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Gianneschi G, Scolpino A, Oleske J. Risk of autoimmunity, cancer seeding, and adverse events in human trials of whole-tissue autologous therapeutic vaccines. CANCER PATHOGENESIS AND THERAPY 2025; 3:129-134. [PMID: 40182122 PMCID: PMC11963168 DOI: 10.1016/j.cpt.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 05/20/2024] [Accepted: 05/26/2024] [Indexed: 04/05/2025]
Abstract
Background Whole-tissue autologous therapeutic vaccines (WATVs) are a form of cancer immunotherapy that use a patient's own pathological tissue. Concerns exist regarding the potential of WATVs to induce autoimmunity or the spread of cancer; however, their adverse events (AEs) have not been adequately studied. This literature review primarily aimed to evaluate the risks of autoimmunity and cancer seeding associated with using WATVs in human clinical trials. Its secondary objectives included assessing the incidence of AEs graded 1-5 using the Common Terminology Criteria for Adverse Events v5.0. Methods The inclusion criteria were any clinical trial using human subjects in which at least part of the cancer vaccine was derived from the patient's own tumor tissue, which likely preserved the unique tumor-associated antigens (TAAs) present in the patient's tumor (i.e., whole-tissue). Tumor vaccine trials that used limited TAAs or highly processed tumor antigens were excluded. Published clinical trials were searched using Google Scholar until March 2024. The authors elaborated on the risk of bias in such cases, as indicated. All reviewed publications were searched for evidence of autoimmunity, cancer seeding, and other AEs. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement guided the review. Results Data from 55 human clinical trials, abstracts, case reports, and unpublished data were analyzed, including 3323 patients treated with WATVs for various cancers. The primary outcomes were: (1) no documented cases of WATV-induced autoimmunity, (2) no documented cases of WATV-induced spreading or seeding of noninfectious cancers, and (3) the observed 0.24% (2/838) risk of spreading or seeding infectious cancers was attributed to inadequate sterilization. The secondary outcomes were: (1) no deaths were attributed to WATV therapy, (2) 0.18% (6/3323) incidence of grade 4 AEs, (3) 0.42% (14/3323) incidence of grade 3 AEs, (4) the incidence of grades 1-2 AEs was 52.21% (478/916). Conclusions WATVs carry no risk of inducing autoimmunity and essentially no risk of cancer seeding if properly sterilized. WATVs also exhibit a side effect profile comparable to that of routine vaccinations, with common, mild, and transient adverse effects. The combined risk of grade 3 and 4 AEs was 0.60% (20/3323). No deaths were causally associated with WATV treatment.
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Affiliation(s)
- Garrett Gianneschi
- Department of Neurology, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA
| | - Anthony Scolpino
- Division of Immunology, Department of Pediatrics, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA
| | - James Oleske
- Division of Immunology, Department of Pediatrics, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA
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2
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Han CL, Yan YC, Yan LJ, Meng GX, Yang CC, Liu H, Ding ZN, Dong ZR, Hong JG, Chen ZQ, Li T. Efficacy and security of tumor vaccines for hepatocellular carcinoma: a systemic review and meta-analysis of the last 2 decades. J Cancer Res Clin Oncol 2023; 149:1425-1441. [PMID: 35482077 DOI: 10.1007/s00432-022-04008-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 03/31/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Tumor vaccines for hepatocellular carcinoma (HCC) is an area of intense interest. Tremendous clinical trials have been conducted globally, but the efficacy and security of tumor vaccines are elusive. The aim of our study was to evaluate the efficacy and security of tumor vaccines. METHODS All relevant studies were identified in PubMed, EMBASE, Web of science and Cochrane Library databases. Objective response rate (ORR), median overall survival (OS), or median progression-free survival (PFS) and 95% CI were meta-analyzed based on the random-effects model. The individual-level data of OS, PFS were pooled by conducting survival analysis. All observed adverse events were collected. RESULTS 31 studies containing 35 eligible cohorts with 932 HCC patients were included. The pooled ORR were 7% (95% CI 3-14%), while ORR of dendritic cell (DC) vaccine (19%, 95% CI 11-29%) were highly significant than ORR of peptide vaccine (1%, 95% CI 0-5%). The pooled median OS and PFS were 13.67 months (95% CI 8.20-22.80) and 6.19 months (95% CI 2.97-12.91), respectively. The pooled median OS (DC vaccine: median OS = 21.77 months, 95% CI 18.33-25.86; Peptide vaccine: median OS = 10.08 months, 95% CI 5.23-19.44) and PFS (DC vaccine: median PFS = 11.01 months, 95% CI 5.25-23.09; Peptide vaccine: median PFS = 1.97 months, 95% CI 1.53-2.54) of DC vaccine were also longer than that of peptide vaccine. HBV-related HCC may acquire more benefits from tumor vaccines than HCV-related HCC. In almost all studies, the observed toxicities were moderate even tiny. CONCLUSIONS Tumor vaccines for HCC, especially DC vaccine, are safe and worth exploring. More high-quality prospective studies are warranted.
