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de Almeida NAA, Ribeiro CRDA, Raposo JV, de Paula VS. Immunotherapy and Gene Therapy for Oncoviruses Infections: A Review. Viruses 2021; 13:822. [PMID: 34063186 PMCID: PMC8147456 DOI: 10.3390/v13050822] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/19/2021] [Accepted: 02/24/2021] [Indexed: 12/24/2022] Open
Abstract
Immunotherapy has been shown to be highly effective in some types of cancer caused by viruses. Gene therapy involves insertion or modification of a therapeutic gene, to correct for inappropriate gene products that cause/may cause diseases. Both these types of therapy have been used as alternative ways to avoid cancers caused by oncoviruses. In this review, we summarize recent studies on immunotherapy and gene therapy including the topics of oncolytic immunotherapy, immune checkpoint inhibitors, gene replacement, antisense oligonucleotides, RNA interference, clustered regularly interspaced short palindromic repeats Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based gene editing, transcription activator-like effector nucleases (TALENs) and custom treatment for Epstein-Barr virus, human T-lymphotropic virus 1, hepatitis B virus, human papillomavirus, hepatitis C virus, herpesvirus associated with Kaposi's sarcoma, Merkel cell polyomavirus, and cytomegalovirus.
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Affiliation(s)
| | | | | | - Vanessa Salete de Paula
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, 21040-360 Rio de Janeiro, Brazil; (N.A.A.d.A.); (C.R.d.A.R.); (J.V.R.)
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Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and the fifth most common cancer worldwide. HCC is recognized as the fourth most common cause of cancer related deaths worldwide due to the lack of effective early diagnostic tools, which often leads to individuals going undiagnosed until the cancer has reached late stage development. The current FDA approved treatments for late stage HCC provide a minimal increase in patient survival and lack tumor specificity, resulting in toxic systemic side effects. Gene therapy techniques, such as chimeric antigen receptor (CAR)-T Cells, viral vectors, and nanoparticles, are being explored as novel treatment options in various genetic diseases. Pre-clinical studies using gene therapy to treat in vitro and in vivo models of HCC have demonstrated potential efficacy for use in human patients. This review highlights genetic targets, techniques, and current clinical trials in HCC utilizing gene therapy.
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Hou J, Zhang H, Sun B, Karin M. The immunobiology of hepatocellular carcinoma in humans and mice: Basic concepts and therapeutic implications. J Hepatol 2020; 72:167-182. [PMID: 31449859 DOI: 10.1016/j.jhep.2019.08.014] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 08/02/2019] [Accepted: 08/14/2019] [Indexed: 02/08/2023]
Abstract
Basic and clinical studies have demonstrated the efficacy of immunotherapy, a technical and conceptual breakthrough that has revolutionised cancer treatment. Hepatocellular carcinoma (HCC), a deadly malignancy with aetiologic diversity and a chronic course, is strongly influenced by the immune system, and was recently found to partially benefit from immune-checkpoint inhibitor therapy. Notably, HCC onco-immunology depends on diverse genetic and environmental factors that together shape cancer-promoting inflammation and immune dysfunction - critical processes that control HCC malignant progression and response to therapy. Herein, we summarise the current understanding of liver and HCC onco-immunology obtained through basic studies with mouse models and clinical practice in humans. In particular, we discuss preclinical and clinical findings that implicate immunomodulation as a major factor in HCC development and explain the basis for HCC-targeting immunotherapy.
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Affiliation(s)
- Jiajie Hou
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China; Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Haiyan Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China; Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA.
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Abstract
INTRODUCTION Immunotherapy is on the way to become the new standard of care for advanced hepatocellular carcinoma (HCC) worldwide. With higher rates of objective responses, and overall less side effects compared to tyrosine-kinase inhibitors (TKIs) immunotherapeutics will probably replace sorafenib from standard first-line treatment. AREAS COVERED This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC focusing on immunotherapy. EXPERT OPINION In unselected patients with advanced HCC immunotherapeutics, namely the programmed cell death-1 (PD-1) antibodies, nivolumab and pembrolizumab have shown promising efficacy in therapy-naïve, as well as pre-treated patients with advanced HCC. However, only 10-20 percent of treated patients show an objective and durable response to the indicated therapeutics. Therefore, combination therapies including different immunotherapeutics, e.g. PD-1/programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies, or combinations of immunotherapeutics and small molecules, or bifunctional antibodies will be needed to improve response rates. ABBREVIATIONS HCC: hepatocellular carcinoma; TKI: tyrosine-kinase inhibitors; PD-1: programmed death receptor-1; PD-L1: programmed cell death 1 ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated Protein 4; CAR-T: chimeric T cell receptors; TACE: transarterial chemoembolization; SIRT: selective internal radiation therapy; SBRT: stereotactic body radiation therapy; VEGF: vascular endothelial growth factor; MEK: mitogen-activated protein kinase kinase; NK cell: natural killer cell; TGFβ: transforming growth factor-β; OV: Oncolytic viruses; PFU: plaque-forming unit.
