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Zhang Y, Zhou XQ, Jiang WD, Wu P, Liu Y, Ren HM, Zhang L, Mi HF, Tang L, Zhong CB, Feng L. Emerging role of vitamin D 3 in alleviating intestinal structure injury caused by Aeromonas hydrophila in grass carp ( Ctenopharyngodon idella). ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2024; 16:202-217. [PMID: 38362511 PMCID: PMC10867611 DOI: 10.1016/j.aninu.2023.07.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/22/2023] [Accepted: 07/21/2023] [Indexed: 02/17/2024]
Abstract
Bacterial pathogens destroy the structural integrity of functional organs in fish, leading to severe challenges in the aquaculture industry. Vitamin D3 (VD3) prevents bacterial infections and strengthens immune system function via vitamin D receptor (VDR). However, the correlation between VD3/VDR and the structural integrity of functional organs remains unclarified. This study aimed to investigate the influence of VD3 supplementation on histological characteristics, apoptosis, and tight junction characteristics in fish intestine during pathogen infection. A total of 540 healthy grass carp (257.24 ± 0.63 g) were fed different levels of VD3 (15.2, 364.3, 782.5, 1,167.9, 1,573.8, and 1,980.1 IU/kg) for 70 d. Subsequently, fish were challenged with Aeromonas hydrophila, a pathogen that causes intestinal inflammation. Our present study demonstrated that optimal supplementation with VD3 (1) alleviated intestinal structural damage, and inhibited oxidative damage by reducing levels of oxidative stress biomarkers; (2) attenuated excessive apoptosis-related death receptor and mitochondrial pathway processes in relation to p38 mitogen-activated protein kinase signaling (P < 0.05); (3) enhanced tight junction protein expression by inhibiting myosin light chain kinase signaling (P < 0.05); and (4) elevated VDR isoform expression in fish intestine (P < 0.05). Overall, the results demonstrated that VD3 alleviates oxidative injury, apoptosis, and the destruction of tight junction protein under pathogenic infection, thereby strengthening pathogen defenses in the intestine. This finding supports the rationale for VD3 intervention as an essential practice in sustainable aquaculture.
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Affiliation(s)
- Yao Zhang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Xiao-Qiu Zhou
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Wei-Dan Jiang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Pei Wu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Yang Liu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Hong-Mei Ren
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Lu Zhang
- Healthy Aquaculture Key Laboratory of Sichuan Province, Tongwei Co., Ltd., Chengdu, China
| | - Hai-Feng Mi
- Healthy Aquaculture Key Laboratory of Sichuan Province, Tongwei Co., Ltd., Chengdu, China
| | - Ling Tang
- Sichuan Animal Science Academy, Sichuan Animtech Feed Co., Ltd., Chengdu, China
| | - Cheng-Bo Zhong
- Sichuan Animal Science Academy, Sichuan Animtech Feed Co., Ltd., Chengdu, China
| | - Lin Feng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
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Moon EK, Wang LCS, Bekdache K, Lynn RC, Lo A, Thorne SH, Albelda SM. Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines. Oncoimmunology 2018; 7:e1395997. [PMID: 29399394 DOI: 10.1080/2162402x.2017.1395997] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 10/19/2017] [Indexed: 12/22/2022] Open
Abstract
T cell trafficking into tumors depends on a "match" between chemokine receptors on effector cells (e.g., CXCR3 and CCR5) and tumor-secreted chemokines. There is often a chemokine/chemokine receptor "mismatch", with tumors producing minute amounts of chemokines, resulting in inefficient targeting of effectors to tumors. We aimed to alter tumors to produce higher levels of CXCL11, a CXCR3 ligand, to attract more effector cells following immunotherapy. Mice bearing established subcutaneous tumors were studied. In our first approach, we used modified chimeric antigen receptor (CAR)-transduced human T cells to deliver CXCL11 (CAR/CXCL11) into tumors. In our second approach, we intravenously (iv) administered a modified oncolytic vaccinia virus (VV) engineered to produce CXCL11 (VV.CXCL11). The effect of these treatments on T cell trafficking into the tumors and anti-tumor efficacy after subsequent CAR T cell injections or anti-tumor vaccines was determined. CAR/CXCL11 and VV.CXCL11 significantly increased CXCL11 protein levels within tumors. For CAR/CXCL11, injection of a subsequent dose of CAR T cells did not result in increased intra-tumoral trafficking, and appeared to decrease the function of the injected CAR T cells. In contrast, VV.CXCL11 increased the number of total and antigen-specific T cells within tumors after CAR T cell injection or vaccination and significantly enhanced anti-tumor efficacy. Both approaches were successful in increasing CXCL11 levels within the tumors; however, only the vaccinia approach was successful in recruiting T cells and augmenting anti-tumor efficacy. VV.CXCL11 should be considered as a potential approach to augment adoptive T cell transfer or vaccine immunotherapy.
