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, 200032, China.
- Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
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22
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2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Gut Liver 2019; 13:227-299. [PMID: 31060120 PMCID: PMC6529163 DOI: 10.5009/gnl19024] [Citation(s) in RCA: 240] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 01/24/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions.
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23
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Chan AWH, Zhong J, Berhane S, Toyoda H, Cucchetti A, Shi K, Tada T, Chong CCN, Xiang BD, Li LQ, Lai PBS, Mazzaferro V, García-Fiñana M, Kudo M, Kumada T, Roayaie S, Johnson PJ. Development of pre and post-operative models to predict early recurrence of hepatocellular carcinoma after surgical resection. J Hepatol 2018; 69:1284-1293. [PMID: 30236834 DOI: 10.1016/j.jhep.2018.08.027] [Citation(s) in RCA: 384] [Impact Index Per Article: 54.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 08/22/2018] [Accepted: 08/28/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Resection is the most widely used potentially curative treatment for patients with early hepatocellular carcinoma (HCC). However, recurrence within 2 years occurs in 30-50% of patients, being the major cause of mortality. Herein, we describe 2 models, both based on widely available clinical data, which permit risk of early recurrence to be assessed before and after resection. METHODS A total of 3,903 patients undergoing surgical resection with curative intent were recruited from 6 different centres. We built 2 models for early recurrence, 1 using preoperative and 1 using pre and post-operative data, which were internally validated in the Hong Kong cohort. The models were then externally validated in European, Chinese and US cohorts. We developed 2 online calculators to permit easy clinical application. RESULTS Multivariable analysis identified male gender, large tumour size, multinodular tumour, high albumin-bilirubin (ALBI) grade and high serum alpha-fetoprotein as the key parameters related to early recurrence. Using these variables, a preoperative model (ERASL-pre) gave 3 risk strata for recurrence-free survival (RFS) in the entire cohort - low risk: 2-year RFS 64.8%, intermediate risk: 2-year RFS 42.5% and high risk: 2-year RFS 20.7%. Median survival in each stratum was similar between centres and the discrimination between the 3 strata was enhanced in the post-operative model (ERASL-post) which included 'microvascular invasion'. CONCLUSIONS Statistical models that can predict the risk of early HCC recurrence after resection have been developed, extensively validated and shown to be applicable in the international setting. Such models will be valuable in guiding surveillance follow-up and in the design of post-resection adjuvant therapy trials. LAY SUMMARY The most effective treatment of hepatocellular carcinoma is surgical removal of the tumour but there is often recurrence. In this large international study, we develop a statistical method that allows clinicians to estimate the risk of recurrence in an individual patient. This facility enhances communication with the patient about the likely success of the treatment and will help in designing clinical trials that aim to find drugs that decrease the risk of recurrence.
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Affiliation(s)
- Anthony W H Chan
- State Key Laboratory in Oncology in South China, Sir Y. K. Pao Centre for Cancer, Department of Anatomical & Cellular Pathology, and Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Jianhong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumour Hospital of Guangxi Medical University, Nanning, China
| | - Sarah Berhane
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8052, Japan
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Italy
| | - KeQing Shi
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Toshifumi Tada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8052, Japan
| | - Charing C N Chong
- State Key Laboratory in Oncology in South China, Sir Y. K. Pao Centre for Cancer, Department of Anatomical & Cellular Pathology, and Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Bang-De Xiang
- Department of Hepatobiliary Surgery, Affiliated Tumour Hospital of Guangxi Medical University, Nanning, China
| | - Le-Qun Li
- Department of Hepatobiliary Surgery, Affiliated Tumour Hospital of Guangxi Medical University, Nanning, China
| | - Paul B S Lai
- State Key Laboratory in Oncology in South China, Sir Y. K. Pao Centre for Cancer, Department of Anatomical & Cellular Pathology, and Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Vincenzo Mazzaferro
- University of Milan and Gastrointestinal Surgery and Liver Transplantation Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8052, Japan
| | - Sasan Roayaie