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Affiliation(s)
- Cheng-Long Han
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, People's Republic of China
| | - Yu-Chuan Yan
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, People's Republic of China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, People's Republic of China
| | - Guang-Xiao Meng
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, People's Republic of China
| | - Chun-Cheng Yang
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, People's Republic of China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, People's Republic of China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, People's Republic of China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, People's Republic of China
| | - Jian-Guo Hong
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, People's Republic of China
| | - Zhi-Qiang Chen
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, People's Republic of China
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, People's Republic of China.
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, 250012, People's Republic of China.
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3
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Bastin DJ, Montroy J, Kennedy MA, Martel AB, Shorr R, Ghiasi M, Boucher DM, Wong B, Gresham L, Diallo JS, Fergusson DA, Lalu MM, Kekre N, Auer RC. Safety and efficacy of autologous cell vaccines in solid tumors: a systematic review and meta-analysis of randomized control trials. Sci Rep 2023; 13:3347. [PMID: 36849805 PMCID: PMC9971202 DOI: 10.1038/s41598-023-29630-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 02/08/2023] [Indexed: 03/01/2023] Open
Abstract
We conducted a systematic review and meta-analysis of randomized control trials to formally assess the safety and efficacy of autologous whole cell vaccines as immunotherapies for solid tumors. Our primary safety outcome was number, and grade of adverse events. Our primary efficacy outcome was clinical responses. Secondary outcomes included survival metrics and correlative immune assays. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for studies published between 1946 and August 2020 using any autologous whole cell product in the treatment of any solid tumor. The Cochrane Randomized Controlled Trial risk of bias tool was used to assess risk of bias. Eighteen manuscripts were identified with a total of 714 patients enrolled in control and 808 in vaccine arms. In 698 patients receiving at least one dose of vaccine, treatment was well tolerated with a total of 5 grade III or higher adverse events. Clinical response was reported in a minority (n = 2, 14%) of studies. Autologous cell vaccines were associated with improved overall (HR 1.28, 95% CI 1.01-1.63) and disease-free survival (HR 1.33, 95% CI 1.05-1.67) over thirteen and ten trials respectively. Where reported, immune assays correlated well with clinical outcomes. Our results suggest that autologous whole cell vaccination is safe and efficacious in increasing survival in patients undergoing treatment for solid tumors.Registration: PROSPERO CRD42019140187.
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Affiliation(s)
- Donald J Bastin
- Cancer Therapeutics Program, The Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada
- Schulich School of Medicine, Western University, London, ON, Canada
| | - Joshua Montroy
- Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Michael A Kennedy
- Cancer Therapeutics Program, The Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada
| | - Andre B Martel
- Cancer Therapeutics Program, The Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada
- Department of Surgery, University of Ottawa, Ottawa, ON, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Risa Shorr
- Learning Services, The Ottawa Hospital, Ottawa, ON, Canada
| | - Maryam Ghiasi
- Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Dominique M Boucher
- Cancer Therapeutics Program, The Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Boaz Wong
- Cancer Therapeutics Program, The Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Louise Gresham
- Department of Surgery, University of Ottawa, Ottawa, ON, Canada
| | - Jean-Simon Diallo
- Cancer Therapeutics Program, The Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Dean A Fergusson
- Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada
| | - Manoj M Lalu
- Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
- Regenerative Medicine Program, The Ottawa Health Research Institute, Ottawa, ON, Canada
| | - Natasha Kekre
- Cancer Therapeutics Program, The Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Rebecca C Auer
- Cancer Therapeutics Program, The Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada.
- Department of Surgery, University of Ottawa, Ottawa, ON, Canada.
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada.