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Affiliation(s)
- Edmund K Moon
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Liang-Chuan S Wang
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.,current address: Preclinical Pharmacology, Incyte Corporation, Wilmington, DE, USA
| | - Kheng Bekdache
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Rachel C Lynn
- Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Albert Lo
- Department of Biomedical Sciences, School of Veterinary Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Stephen H Thorne
- University of Pittsburgh Cancer Institute, and Departments of Surgery and Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Steven M Albelda
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Han Z, Yang D, Trivett A, Oppenheim JJ. Therapeutic vaccine to cure large mouse hepatocellular carcinomas. Oncotarget 2017; 8:52061-52071. [PMID: 28881713 PMCID: PMC5581012 DOI: 10.18632/oncotarget.19367] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 05/10/2017] [Indexed: 01/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Here we report the development of a therapeutic vaccination regimen (shortened as ‘TheraVac’) consisting of intratumoral delivery of high-mobility group nucleosome-binding protein 1 (HMGN1), R848/resiquimod, and one of the checkpoint inhibitors (e.g. anti-CTLA4, anti-PD-L1, or low dose of Cytoxan). C57BL/6 mice harboring large (approximately 1 cm in diameter) established subcutaneous Hepa1-6 hepatomas were cured by intratumoral injections of TheraVac and became tumor-free long-term survivors. Importantly, the resultant tumor-free mice were resistant to re-challenge with Hepa1-6 hepatoma, not B16 melanoma, demonstrating the acquisition of hepatoma-specific immunity in the absence of any administered tumor antigen. Mechanistic studies showed that upon treatment with TheraVac, Hepa1-6-bearing mice generated increased Hepa1-6-specific CTLs in the draining lymph nodes and showed greatly upregulated expression of CXCL9, CXCL10, and IFN-γ and elevated infiltration of T lymphocytes in tumor tissues. Treatment of large Hepa1-6 hepatomas on one mouse flank also eliminated smaller (approximately 0.5 cm in diameter) hepatomas implanted on the other flank. Thus, TheraVac has potential as a curative immunotherapeutic regimen for the treatment of human HCC.
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Affiliation(s)
- Zhen Han
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
| | - De Yang
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
| | - Anna Trivett
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
| | - Joost J Oppenheim
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
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Liang CM, Chen L, Hu H, Ma HY, Gao LL, Qin J, Zhong CP. Chemokines and their receptors play important roles in the development of hepatocellular carcinoma. World J Hepatol 2015; 7:1390-1402. [PMID: 26052384 PMCID: PMC4450202 DOI: 10.4254/wjh.v7.i10.1390] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/08/2014] [Accepted: 04/07/2015] [Indexed: 02/06/2023] Open
Abstract
The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma (HCC). The chemokines and their receptors in the microenvironment influence the development of HCC by several aspects including: inflammation, effects on immune cells, angiogenesis, and direct effects on HCC cells. Regarding these aspects, pre-clinical research by targeting the chemokine system has yielded promising data, and these findings bring us new clues in the chemokine-based therapies for HCC.
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He Y, Hong Y, Mizejewski GJ. Engineering α-fetoprotein-based gene vaccines to prevent and treat hepatocellular carcinoma: review and future prospects. Immunotherapy 2015; 6:725-36. [PMID: 25041030 DOI: 10.2217/imt.14.46] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Activation of a patient's immune system offers an attractive approach to prevent and treat hepatocellular carcinoma (HCC). However, the antitumor efficacy of current HCC vaccines was weak owing to insufficient immune activation of targeting self/tumor antigens. We recently found that epitope-optimized α-fetoprotein effectively activated CD8 T cells and generated potent antitumor effects in the carcinogen-induced autochthonous HCC mouse model. We predict that the same antigen engineering approach of epitope-optimization will enable us to develop effective human vaccines to prevent HCC recurrence after liver resection. The engineered human HCC vaccines may also allow us to identify high-affinity T-cell receptors and antibodies that can be used to reprogram T cells to treat HCC tumors via adoptive transfer.