- Liver Cancer Program, White Plains Hospital - Montefiore Health System, White Plains, NY, United States
| | - Philip J Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
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Fibrosis-4 Model Influences Results of Patients with Hepatocellular Carcinoma Undergoing Hepatectomy. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4305408. [PMID: 30057907 PMCID: PMC6051273 DOI: 10.1155/2018/4305408] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 05/24/2018] [Accepted: 06/07/2018] [Indexed: 12/16/2022]
Abstract
Background Several noninvasive models based on routine laboratory index have been developed to predict liver fibrosis. Our aim is to discuss whether these indexes could predict prognosis in patients with hepatocellular carcinoma undergoing hepatectomy. Methods This study retrospectively enrolled 788 consecutive hepatocellular carcinoma patients undergoing liver resection in the cohort. Univariate and multivariate analysis were used to identify the risk factors of complications, survival, and disease-free survival. Results Fibrosis-4 index had the best prediction ability for cirrhosis among other noninvasive models. Both the univariate and multivariate analyses showed that fibrosis-4 was independent risk factor for survival and disease-free survival. With the optimal cutoff value of 3.15, patients with fibrosis-4 ⩾3.15 had higher postoperative hepatic insufficiency (P=0.006) and worse survival than the fibrosis-4<3.15 group. The corresponding 1-year, 3-year, and 5-year overall survival were 80.9%, 56.3%, and 44.6% in the High fibrosis-4 group and were 86.5%, 69.9%, and 63.2% in the Low fibrosis-4 group, respectively (P<0.001). Worse disease-free survival was also observed in the fibrosis-4 ⩾3.15 group; the corresponding 1-year, 3-year, and 5-year disease-free survival were 74.9%, 45.3%, and 24.6% for the fibrosis-4 ⩾3.15 group and were 81.8%, 54.9%, and 34.4% for the fibrosis-4<3.15 group (P=0.009). Conclusions Fibrosis-4 is useful for assessing the short-term and long-term results for hepatocellular carcinoma patients with liver resection.
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Kumar N, Khakoo SI. Hepatocellular carcinoma: Prospects for natural killer cell immunotherapy. HLA 2018; 92:3-11. [PMID: 29667374 DOI: 10.1111/tan.13275] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 04/11/2018] [Accepted: 04/12/2018] [Indexed: 12/12/2022]
Abstract
Liver disease is a growing cause of death in the United Kingdom and the incidence of hepatocellular carcinoma (HCC) is rising (http://www.cancerresearchuk.org/). The combination of an immunosuppressive environment within the liver and suboptimal host anti-tumour immune responses may account for the poor survival outcome of HCC. Understanding how tumours evade immune recognition coupled with new insights into the unique immunological environment within the liver will be critical to developing liver-specific immunotherapies.
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Affiliation(s)
- N Kumar
- Section of Hepatology, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
| | - S I Khakoo
- Department of Clinical and Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton, UK
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26
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Lee B, Hutchinson R, Wong HL, Tie J, Putoczki T, Tran B, Gibbs P, Christie M. Emerging biomarkers for immunomodulatory cancer treatment of upper gastrointestinal, pancreatic and hepatic cancers. Semin Cancer Biol 2017; 52:241-252. [PMID: 29258858 DOI: 10.1016/j.semcancer.2017.12.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 12/14/2017] [Accepted: 12/15/2017] [Indexed: 12/14/2022]
Abstract
Carcinomas of the oesophagus, stomach, pancreas and liver are common and account for a disproportionately high number of cancer deaths. There is a need for new treatment options for patients with advanced disease. Immunomodulatory treatments including immune checkpoint blockade offer a promising new approach, with efficacy shown in other solid tumour types. However, only a small proportion of patients with carcinomas of the oesophagus, stomach, pancreas and liver have responded to single agent checkpoint inhibitors, and there is a need for markers that are predictive of response to guide treatment of individual patients. Predictive markers may include epidemiological factors such as ethnicity, the genomic status of the tumour, circulating markers, expression of immune checkpoint molecules, and other features of the stromal/immune response at the site of the tumour. This review will focus on predictive biomarkers for immune checkpoint blockade in oesophageal, gastric, pancreatic and hepatocellular carcinomas, including the genomic context and immune landscape in which they occur. Pancreatic carcinomas are largely resistant to immune checkpoint inhibition in trials to date, therefore emerging immunomodulatory treatments in this tumour type are also reviewed.