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Affiliation(s)
- Oliver Waidmann
- a Medizinische Klinik 1 , Universitätsklinikum Frankfurt , Frankfurt , Germany
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Tenneti P, Borad MJ, Babiker HM. Exploring the role of oncolytic viruses in hepatobiliary cancers. Immunotherapy 2018; 10:971-986. [PMID: 29900755 DOI: 10.2217/imt-2018-0048] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The standard of care for early hepatobiliary cancers (HBC) includes surgical resection. Liver transplantations or locoregional therapies are beneficial in early hepatocellular carcinoma (HCC) under certain circumstances. Systemic treatments have some benefit in advanced HBC, though long-term prognosis remains poor. We evaluated the role of oncolytic viruses in the treatment of HBCs through a systematic literature review. The recombinant vaccinia virus JX-594 improved median survival in patients with local/metastatic HCC more strongly at high dose than at low dose (14.1 vs 6.7 months; p = 0.08) in a Phase II study. A Phase III study with JX-594 and sorafenib in advanced HCC is ongoing. No survival benefit in HCC was seen with two other recombinant adenoviruses (Ad-TK and DL1520). Several preclinical trials using oncolytic viruses in HBC showed promising results, warranting clinical studies.
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Affiliation(s)
- Pavan Tenneti
- Assistant Professor of Medicine, Department of Medicine, Banner University Medical Center, Tucson, AZ 85721, USA
| | - Mitesh J Borad
- Associate Professor of Medicine, Department of Medicine, Hematology & Oncology division, Mayo Clinic, Scottsdale, AZ 85205, USA
| | - Hani M Babiker
- Assistant Professor of Medicine, Department of Medicine, Hematology & Oncology division, University of Arizona, Tucson, AZ 85721, USA
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Khemlina G, Ikeda S, Kurzrock R. The biology of Hepatocellular carcinoma: implications for genomic and immune therapies. Mol Cancer 2017; 16:149. [PMID: 28854942 PMCID: PMC5577674 DOI: 10.1186/s12943-017-0712-x] [Citation(s) in RCA: 302] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 08/15/2017] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is a leading cause of cancer-related death worldwide. It is highly refractory to most systemic therapies. Recently, significant progress has been made in uncovering genomic alterations in HCC, including potentially targetable aberrations. The most common molecular anomalies in this malignancy are mutations in the TERT promoter, TP53, CTNNB1, AXIN1, ARID1A, CDKN2A and CCND1 genes. PTEN loss at the protein level is also frequent. Genomic portfolios stratify by risk factors as follows: (i) CTNNB1 with alcoholic cirrhosis; and (ii) TP53 with hepatitis B virus-induced cirrhosis. Activating mutations in CTNNB1 and inactivating mutations in AXIN1 both activate WNT signaling. Alterations in this pathway, as well as in TP53 and the cell cycle machinery, and in the PI3K/Akt/mTor axis (the latter activated in the presence of PTEN loss), as well as aberrant angiogenesis and epigenetic anomalies, appear to be major events in HCC. Many of these abnormalities may be pharmacologically tractable. Immunotherapy with checkpoint inhibitors is also emerging as an important treatment option. Indeed, 82% of patients express PD-L1 (immunohistochemistry) and response rates to anti-PD-1 treatment are about 19%, and include about 5% complete remissions as well as durable benefit in some patients. Biomarker-matched trials are still limited in this disease, and many of the genomic alterations in HCC remain challenging to target. Future studies may require combination regimens that include both immunotherapies and molecularly matched targeted treatments.