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Affiliation(s)
- Yukai He
- Georgia Regents University Cancer Center, Cancer Immunology, Inflammation & Tolerance Program, Augusta, GA 30907, USA
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Hong Y, Peng Y, Guo ZS, Guevara-Patino J, Pang J, Butterfield LH, Mivechi N, Munn DH, Bartlett DL, He Y. Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma. Hepatology 2014; 59:1448-58. [PMID: 24122861 PMCID: PMC4151349 DOI: 10.1002/hep.26893] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Revised: 09/25/2013] [Accepted: 10/06/2013] [Indexed: 12/12/2022]
Abstract
UNLABELLED Immunization with effective cancer vaccines can offer a much needed adjuvant therapy to fill the treatment gap after liver resection to prevent relapse of hepatocellular carcinoma (HCC). However, current HCC cancer vaccines are mostly based on native shared-self/tumor antigens that are only able to induce weak immune responses. In this study we investigated whether the HCC-associated self/tumor antigen of alpha-fetoprotein (AFP) could be engineered to create an effective vaccine to break immune tolerance and potently activate CD8 T cells to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. We found that the approach of computer-guided methodical epitope-optimization created a highly immunogenic AFP and that immunization with lentivector expressing the epitope-optimized AFP, but not wild-type AFP, potently activated CD8 T cells. Critically, the activated CD8 T cells not only cross-recognized short synthetic wild-type AFP peptides, but also recognized and killed tumor cells expressing wild-type AFP protein. Immunization with lentivector expressing optimized AFP, but not native AFP, completely protected mice from tumor challenge and reduced the incidence of carcinogen-induced autochthonous HCC. In addition, prime-boost immunization with the optimized AFP significantly increased the frequency of AFP-specific memory CD8 T cells in the liver that were highly effective against emerging HCC tumor cells, further enhancing the tumor prevention of carcinogen-induced autochthonous HCC. CONCLUSIONS Epitope-optimization is required to break immune tolerance and potently activate AFP-specific CD8 T cells, generating effective antitumor effect to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. Our study provides a practical roadmap to develop effective human HCC vaccines that may result in an improved outcome compared to the current HCC vaccines based on wild-type AFP.
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Affiliation(s)
- Yuan Hong
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA
| | - Yibing Peng
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA
| | - Z. Sheng Guo
- Department of Surgery and University of Pittsburgh Cancer Institute, Pittsburgh, PA
| | - Jose Guevara-Patino
- Depart of Surgery, Cardinal Bernardin Cancer Center, Loyola University, Maywood, IL
| | - Junfeng Pang
- Department of Radiology and Molecular Chaperone Program, Georgia Regents University Cancer Center, Augusta, GA
| | - Lisa H. Butterfield
- Department of Medicine, Surgery, and Immunology, University of Pittsburgh Cancer Institute, Pittsburgh, PA
| | - Nahid Mivechi
- Department of Radiology and Molecular Chaperone Program, Georgia Regents University Cancer Center, Augusta, GA
| | - David H Munn
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA,Department of Pediatrics, Medical College of Georgia, Augusta, GA
| | - David L Bartlett
- Department of Surgery and University of Pittsburgh Cancer Institute, Pittsburgh, PA
| | - Yukai He
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA,Department of Medicine, Medical College of Georgia, Augusta, GA
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Mohit E, Rafati S. Chemokine-based immunotherapy: delivery systems and combination therapies. Immunotherapy 2013; 4:807-40. [PMID: 22947009 DOI: 10.2217/imt.12.72] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
A major role of chemokines is to mediate leukocyte migration through interaction with G-protein-coupled receptors. Various delivery systems have been developed to utilize the chemokine properties for combating disease. Viral and mutant viral vectors expressing chemokines, genetically modified dendritic cells with chemokine or chemokine receptors, engineered chemokine-expressing tumor cells and pDNA encoding chemokines are among these methods. Another approach for inducing a targeted immune response is fusion of a targeting antibody or antibody fragment to a chemokine. In addition, chemokines induce more effective antitumor immunity when used as adjuvants. In this regard, chemokines are codelivered along with antigens or fused as a targeting unit with antigenic moieties. In this review, several chemokines with their role in inducing immune response against different diseases are discussed, with a major emphasis on cancer.