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Affiliation(s)
- Belinda Lee
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Ryan Hutchinson
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Hui-Li Wong
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
| | - Jeanne Tie
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Tracy Putoczki
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Ben Tran
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
| | - Peter Gibbs
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
| | - Michael Christie
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Pathology, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
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27
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T Cell-Activating Mesenchymal Stem Cells as a Biotherapeutic for HCC. MOLECULAR THERAPY-ONCOLYTICS 2017; 6:69-79. [PMID: 28856237 PMCID: PMC5562179 DOI: 10.1016/j.omto.2017.07.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Accepted: 07/25/2017] [Indexed: 01/10/2023]
Abstract
The outcome for advanced stage hepatocellular carcinoma (HCC) remains poor, highlighting the need for novel therapies. Genetically modified mesenchymal stem cells (MSCs) are actively being explored as cancer therapeutics due to their inherent ability to migrate to tumor sites. We reasoned that MSCs can be genetically modified to redirect T cells to Glypican-3 (GPC3)+ HCC, and genetically modified these with viral vectors encoding a GPC3/CD3 bispecific T cell engager (GPC3-ENG), a bispecifc T cell engager specific for an irrelevant antigen (EGFRvIII), and/or costimulatory molecules (CD80 and 41BBL). Coculture of GPC3+ cells, GPC3-ENG MSCs, and T cells resulted in T cell activation, as judged by interferon γ (IFNγ) production and killing of tumor cells by T cells. Modification of GPC3-ENG MSCs with CD80 and 41BBL was required for antigen-dependent interleukin-2 (IL-2) production by T cells and resulted in faster tumor cell killing by redirected T cells. In vivo, GPC3-ENG MSCs ± costimulatory molecules had antitumor activity in the HUH7 HCC xenograft model, resulting in a survival advantage. In conclusion, MSCs genetically modified to express GPC3-ENG ± costimulatory molecules redirect T cells to GPC3+ tumor cells and have potent antitumor activity. Thus, further preclinical exploration of our modified approach to GPC3-targeted immunotherapy for HCC is warranted.
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28
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Gu Y, Lv H, Zhao J, Li Q, Mu G, Li J, Wuyang J, Lou G, Wang R, Zhang Y, Huang X. Influence of the number and interval of treatment cycles on cytokine-induced killer cells and their adjuvant therapeutic effects in advanced non-small-cell lung cancer (NSCLC). Int Immunopharmacol 2017; 50:263-269. [PMID: 28711032 DOI: 10.1016/j.intimp.2017.07.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 07/01/2017] [Accepted: 07/07/2017] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Cytokine-induced killer (CIK) cells have important therapeutic effects in adoptive cell transfer (ACT) for the treatment of various malignancies. In this study, we focused on in vitro expansion of CIK cells and their clinical efficacy in combination with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). METHODS A total of 64 patients with NSCLC (enrolled from 2011 to 2012), including 32 patients who received chemotherapy alone or with sequential radiotherapy (conventional treatment, control group) and 32 patients who received conventional treatment and sequential CIK infusion (study group), were retrospectively analyzed. The time to progression (TTP), overall survival (OS) and adverse effects were analyzed and the phenotype of lymphocytes in CIK population was also determined by flow cytometry. RESULTS After in vitro expansion, the average percentage of CIK cells was 26.35%. During the 54-month follow up, the median OS and TTP were significantly longer in the study group than in the control group (P=0.0189 and P=0.0129, respectively). The median OS of the ACT≥4cycles subgroup was significantly longer than that of the ACT<4cycles subgroup (P=0.0316). The percentage of CIK cells in patients who received ≥4cycles of ACT was higher than that in patients treated with <4cycles of ACT (P=0.0376). Notably, CIK cells were difficult to expand in vitro in some patients after the first ACT cycle but became much easier as the treatment cycles increased monthly. Longer treatment interval negatively impacted the expansion of CIK cells. CONCLUSIONS Systematic immune levels can be increasingly boosted by reinfusion of ACT. Conventional treatment plus CIK cells is an effective therapeutic strategy to prevent progression and prolong survival of patients with advanced NSCLC.