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Zhang Y, Lei X, Xu L, Lv X, Xu M, Tang H. Preoperative and postoperative nomograms for predicting early recurrence of hepatocellular carcinoma without macrovascular invasion after curative resection. BMC Surg 2022; 22:233. [PMID: 35715787 PMCID: PMC9205542 DOI: 10.1186/s12893-022-01682-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/06/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Postoperative early recurrence (ER) is a major obstacle to long-term survival after curative liver resection (LR) in patients with hepatocellular carcinoma (HCC). This study aimed to establish preoperative and postoperative nomograms to predict ER in HCC without macrovascular invasion. METHODS Patients who underwent curative LR for HCC between January 2012 and December 2016 were divided into training and internal prospective validation cohorts. Nomograms were constructed based on independent risk factors derived from the multivariate logistic regression analyses in the training cohort. The predictive performances of the nomograms were validated using the internal prospective validation cohort. RESULTS In total, 698 patients fulfilled the eligibility criteria. Among them, 265 of 482 patients (55.0%) in the training cohort and 120 of 216 (55.6%) patients in the validation cohort developed ER. The preoperative risk factors associated with ER were age, alpha-fetoprotein, tumor diameter, and tumor number, and the postoperative risk factors associated with ER were age, tumor diameter, tumor number, microvascular invasion, and differentiation. The pre- and postoperative nomograms based on these factors showed good accuracy, with concordance indices of 0.712 and 0.850 in the training cohort, respectively, and 0.754 and 0.857 in the validation cohort, respectively. The calibration curves showed optimal agreement between the predictions by the nomograms and actual observations. The area under the receiver operating characteristic curves of the pre- and postoperative nomograms were 0.721 and 0.848 in the training cohort, respectively, and 0.754 and 0.844 in the validation cohort, respectively. CONCLUSIONS The nomograms constructed in this study showed good performance in predicting ER for HCC without macrovascular invasion before and after surgery. These nomograms would be helpful for doctors when determining treatments and selecting patients for regular surveillance or administration of adjuvant therapies.
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Affiliation(s)
- Yanfang Zhang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Xuezhong Lei
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Liangliang Xu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoju Lv
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Mingqing Xu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
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5
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Greten TF, Abou-Alfa GK, Cheng AL, Duffy AG, El-Khoueiry AB, Finn RS, Galle PR, Goyal L, He AR, Kaseb AO, Kelley RK, Lencioni R, Lujambio A, Mabry Hrones D, Pinato DJ, Sangro B, Troisi RI, Wilson Woods A, Yau T, Zhu AX, Melero I. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma. J Immunother Cancer 2021; 9:e002794. [PMID: 34518290 PMCID: PMC8438858 DOI: 10.1136/jitc-2021-002794] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2021] [Indexed: 12/11/2022] Open
Abstract
Patients with advanced hepatocellular carcinoma (HCC) have historically had few options and faced extremely poor prognoses if their disease progressed after standard-of-care tyrosine kinase inhibitors (TKIs). Recently, the standard of care for HCC has been transformed as a combination of the immune checkpoint inhibitor (ICI) atezolizumab plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was shown to offer improved overall survival in the first-line setting. Immunotherapy has demonstrated safety and efficacy in later lines of therapy as well, and ongoing trials are investigating novel combinations of ICIs and TKIs, in addition to interventions earlier in the course of disease or in combination with liver-directed therapies. Because HCC usually develops against a background of cirrhosis, immunotherapy for liver tumors is complex and oncologists need to account for both immunological and hepatological considerations when developing a treatment plan for their patients. To provide guidance to the oncology community on important concerns for the immunotherapeutic care of HCC, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for HCC, including diagnosis and staging, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with HCC.
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Affiliation(s)
- Tim F Greten
- Thoracic and GI Malignancies Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Medical College at Cornell University, New York, New York, USA
| | - Ann-Lii Cheng
- Department of Medical Oncology, National Taiwan University Cancer Center and National Taiwan University Hospital, Taipei, Taiwan
| | - Austin G Duffy
- The Mater Hospital/University College Dublin, Dublin, Ireland
| | - Anthony B El-Khoueiry
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
| | - Richard S Finn
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | | | - Lipika Goyal
- Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Aiwu Ruth He
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Robin Kate Kelley
- Department of Medicine (Hematology/Oncology), UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA
| | - Riccardo Lencioni
- Department of Radiology, University of Pisa School of Medicine, Pisa, Italy
- Miami Cancer Institute, Miami, Florida, USA
| | - Amaia Lujambio
- Oncological Sciences Department, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Donna Mabry Hrones