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Affiliation(s)
- Elham Mohit
- Molecular Immunology & Vaccine Research Lab, Pasteur Institute of Iran, Tehran 13164, Iran
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Kim KI, Park JH, Lee YJ, Lee TS, Park JJ, Song I, Nahm SS, Cheon GJ, Lim SM, Chung JK, Kang JH. In vivo bioluminescent imaging of α-fetoprotein-producing hepatocellular carcinoma in the diethylnitrosamine-treated mouse using recombinant adenoviral vector. J Gene Med 2013; 14:513-20. [PMID: 22761128 DOI: 10.1002/jgm.2648] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The in vivo molecular imaging method is a useful tool for monitoring carcinogenesis in various hepatocellular carcinoma (HCC) models, such as xenografted-, chemical induced- and transgenic mice. The tumor-specific gene expression strategy, such as transcriptional targeting, is essential for achieving a lower toxicity for normal liver tissue in therapy and the monitoring of tumor progression in diagnosis, respectively. The present study aimed to visualize spontaneously developing α-fetoprotein (AFP)-producing HCC through targeted gene expression in tumors using recombinant adenoviral vector. METHODS The recombinant adenovirus vector, AdAFPfLuc (containing firefly luciferase gene driven by human AFP enhancer/promoter) was prepared. After in vitro infection by adenovirus, gene expression was confirmed using the luciferase assay, semi-quantitative reverse transcriptase-polymerase chain reaction and western blotting in AFP-producing and nonproducing cells. Tumor-bearing mice were intravenously injected with adenovirus, and bioluminescent images were obtained. RESULTS The expression of fLuc was efficiently demonstrated by the luciferase assay in AFP-producing cells but not in AFP-nonproducing cells. AFP-producing HCC targeted gene expression was confirmed at the mRNA and protein levels. After being injected intravenously in HuH-7 xenografts and HCC-bearing diethylnitrosamine-treated mice using adenovirus, functional reporter gene expression was confirmed in tumors by in vivo bioluminescent imaging (BLI). CONCLUSIONS The recombinant adenovirus vector system can be used to monitor spontaneously developing AFP-producing HCC and to evaluate targeted gene expression in tumors by in vivo BLI in a small animal model.
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Affiliation(s)
- Kwang Il Kim
- Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
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Kim KI, Lee YJ, Lee TS, Song I, Cheon GJ, Lim SM, Chung JK, Kang JH. In vitro radionuclide therapy and in vivo scintigraphic imaging of alpha-fetoprotein-producing hepatocellular carcinoma by targeted sodium iodide symporter gene expression. Nucl Med Mol Imaging 2012; 47:1-8. [PMID: 24895502 DOI: 10.1007/s13139-012-0166-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Revised: 08/10/2012] [Accepted: 08/20/2012] [Indexed: 12/23/2022] Open
Abstract
PURPOSE This study aimed to develop a gene expression targeting method for specific imaging and therapy of alpha-fetoprotein (AFP)-producing hepatocellular carcinoma (HCC) cells, using an adenovirus vector containing the human sodium/iodide symporter (hNIS) gene driven by an AFP enhancer/promoter. METHODS The recombinant adenovirus vector, AdAFPhNIS (containing the hNIS gene driven by human AFP enhancer/promoter) was prepared. After in vitro infection by the adenovirus, hNIS gene expression in AFP-producing cells and in AFP-nonproducing cells was investigated using (125)I uptake assay and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). The killing effect of (131)I on AdAFPhNIS-infected HCC cells was studied using an in vitro clonogenic assay. In addition, tumor-bearing mice were intravenously injected with the adenovirus, and scintigraphic images were obtained. RESULTS The expression of hNIS was efficiently demonstrated by (125)I uptake assay in AFP-producing cells, but not in AFP-nonproducing cells. AFP-producing HCC-targeted gene expression was confirmed at the mRNA level. Furthermore, in vitro clonogenic assay showed that hNIS gene expression induced by AdAFPhNIS infection in AFP-producing cells caused more sensitivity to (131)I than that in AFP-nonproducing cells. Injected intravenously in HuH-7 tumor xenografts mice by adenovirus, the functional hNIS gene expression was confirmed in tumor by in vivo scintigraphic imaging. CONCLUSIONS An AFP-producing HCC was targeted with an adenovirus vector containing the hNIS gene using the AFP enhancer/promoter in vitro and in vivo. These findings demonstrate that AFP-producing HCC-specific molecular imaging and radionuclide gene therapy are feasible using this recombinant adenovirus vector system.