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Affiliation(s)
- Galina Khemlina
- Department of Geriatrics, University of California, UC San Diego, 9500 Gilman Drive, #9111, La Jolla, CA, 92093-9111, USA. .,Kaiser Permanente Southern California, San Diego, USA.
| | - Sadakatsu Ikeda
- Department of Medicine, Division of Hematology/Oncology, and Center for Personalized Cancer Therapy, University of California, Moores Cancer Center, San Diego, USA.,Tokyo Medical and Dental University, Tokyo, Japan
| | - Razelle Kurzrock
- Department of Medicine, Division of Hematology/Oncology, and Center for Personalized Cancer Therapy, University of California, Moores Cancer Center, San Diego, USA
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Waidmann O, Trojan J. Novel drugs in clinical development for hepatocellular carcinoma. Expert Opin Investig Drugs 2015; 24:1075-82. [PMID: 26108356 DOI: 10.1517/13543784.2015.1058776] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Within recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development either due to toxicity or lack of benefit. AREAS COVERED This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC. EXPERT OPINION In unselected patients with advanced HCC, disappointing results have been reported from several large trials. However, in two subgroups encouraging results have been achieved. Treatment with the MET inhibitor tivantinib resulted in a substantial survival benefit in the subgroup of MET overexpressing tumors in a randomized Phase II trial. Furthermore, the vascular endothelial growth factor receptor 2 antibody ramucirumab resulted in improved overall survival in patients with baseline α-fetoprotein (AFP) ≥ 400 ng/ml in a Phase III trial. These two agents, and several others, will be further developed in HCC. Moreover, immunotherapeutics such as checkpoint inhibitors, programmed death receptor-1 blocking antibodies and oncolytic viruses are under investigation in advanced HCC.
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Affiliation(s)
- Oliver Waidmann
- Universitätsklinikum Frankfurt, Medizinische Klinik 1 , Theodor-Stern-Kai 7, Frankfurt am Main , Germany +49 0 69 6301 7860 ; +49 0 69 6301 6448 ;
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Selective targeting of HPV-16 E6/E7 in cervical cancer cells with a potent oncolytic adenovirus and its enhanced effect with radiotherapy in vitro and vivo. Cancer Lett 2009; 291:67-75. [PMID: 19903581 DOI: 10.1016/j.canlet.2009.09.022] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2009] [Accepted: 09/30/2009] [Indexed: 11/23/2022]
Abstract
Recent studies have shown that oncolytic adenovirus specifically targeted tumor cells while sparing normal cells. Here, we report a novel E1A-mutant adenovirus (M6) with antisense HPV16 E6 E7 DNA inserted into the deleted 6.7K/gp19K region of E3. The target effects of M6 on HPV16-positive cervical cancer cells were evaluated in vivo and in vitro. By using cytopathic effect (CPE) and viral replication assays, we verified M6 was competent to selectively replicate in cervical cancer cells in vitro. Moreover, we found infection of M6 was able to inhibit the expression of HPV16 E6 and E7 oncogenes and induce apoptosis of HPV16-positive cervical cancer cells. Further analysis in vitro revealed that the invasive ability of SiHa cells was significantly inhibited by M6. To determine if M6 synergized with radiotherapy-induced anti-tumor activity against HPV16-related cancer cells, we transfected SiHa cells with M6 followed by a single exposure to radiation. A significantly suppression of cell growth and induced apoptosis was observed in SiHa cells received M6 transfection combined with radiotherapy. Animal experiments showed that M6 transfection notably improved the survival of tumor-bearing mice in combination with radiotherapy, much superior to that of those treated by Adv5/dE1A plus radiation or M6 alone. These findings indicated the anti-tumoral efficacy of M6 on HPV16-positive cervical cancer cells and its synergic therapeutic application in radiation for cervical cancer.