- Thoracic and GI Malignancies Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, London, UK
| | - Bruno Sangro
- Clinica Universidad de Navarra-Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | | | - Andrea Wilson Woods
- Blue Faery: The Adrienne Wilson Liver Cancer Association, Birmingham, Alabama, USA
| | - Thomas Yau
- Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong
| | - Andrew X Zhu
- Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA
- Jiahui Health, Jiahui International Cancer Center, Shanghai, China
| | - Ignacio Melero
- Clinica Universidad de Navarra-Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Foundation for Applied Medical Research (FIMA), Pamplona, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain
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Taniguchi M, Mizuno S, Yoshikawa T, Fujinami N, Sugimoto M, Kobayashi S, Takahashi S, Konishi M, Gotohda N, Nakatsura T. Peptide vaccine as an adjuvant therapy for glypican-3-positive hepatocellular carcinoma induces peptide-specific CTLs and improves long prognosis. Cancer Sci 2020; 111:2747-2759. [PMID: 32449239 PMCID: PMC7419030 DOI: 10.1111/cas.14497] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/12/2020] [Accepted: 05/14/2020] [Indexed: 12/20/2022] Open
Abstract
There is no established postoperative adjuvant therapy for hepatocellular carcinoma (HCC), and improvement of patient prognosis has been limited. We conducted long‐term monitoring of patients within a phase II trial that targeted a cancer antigen, glypican‐3 (GPC3), specifically expressed in HCC. We sought to determine if the GPC3 peptide vaccine was an effective adjuvant therapy by monitoring disease‐free survival and overall survival. We also tracked GPC3 immunohistochemical (IHC) staining, CTL induction, and postoperative plasma GPC3 for a patient group that was administered the vaccine (n = 35) and an unvaccinated patient group that underwent surgery only (n = 33). The 1‐y recurrence rate after surgery was reduced by approximately 15%, and the 5‐y and 8‐y survival rates were improved by approximately 10% and 30%, respectively, in the vaccinated group compared with the unvaccinated group. Patients who were positive for GPC3 IHC staining were more likely to have induced CTLs, and 60% survived beyond 5 y. Vaccine efficacy had a positive relationship with plasma concentration of GPC3; high concentrations increased the 5‐y survival rate to 75%. We thus expect GPC3 vaccination in patients with HCC, who are positive for GPC3 IHC staining and/or plasma GPC3 to induce CTL and have significantly improved long‐term prognosis.
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Affiliation(s)
- Masatake Taniguchi
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.,Department of Medical Oncology and Translational Research, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shoichi Mizuno
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Toshiaki Yoshikawa
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Norihiro Fujinami
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Motokazu Sugimoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shin Kobayashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shinichiro Takahashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masaru Konishi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Naoto Gotohda
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Medical Oncology and Translational Research, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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7
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Hirokawa F, Komeda K, Taniguchi K, Asakuma M, Shimizu T, Inoue Y, Kagota S, Tomioka A, Yamamoto K, Uchiyama K. Is Postoperative Adjuvant Transcatheter Arterial Infusion Therapy Effective for Patients with Hepatocellular Carcinoma who Underwent Hepatectomy? A Prospective Randomized Controlled Trial. Ann Surg Oncol 2020; 27:4143-4152. [PMID: 32500344 DOI: 10.1245/s10434-020-08699-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND The effectiveness of adjuvant transcatheter arterial chemo- or/and chemoembolization therapy after curative hepatectomy of initial hepatocellular carcinoma (HCC) is controversial. This study aimed to evaluate whether hepatectomy combined with adjuvant transcatheter arterial infusion therapy (TAI) for initial HCC has better long-term survival outcomes than hepatectomy alone. METHODS From January 2012 to December 2014, a prospective randomized controlled trial of patients with initial HCC was conducted. Then, 114 initial HCC patients were recruited to undergo hepatectomy with adjuvant TAI (TAI group, n = 55) or hepatectomy alone (control group, n = 59) at our institution. The TAI therapy was performed twice, at 3 and 6 months after curative hepatectomy (UMIN 000011900). RESULTS The patients treated with TAI had no serious side effects, and operative outcomes did not differ between the two groups. No significant differences were found in the pattern of intrahepatic recurrence or time until recurrence between the two groups. Moreover, no significant differences were found in the relapse-free survival or overall survival. Low cholinesterase level (< 200) had been identified as a risk factor affecting relapse-free survival. Furthermore, compared with surgery alone, adjuvant TAI with hepatectomy improved the overall survival for lower-cholinesterase patients. CONCLUSIONS Adjuvant TAI is safe and feasible, but it cannot reduce the incidence of postoperative recurrence or prolong survival for patients who underwent curative hepatectomy for initial HCC.
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Affiliation(s)
- Fumitoshi Hirokawa
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki City, Osaka, Japan.