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Affiliation(s)
- Kwang Il Kim
- Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, 75, Nowon-gil, Gongneung-dong, Nowon-gu, Seoul 139-706 Korea
| | - Yong Jin Lee
- Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, 75, Nowon-gil, Gongneung-dong, Nowon-gu, Seoul 139-706 Korea
| | - Tae Sup Lee
- Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, 75, Nowon-gil, Gongneung-dong, Nowon-gu, Seoul 139-706 Korea
| | - Inho Song
- Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, 75, Nowon-gil, Gongneung-dong, Nowon-gu, Seoul 139-706 Korea
| | - Gi Jeong Cheon
- Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, 75, Nowon-gil, Gongneung-dong, Nowon-gu, Seoul 139-706 Korea ; Department of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Sang Moo Lim
- Department of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - June-Key Chung
- Department of Nuclear Medicine, Seoul National University College of Medicine, 28, Yongon-dong, Jongno-gu, Seoul 110-744 Korea
| | - Joo Hyun Kang
- Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, 75, Nowon-gil, Gongneung-dong, Nowon-gu, Seoul 139-706 Korea
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Morozov AV, Morozov VA, Astakhova TM, Timofeev AV, Karpov VL. DNA vaccine encoding α-fetoprotein fused with the ornithine decarboxylase degradation signal significantly suppresses the hepatocellular carcinoma growth in mice. Mol Biol 2012. [DOI: 10.1134/s0026893312030089] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Lyra-González I, Flores-Fong LE, González-García I, Medina-Preciado D, Armendáriz-Borunda J. Adenoviral gene therapy in hepatocellular carcinoma: a review. Hepatol Int 2012. [DOI: 10.1007/s12072-012-9367-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Touchefeu Y, Harrington KJ, Galmiche JP, Vassaux G. Review article: gene therapy, recent developments and future prospects in gastrointestinal oncology. Aliment Pharmacol Ther 2010; 32:953-68. [PMID: 20937041 DOI: 10.1111/j.1365-2036.2010.04424.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gene therapy consists of the introduction of genetic material into cells for a therapeutic purpose. A wide range of gene therapy vectors have been developed and used for applications in gastrointestinal oncology. AIM To review recent developments and published clinical trials concerning the application of gene therapy in the treatment of liver, colon and pancreatic cancers. METHODS Search of the literature published in English using the PubMed database. RESULTS A large variety of therapeutic genes are under investigation, such as tumour suppressor, suicide, antiangiogenesis, inflammatory cytokine and micro-RNA genes. Recent progress concerns new vectors, such as oncolytic viruses, and the synergy between viral gene therapy, chemotherapy and radiation therapy. As evidence of these basic developments, recently published phase I and II clinical trials, using both single agents and combination strategies, in adjuvant or advanced disease settings, have shown encouraging results and good safety records. CONCLUSIONS Cancer gene therapy is not yet indicated in clinical practice. However, basic and clinical advances have been reported and gene therapy is a promising, new therapeutic approach for the treatment of gastrointestinal tumours.
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Affiliation(s)
- Y Touchefeu
- Institut des Maladies de l'Appareil Digestif, INSERM U, University Hospital, Nantes, France.
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Kosinska AD, Zhang E, Lu M, Roggendorf M. Therapeutic vaccination in chronic hepatitis B: preclinical studies in the woodchuck. HEPATITIS RESEARCH AND TREATMENT 2010; 2010:817580. [PMID: 21188201 PMCID: PMC3003998 DOI: 10.1155/2010/817580] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Accepted: 07/29/2010] [Indexed: 02/07/2023]
Abstract
Recommended treatment of chronic hepatitis B with interferon-α and/or nucleos(t)ide analogues does not lead to a satisfactory result. Induction of HBV-specific T cells by therapeutic vaccination or immunotherapies may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients did not result in effective control of HBV infection, suggesting that new formulations of therapeutic vaccines are needed. The woodchuck (Marmota monax) is a useful preclinical model for developing the new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments with nucleos(t)ide analogues, DNA vaccines, and protein vaccines were tested in the woodchuck model. In this paper we summarize the available data concerning therapeutic immunization and gene therapy using recombinant viral vectors approaches in woodchucks, which show encouraging results. In addition, we present potential innovations in immunomodulatory strategies to be evaluated in this animal model.