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Affiliation(s)
- Yuanlong Gu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Huimin Lv
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Juan Zhao
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Qi Li
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Guannan Mu
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Jiade Li
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Jiazi Wuyang
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Ge Lou
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Ruitao Wang
- Department of Internal medicine, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
| | - Xiaoyi Huang
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin 150081, China; Center of Translational Medicine, Harbin Medical University, Harbin 150086, China.
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29
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Gao X, Mi Y, Guo N, Xu H, Xu L, Gou X, Jin W. Cytokine-Induced Killer Cells As Pharmacological Tools for Cancer Immunotherapy. Front Immunol 2017; 8:774. [PMID: 28729866 PMCID: PMC5498561 DOI: 10.3389/fimmu.2017.00774] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 06/19/2017] [Indexed: 12/31/2022] Open
Abstract
Cytokine-induced killer (CIK) cells are a heterogeneous population of effector CD3+CD56+ natural killer T cells, which can be easily expanded in vitro from peripheral blood mononuclear cells. CIK cells work as pharmacological tools for cancer immunotherapy as they exhibit MHC-unrestricted, safe, and effective antitumor activity. Much effort has been made to improve CIK cells cytotoxicity and treatments of CIK cells combined with other antitumor therapies are applied. This review summarizes some strategies, including the combination of CIK with additional cytokines, dendritic cells, check point inhibitors, antibodies, chemotherapeutic agents, nanomedicines, and engineering CIK cells with a chimeric antigen receptor. Furthermore, we briefly sum up the clinical trials on CIK cells and compare the effect of clinical CIK therapy with other immunotherapies. Finally, further research is needed to clarify the pharmacological mechanism of CIK and provide evidence to formulate uniform culturing criteria for CIK expansion.
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Affiliation(s)
- Xingchun Gao
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, China.,State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, The Fourth Military Medical University, Xi'an, China.,Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, Key Lab for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yajing Mi
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, China.,State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Na Guo
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, China
| | - Hao Xu
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, China
| | - Lixian Xu
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Xingchun Gou
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, China
| | - Weilin Jin
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, China.,Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, Key Lab for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, China.,National Centers for Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
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30
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Wörns MA, Galle PR. Immune oncology in hepatocellular carcinoma-hype and hope. Lancet 2017; 389:2448-2449. [PMID: 28434649 DOI: 10.1016/s0140-6736(17)31044-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 03/28/2017] [Indexed: 12/30/2022]
Affiliation(s)
- Marcus-Alexander Wörns
- Department of Internal Medicine I and Cirrhosis Centre Mainz, University Medical Centre of the Johannes Gutenberg-University, Mainz 55131, Germany
| | - Peter R Galle
- Department of Internal Medicine I and Cirrhosis Centre Mainz, University Medical Centre of the Johannes Gutenberg-University, Mainz 55131, Germany.
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31
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Cellular and molecular targets for the immunotherapy of hepatocellular carcinoma. Mol Cell Biochem 2017; 437:13-36. [PMID: 28593566 DOI: 10.1007/s11010-017-3092-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023]
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32
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Yuan BH, Li RH, Yuan WP, Yang T, Tong TJ, Peng NF, Li LQ, Zhong JH. Harms and benefits of adoptive immunotherapy for postoperative hepatocellular carcinoma: an updated review. Oncotarget 2017; 8:18537-18549. [PMID: 28061472 PMCID: PMC5392348 DOI: 10.18632/oncotarget.14507] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 12/27/2016] [Indexed: 01/27/2023] Open
Abstract
The harms and benefits of adoptive immunotherapy (AIT) for patients with postoperative hepatocellular carcinoma (HCC) are controversial among studies. This study aims to update the current evidence on efficacy and safety of AIT for patients with HCC who have received curative therapy. Electronic databases were systematically searched to identify randomized controlled trials (RCTs) and cohort studies evaluating adjuvant AIT for patients with HCC after curative therapies. Recurrence and mortality were compared between patients with or without adjuvant AIT. Eight RCTs and two cohort studies involving 2,120 patients met the eligibility criteria and were meta-analyzed. Adjuvant AIT was associated with significantly lower recurrence rate than curative therapies alone at 1 year [risk ratio (RR) 0.64, 95%CI 0.49-0.82], 3 years (RR 0.85, 95%CI 0.79-0.91) and 5 years (RR 0.90, 95%CI 0.85-0.95). Similarly, adjuvant AIT was associated with significantly lower mortality at 1 year (RR 0.64, 95%CI 0.52-0.79), 3 years (RR 0.73, 95%CI 0.65-0.81) and 5 years (RR 0.86, 95%CI 0.79-0.94). Short-term outcomes were confirmed in sensitivity analyses based on RCTs or choice of a fixed- or random-effect meta-analysis model. None of the included patients experienced grade 3 or 4 adverse events. Therefore, this update reinforces the evidence that adjuvant AIT after curative treatment for HCC lowers risk of recurrence and mortality.