| | - Koji Komeda
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki City, Osaka, Japan
| | - Kohei Taniguchi
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki City, Osaka, Japan.,Translational Research Program, Osaka Medical College, Osaka, Japan
| | - Mitsuhiro Asakuma
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki City, Osaka, Japan
| | - Tetsunosuke Shimizu
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki City, Osaka, Japan
| | - Yoshihiro Inoue
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki City, Osaka, Japan
| | - Shuji Kagota
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki City, Osaka, Japan
| | - Atsushi Tomioka
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki City, Osaka, Japan
| | | | - Kazuhisa Uchiyama
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki City, Osaka, Japan
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8
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Hack SP, Spahn J, Chen M, Cheng AL, Kaseb A, Kudo M, Lee HC, Yopp A, Chow P, Qin S. IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncol 2020; 16:975-989. [PMID: 32352320 DOI: 10.2217/fon-2020-0162] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma recurs in 70-80% of cases following potentially curative resection or ablation and the immune component of the liver microenvironment plays a key role in recurrence. Many immunosuppressive mechanisms implicated in HCC recurrence are modulated by VEGF and/or immune checkpoints such as PD-L1. Atezolizumab (PD-L1 inhibitor) plus bevacizumab (VEGF inhibitor) has been shown to significantly improve overall survival, progression-free survival and overall response rate in unresectable HCC. Dual PD-L1/VEGF blockade may be effective in reducing HCC recurrence by creating a more immune-favorable microenvironment. We describe the rationale and design of IMbrave 050 (NCT04102098), a randomized, open-label, Phase III study comparing atezolizumab plus bevacizumab versus active surveillance in HCC patients at high-risk of recurrence following curative resection or ablation. The primary end point is recurrence-free survival. Clinical Trial Registration: NCT04102098.
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Affiliation(s)
- Stephen P Hack
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
| | - Jessica Spahn
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
| | - Minshan Chen
- Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, PR China
| | - Ann-Lii Cheng
- National Taiwan University Cancer Center & National Taiwan University Hospital, Taipei, Taiwan
| | - Ahmed Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Masatoshi Kudo
- Department of Gastroenterology & Hepatology, Kindai University School of Medicine, Osaka, Japan
| | - Han Chu Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Adam Yopp
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Pierce Chow
- Division of Surgical Oncology, National Cancer Centre, Singapore
| | - Shukui Qin
- PLA Cancer Center, People's Liberation Army (PLA) 81 Hospital, Nanjing 210016, PR China
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9
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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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10
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Akateh C, Black SM, Conteh L, Miller ED, Noonan A, Elliott E, Pawlik TM, Tsung A, Cloyd JM. Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma. World J Gastroenterol 2019; 25:3704-3721. [PMID: 31391767 PMCID: PMC6676544 DOI: 10.3748/wjg.v25.i28.3704] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 06/13/2019] [Accepted: 06/22/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver malignancy worldwide and a major cause of cancer-related mortality for which liver resection is an important curative-intent treatment option. However, many patients present with advanced disease and with underlying chronic liver disease and/or cirrhosis, limiting the proportion of patients who are surgical candidates. In addition, the development of recurrent or de novo cancers following surgical resection is common. These issues have led investigators to evaluate the benefit of neoadjuvant and adjuvant treatment strategies aimed at improving resectability rates and decreasing recurrence rates. While high-level evidence to guide treatment decision making is lacking, recent advances in locoregional and systemic therapies, including antiviral treatment and immunotherapy, raise the prospect of novel approaches that may improve the outcomes of patients with HCC. In this review, we evaluate the evidence for various neoadjuvant and adjuvant therapies and discuss opportunities for future clinical and translational research.
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Affiliation(s)
- Clifford Akateh
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Sylvester M Black
- Division of Transplant Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Lanla Conteh
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Eric D Miller
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Anne Noonan
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Eric Elliott
- Division of Diagnostic Radiology, Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Allan Tsung
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Jordan M Cloyd
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
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11
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Akazawa Y, Suzuki T, Yoshikawa T, Mizuno S, Nakamoto Y, Nakatsura T. Prospects for immunotherapy as a novel therapeutic strategy against hepatocellular carcinoma. World J Meta-Anal 2019; 7:80-95. [DOI: 10.13105/wjma.v7.i3.80] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/12/2019] [Accepted: 03/16/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive malignant disease, with a poor clinical prognosis. Many standard therapies are often considered for HCC treatment today; however, these conventional therapies often fail to achieve sufficiently effective clinical results. Today, HCC therapy is set to undergo a major revolution, owing to rapid developments in cancer immunotherapy, particularly immune checkpoint inhibitor therapy. Cancer immunotherapy is a novel and promising treatment strategy that differs significantly from conventional therapies in its approach to achieve antitumor effects. In fact, many cancer immunotherapies have been tested worldwide and shown to be effective against various types of cancer; HCC is no exception to this trend. For example, we identified a specific cancer antigen called glypican-3 (GPC3) and performed clinical trials of GPC3-targeted peptide vaccine immunotherapy in patients with HCC. Here, we present an overview of the immune mechanisms for development and progression of HCC, our GPC3-based immunotherapy, and immune checkpoint inhibitor therapy against HCC. Finally, we discuss the future prospects of cancer immunotherapy against HCC. We believe that this review and discussion of cancer immunotherapy against HCC could stimulate more interest in this promising strategy for cancer therapy and help in its further development.