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Affiliation(s)
- Anna D. Kosinska
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Virchowstraβe 179, 45122, Essen, Germany
| | - Ejuan Zhang
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Virchowstraβe 179, 45122, Essen, Germany
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Virchowstraβe 179, 45122, Essen, Germany
| | - Michael Roggendorf
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Virchowstraβe 179, 45122, Essen, Germany
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Semliki forest virus expressing interleukin-12 induces antiviral and antitumoral responses in woodchucks with chronic viral hepatitis and hepatocellular carcinoma. J Virol 2009; 83:12266-78. [PMID: 19740992 DOI: 10.1128/jvi.01597-09] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
A vector based on Semliki Forest virus (SFV) expressing high levels of interleukin-12 (SFV-enhIL-12) has previously demonstrated potent antitumoral efficacy in small rodents with hepatocellular carcinoma (HCC) induced by transplantation of tumor cells. In the present study, the infectivity and antitumoral/antiviral effects of SFV vectors were evaluated in the clinically more relevant woodchuck model, in which primary HCC is induced by chronic infection with woodchuck hepatitis virus (WHV). Intratumoral injection of SFV vectors expressing luciferase or IL-12 resulted in high reporter gene activity within tumors and cytokine secretion into serum, respectively, demonstrating that SFV vectors infect woodchuck tumor cells. For evaluating antitumoral efficacy, woodchuck tumors were injected with increasing doses of SFV-enhIL-12, and tumor size was measured by ultrasonography following treatment. In five (83%) of six woodchucks, a dose-dependent, partial tumor remission was observed, with reductions in tumor volume of up to 80%, but tumor growth was restored thereafter. Intratumoral treatment further produced transient changes in WHV viremia and antigenemia, with >or=1.5-log(10) reductions in serum WHV DNA in half of the woodchucks. Antitumoral and antiviral effects were associated with T-cell responses to tumor and WHV antigens and with expression of CD4 and CD8 markers, gamma interferon, and tumor necrosis factor alpha in peripheral blood mononuclear cells, suggesting that immune responses against WHV and HCC had been induced. These experimental observations suggest that intratumoral administration of SFV-enhIL-12 may represent a strategy for treatment of chronic HBV infection and associated HCC in humans but indicate that this approach could benefit from further improvements.
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Rinaldi M, Iurescia S, Fioretti D, Ponzetto A, Carloni G. Strategies for Successful Vaccination against Hepatocellular Carcinoma. Int J Immunopathol Pharmacol 2009; 22:269-77. [DOI: 10.1177/039463200902200203] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Current therapies against hepatocellular carcinoma (HCC) are not curative in the majority of patients. In the past, immunotherapy approaches aimed to non-specifically stimulate immune response were quite ineffective. New treatments based on stimulation of specific anti-tumor immune response are currently proposed and appear more promising. Tumor-specific antigens identified in HCC demonstrated immunogenicity both in preclinical and clinical trials. Effectiveness in animal studies raised interest in the clinical applicability of non-specific adoptive immunotherapy that prevented disease recurrence after tumor resection. Dendritic cell (DC)-based tumor vaccines achieved encouraging results, and cellular vaccines based on DCs have already entered clinical trials. Preventive and therapeutic DNA vaccination have been proposed, all based on tumor-associated antigens (TAAs), either modified or not, an example being alpha-fetoprotein (AFP). The concomitant expression of co-stimulatory molecules and cytokines was used to increase tumor immunogenicity. Syngeneic or nude mice models indicated that immunotherapy for HCC could stimulate an anti-tumor T-cell response leading to clinical benefit devoid of significant toxicity. The use of DNA-based vaccination raises exciting possibilities in preventing HCC in high-risk individuals such as those with cirrhosis. Novel immunotherapy strategies may contribute in the future to prevention and treatment of HCC.
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Affiliation(s)
| | | | | | - A. Ponzetto
- Department of Internal Medicine, University of Turin, Italy
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