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Affiliation(s)
- Bao-Hong Yuan
- Department of General Surgery, YanAn Hospital Affiliated to Kunming Medical University, Kunming, P.R. China
| | - Ru-Hong Li
- Department of General Surgery, YanAn Hospital Affiliated to Kunming Medical University, Kunming, P.R. China
| | - Wei-Ping Yuan
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, P.R. China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China
| | - Tie-Jun Tong
- Department of Mathematics, Hong Kong Baptist University, Hong Kong, P.R. China
| | - Ning-Fu Peng
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, P.R. China
| | - Le-Qun Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, P.R. China
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, P.R. China
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33
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Iudicone P, Fioravanti D, Cicchetti E, Zizzari IG, Pandolfi A, Scocchera R, Fazzina R, Pierelli L. Interleukin-15 enhances cytokine induced killer (CIK) cytotoxic potential against epithelial cancer cell lines via an innate pathway. Hum Immunol 2016; 77:1239-1247. [PMID: 27615504 DOI: 10.1016/j.humimm.2016.09.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 09/06/2016] [Accepted: 09/06/2016] [Indexed: 01/29/2023]
Abstract
CIK cells are a subset of effector lymphocytes endowed with a non-MHC restricted anti-tumor activity making them an appealing and promising cell population for adoptive immunotherapy. CIK are usually generated ex-vivo by initial priming with Interferon-γ (IFN-γ) and monoclonal antibody against CD3 (anti-CD3), followed by culture in medium containing Interleukin-2 (IL-2). Interleukin-15 (IL-15) shares with IL-2 similar biological functions and recently it has been reported to induce CIK with increased anti-leukemic potential. The aim of the study was to compare the killing efficacy of CIK generated by IL-2 alone or IL-2 and IL-15 toward tumor targets of different origins, leukemic cells and malignant cells from epithelial solid tumors. CIK bulk cultures were examined for cell proliferation, surface phenotype and cytotoxic potential against tumor cell lines K562, HL60, HeLa and MCF-7. The results showed that IL-15 is able to induce a selective expansion of CIK cells, but it is less effective in sustaining CIK cell proliferation compared to IL-2. Conversely, our data confirm and reinforce the feature of IL-15 to induce CIK cells with a potent cytotoxic activity mostly against tumor cells from epithelial solid malignancies via NKG2D-mediated mechanism.
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Affiliation(s)
- Paola Iudicone
- Stem Cell and Cell Therapy Unit, S. Camillo-Forlanini Hospital, Rome, Italy
| | - Daniela Fioravanti
- Stem Cell and Cell Therapy Unit, S. Camillo-Forlanini Hospital, Rome, Italy
| | - Elisabetta Cicchetti
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | | | - Annino Pandolfi
- Stem Cell and Cell Therapy Unit, S. Camillo-Forlanini Hospital, Rome, Italy
| | - Rita Scocchera
- Stem Cell and Cell Therapy Unit, S. Camillo-Forlanini Hospital, Rome, Italy
| | | | - Luca Pierelli
- Stem Cell and Cell Therapy Unit, S. Camillo-Forlanini Hospital, Rome, Italy; Department of Experimental Medicine, Sapienza University, Rome, Italy.
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