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Affiliation(s)
- Yu Akazawa
- Toshiaki Yoshioka, Shoichi Mizuno, Tetsuya Nakatsura, Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Toshihiro Suzuki
- Toshiaki Yoshioka, Shoichi Mizuno, Tetsuya Nakatsura, Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan
| | | | | | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
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12
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Noveiry BB, Hirbod-Mobarakeh A, Khalili N, Hourshad N, Greten TF, Abou-Alfa GK, Rezaei N. Specific immunotherapy in hepatocellular cancer: A systematic review. J Gastroenterol Hepatol 2017; 32:339-351. [PMID: 27206802 PMCID: PMC6377153 DOI: 10.1111/jgh.13449] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/07/2016] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIM In recent years, several novel immunotherapeutic approaches were developed and investigated in patients with hepatocellular carcinoma (HCC). We designed this systematic review, to evaluate clinical efficacy of specific immunotherapy in patients with HCC, according to the guidelines of Border of Immune Tolerance Education and Research Network (BITERN) and Cochrane collaboration. METHODS We searched Medline, Scopus, CENTRAL, TRIP, DART, OpenGrey, and ProQuest through the 9th of December 2015. One author reviewed and retrieved citations from these seven databases for irrelevant and duplicate studies, and two other authors independently extracted data from the studies and rated their quality. We collated study findings and calculated a weighted treatment effect across studies using Review Manager. RESULTS We found 12144 references in seven databases of which 21 controlled studies with 1885 HCC patients in different stages were included in this systematic review after the primary and secondary screenings. Overall, patients undergoing specific immunotherapy had significantly higher overall survival than those in control group (HR = 0.59; 95% CI = 0.47-0.76, P < 0.0001). There was a significant difference in recurrence-free survival between patients undergoing specific immunotherapy and patients in control groups and patients in immunotherapy groups overall had less recurrence than control group (HR = 0.54; 95% CI = 0.46-0.63, P < 0.00001). CONCLUSIONS Results of this systematic review based on the available literature suggest that overall specific immunotherapeutic approaches could be beneficiary for the treatment of patients with HCC. This further supports the current and ongoing evaluations of specific immunotherapies in the field.
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Affiliation(s)
- Behnoud Baradaran Noveiry
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Armin Hirbod-Mobarakeh
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran,Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran, Iran,Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nastaran Khalili
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Niloufar Hourshad
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, USA,Weill Cornell Medical College, New York, USA
| | - Nima Rezaei
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran,Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran, Iran,Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran,Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Sheffield, UK
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13
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Tumour antigen expression in hepatocellular carcinoma in a low-endemic western area. Br J Cancer 2015; 112:1911-20. [PMID: 26057582 PMCID: PMC4580401 DOI: 10.1038/bjc.2015.92] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 01/21/2015] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
Background: Identification of tumour antigens is crucial for the development of
vaccination strategies against hepatocellular carcinoma (HCC). Most studies
come from eastern-Asia, where hepatitis-B is the main cause of HCC. However,
tumour antigen expression is poorly studied in low-endemic, western areas
where the aetiology of HCC differs. Methods: We constructed tissue microarrays from resected HCC tissue of 133 patients.
Expression of a comprehensive panel of cancer-testis (MAGE-A1,
MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, sperm protein
17), onco-fetal (AFP, Glypican-3) and overexpressed tumour antigens
(Annexin-A2, Wilms tumor-1, Survivin, Midkine, MUC-1) was determined by
immunohistochemistry. Results: A higher prevalence of MAGE antigens was observed in patients with
hepatitis-B. Patients with expression of more tumour antigens in general had
better HCC-specific survival (P=0.022). The four tumour
antigens with high expression in HCC and no, or weak, expression in
surrounding tumour-free-liver tissue, were Annexin-A2, GPC-3, MAGE-C1 and
MAGE-C2, expressed in 90, 39, 17 and 20% of HCCs, respectively.
Ninety-five percent of HCCs expressed at least one of these four tumour
antigens. Interestingly, GPC-3 was associated with SALL-4 expression
(P=0.001), an oncofetal transcription factor highly
expressed in embryonal stem cells. SALL-4 and GPC-3 expression levels were
correlated with vascular invasion, poor differentiation and higher AFP
levels before surgery. Moreover, patients who co-expressed higher levels of
both GPC-3 and SALL-4 had worse HCC-specific survival
(P=0.018). Conclusions: We describe a panel of four tumour antigens with excellent coverage and good
tumour specificity in a western area, low-endemic for hepatitis-B. The
association between GPC-3 and SALL-4 is a novel finding and suggests that
GPC-3 targeting may specifically attack the tumour stem-cell
compartment.
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14
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He H, Tu X, Zhang J, Acheampong DO, Ding L, Ma Z, Ren X, Luo C, Chen Z, Wang T, Xie W, Wang M. A novel antibody targeting CD24 and hepatocellular carcinoma in vivo by near-infrared fluorescence imaging. Immunobiology 2015; 220:1328-36. [PMID: 26255089 DOI: 10.1016/j.imbio.2015.07.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 03/13/2015] [Accepted: 07/07/2015] [Indexed: 12/24/2022]
Abstract
Liver cancer is one of the most common malignant cancers worldwide. The poor response of liver cancer to chemotherapy has whipped up the interest in targeted therapy with monoclonal antibodies because of its potential efficiency. One promising target is cluster of differentiation 24 (CD24), which is known to beover-expressed on hepatocellular carcinoma (HCC), providing prospect for HCC targeted diagnosis and therapy. In this study we developed a novel CD24 targeted monoclonal antibody G7mAb based on hybridoma technology and then generated a single-chain antibodyfragment (scFv) G7S. Firstly, ELISA, western blot, and flow cytometry assays demonstrated specific binding of CD24 by G7mAb and G7S. Further, G7mAb was demonstrated to have similar binding capacity as ML5 (a commercial Anti-CD24 Mouse Antibody) inimmunohistochemical assay. Further more, a near-infrared fluorescent dye multiplex probe amplification (MPA) was conjugated to G7mAb and G7S to form G7mAb-MPA and G7S-MPA. The near-infrared fluorescence imaging revealed that G7mAb and G7S aggregate in CD24+Huh7 hepatocellular carcinoma xenograft tissuevia specific binding to CD24 in vivo. In conclussion, G7mAb and G7S were tumor targeted therapeutic and diagnostic potentials in vitro and in vivo as anticipated.
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Affiliation(s)
- Hua He
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Xiaojie Tu
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Juan Zhang
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Desmond Omane Acheampong
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Li Ding
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Zhaoxiong Ma
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Xueyan Ren
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Chen Luo
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Zhiguo Chen
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Tong Wang
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Wei Xie
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Min Wang
- State Key Laboratory of Natural Medicines (China Pharmaceutical University), School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China.
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15
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Fatourou EM, Koskinas JS. Adaptive immunity in hepatocellular carcinoma: prognostic and therapeutic implications. Expert Rev Anticancer Ther 2014; 9:1499-510. [DOI: 10.1586/era.09.103] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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16
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Fournier P, Schirrmacher V. Randomized clinical studies of anti-tumor vaccination: state of the art in 2008. Expert Rev Vaccines 2014; 8:51-66. [DOI: 10.1586/14760584.8.1.51] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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17
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18
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Colombo M, Raoul JL, Lencioni R, Galle PR, Zucman-Rossi J, Bañares R, Seehofer D, Neuhaus P, Johnson P. Multidisciplinary strategies to improve treatment outcomes in hepatocellular carcinoma: a European perspective. Eur J Gastroenterol Hepatol 2013; 25:639-51. [PMID: 23628963 DOI: 10.1097/meg.0b013e32835e33bb] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is a complex disease with a poor prognosis. Incidence and mortality rates are increasing in many geographical regions, indicating a need for better management strategies. Among several risk factors for HCC, the most common are cirrhosis because of chronic hepatitis B virus or hepatitis C virus infection and alcohol consumption, obesity, and diabetes. In some patients, combined risk factors present additional challenges to the prevention and treatment of HCC. Screening and surveillance of high-risk populations varies widely by geographic regions, and access to optimal surveillance is critical for early diagnosis. The treatment choice for HCC depends on the cancer stage, patient performance status, and liver function and requires a multidisciplinary approach and close cooperation among specialists for the best patient outcomes. Despite advances in surgical treatments and locoregional therapies, recurrence and liver failure remain significant challenges. The pathogenesis of HCC is a multistep and complex process, wherein angiogenesis plays an important role. The multikinase inhibitor sorafenib is the only approved targeted agent for advanced HCC, although promising results have been obtained with other targeted agents and combinations, and the results of ongoing trials are eagerly awaited. Clinical trials with rigorous study designs, including molecular classification and validation of new molecular biomarkers, are required to improve the personalized treatment of HCC. This article provides an overview of HCC and was developed through a review of relevant literature, clinical trial data, and updated clinical guidelines.
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Affiliation(s)
- Massimo Colombo
- 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
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19
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Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S. Immunotherapy of cancer in 2012. CA Cancer J Clin 2012; 62:309-35. [PMID: 22576456 PMCID: PMC3445708 DOI: 10.3322/caac.20132] [Citation(s) in RCA: 321] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology. These principles have been critical in the development of immunotherapy in the laboratory and in the implementation of immunotherapy in the clinic. This improved understanding of immunotherapy, enhanced by increased insights into the mechanism of tumor immune response and its evasion by tumors, now permits manipulation of this interaction and elucidates the therapeutic role of immunity in cancer. Also important, this improved understanding of immunotherapy and the mechanisms underlying immunity in cancer has fueled an expanding array of new therapeutic agents for a variety of cancers. Pegylated interferon-α2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an increased understanding of the principles of tumor biology and immunology have been translated successfully from the laboratory to the clinical setting. Principles that guide the development and application of immunotherapy include antibodies, cytokines, vaccines, and cellular therapies. The identification and further elucidation of the role of immunotherapy in different tumor types, and the development of strategies for combining immunotherapy with cytotoxic and molecularly targeted agents for future multimodal therapy for cancer will enable even greater progress and ultimately lead to improved outcomes for patients receiving cancer immunotherapy.
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Affiliation(s)
- John M Kirkwood
- Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
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20
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Tong X, Wang L, Liu Y, Qi Y, Qin Y, Xu Y, Tong T. The complete preventive effect of homologous tumor vaccines--based on a 5-year experimental study in mice. Biomed Pharmacother 2010; 64:605-8. [PMID: 20961730 DOI: 10.1016/j.biopha.2010.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2010] [Accepted: 09/05/2010] [Indexed: 11/26/2022] Open
Abstract
By using a frozen-thaw method, we developed homologous and heterologous cell-based tumor vaccines, which were derived from mouse H22 hepatoma, S180 sarcoma and human A549 lung carcinoma, SK-OV-3 ovarian, and SMMC-7721 hepatoma cell lines. The prophylactic and therapeutic effects of those vaccines were evaluated in mice challenged with live H22 or S180 cells. The result demonstrated that homologous vaccines and heterologous vaccines had no therapeutic effect on tumor growth. However, homologous vaccines showed a complete prevention against live H22 and S180 cell challenge and they could stimulate cross-immune response of anti-tumor in mice. Furthermore, these tumor-free mice immunized with homologous vaccines showed full protection against the repeat challenge every 3 months for 5 years. The study also revealed that tumor-free female, not male, mice transferred anti-tumor ability to some of their offsprings. Heterologous vaccines exhibited no protective effect on tumor development. Immunological analysis discovered that activities of CTLs and NK were enhanced and the levels of IL-2, IL-12 and IFN-γ were significantly increased. Our results demonstrated that homologous tumor vaccines could elicit complete cross-protection against the lethal challenge of tumor cells through enhancing cell-mediated immune response, which lasted for 5 years in mice. These observations may provide a new vaccine strategy for tumor prevention.
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Affiliation(s)
- Xinglong Tong
- Hebei Xinglong medical and pharmaceutical institute, 232 South Zhonghua Street, Shijiazhuang 050056, PR China.
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21
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Zhong JH, Li LQ. Postoperative adjuvant transarterial chemoembolization for participants with hepatocellular carcinoma: A meta-analysis. Hepatol Res 2010; 40:943-953. [PMID: 20887328 DOI: 10.1111/j.1872-034x.2010.00710.x] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
AIM The efficacy of transarterial chemoembolization (TACE) for inoperable hepatocellular carcinoma (HCC) is positive, but for postoperative HCC, many studies have reported controversial results. The present study aimed to evaluate the efficacy of postoperative adjuvant TACE for participants with HCC. METHODS Electronic and manual searches were conducted to identify randomized controlled trials (RCT) evaluating postoperative adjuvant TACE for participants with HCC. RESULTS Six RCT totaling 659 participants, of whom almost all were of stage IIIA HCC, were included. For the 1-year tumor recurrence rate, hepatectomy plus TACE showed statistically significant less incidence of recurrence, with a pooled risk ratio (RR) of 0.68 (95% confidence interval [CI] = 0.55-0.84, P = 0.0003). For 1-year mortality, the trials were favorable for TACE with a pooled risk ratio of 0.48 (95% CI = 0.35-0.65, P < 0.00001). For 3-year mortality, the trials also revealed statistically significant less incidence, with a pooled risk ratio of 0.76 (95% CI = 0.64-0.90, P = 0.002). However, for 5-year mortality, TACE did not demonstrate statistically significant less incidence (RR = 0.94, 95% CI = 0.81-1.08, P = 0.36). Transient fever and nausea/vomiting were reported as side-effects of TACE but were well tolerated by most participants. CONCLUSION Postoperative adjuvant TACE seems promising for participants with HCC with risk factors (multiple nodules of >5 cm or vascular invasion) but requires further trial.
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Affiliation(s)
- Jian-Hong Zhong
- Hepatobiliary Surgery Department, Tumor Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
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