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Brown CW, Bell JC. Oncolytic Viruses: A New Weapon to Fight Cancer. J Med Imaging Radiat Sci 2008; 39:115-127. [PMID: 31051886 DOI: 10.1016/j.jmir.2008.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Remission from cancer after viral infection was first noted in the beginning of the 20th century, and with advances in virotherapy and genetic engineering, the advent of an approved viral therapeutic in North America is fast approaching. Mechanisms of tumour selectivity and killing, along with information obtained from clinical trials are reviewed here. Although oncolytic viruses are generally safe and well tolerated, their overall anti-tumour efficacy has varied. This article outlines strategies to improve the efficacy of the oncolytic platform without compromising its impressive safety profile. It will highlight new methods being developed to quantify the activity of oncolytic viruses in real time. Harnessing the factors that control the tumour microenvironment and the immune system are the key to enhancing the oncolytic activity. The purpose of this article is to introduce and provide an overview of the current state of cancer killing of oncolytic viruses. The reader will acquire knowledge of the basic principles of oncolytic viruses and their use in the clinical setting. This review summarizes articles retrieved from Medline using key words such as "virus," "oncolytic virus," "virotherapy," "cancer," and "clinical trials." Review articles published in the English language from 2005 onward were read and corroborating data and conclusions were summarized. When appropriate, cited references were also reviewed and incorporated. The reader is directed to references we found most concise.
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Affiliation(s)
- Christopher W Brown
- Department of Microbiology & Immunology and the Ottawa Health Research Institute, University of Ottawa, Ottawa Regional Cancer Center, Ottawa, Ontario; Division of Orthopaedic Surgery, University of Ottawa, Ottawa Hospital General Campus, Ottawa, Ontario
| | - John C Bell
- Department of Microbiology & Immunology and the Ottawa Health Research Institute, University of Ottawa, Ottawa Regional Cancer Center, Ottawa, Ontario.
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Dual induction of PKR with E2F-1 and IFN-α to enhance gene therapy against hepatocellular carcinoma. Cancer Gene Ther 2008; 15:636-44. [DOI: 10.1038/cgt.2008.34] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Cabrele C, Vogel M, Piso P, Rentsch M, Schröder J, Jauch KW, Schlitt HJ, Beham A. 5-Fluorouracil-related enhancement of adenoviral infection is Coxsackievirus-adenovirus receptor independent and associated with morphological changes in lipid membranes. World J Gastroenterol 2006; 12:5168-74. [PMID: 16937527 PMCID: PMC4088014 DOI: 10.3748/wjg.v12.i32.5168] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the mechanism underlying the effects of 5-Fluorouracil (5-FU) on adenoviral infection.
METHODS: Low and high Coxsackievirus-Adenovirus Receptor (CAR) expressing human colon carcinoma cell lines were treated with 5-FU and two E1-deleted adenoviral constructs, one transferring GFP (Ad/CMV-GFP) the other bax (Ad/CEA-bax). The number of infected cells were monitored by GFP expression. To evaluate the effects of 5-FU in a receptor free system, Ad/GFP were encapsulated in liposomes and treated with 5-FU. Ad/GFP release was estimated with PCR and infection of 293 cells with the supernatant. Electron microscopy of the Ad5-GFP-liposome complex was made to investigate morphological changes of the liposomes after 5-FU.
RESULTS: Infection rates of all cell lines increased from 50% to 98% with emerging 5-FU concentrations. The enhanced viral uptake was independent of the CAR expression. Additionally, 5-FU treated liposomes released 2-2.5 times more adenoviruses. Furthermore, 5-FU-treated liposomes appeared irregular and porous-like.
CONCLUSION: adenoviral uptake is enhanced in the presence of 5-FU irrespective of CAR and is associated with morphological changes in membranes making the combination of both a promising option in gene therapy.
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Affiliation(s)
- Chiara Cabrele
- Department of Surgery, Clinic of the Regensburg University, Franz-Josef-Strauss-Allee 11, D-93053, Regensburg, Germany
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Wang W, Tai CK, Kershaw AD, Solly SK, Klatzmann D, Kasahara N, Chen TC. Use of replication-competent retroviral vectors in an immunocompetent intracranial glioma model. Neurosurg Focus 2006; 20:E25. [PMID: 16709031 PMCID: PMC8295718 DOI: 10.3171/foc.2006.20.4.1] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT The authors had previously reported on a replication-competent retrovirus (RCR) that has been demonstrated to be stable, capable of effective transduction, and able to prolong survival in an intracranial tumor model in nude mice. The purpose of this study was further investigation of this gene therapy option. METHODS The transduction efficiency of RCR in RG2, an immunocompetent intracranial tumor model, was tested in Fischer 344 rats. The immune response to the RCR vector was expressed by the quantification of CD4, CD8, and CD11/b in tumors. The pharmaceutical efficacy of the suicide gene CD in converting prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU) was measured using fluorine-19 nuclear magnetic resonance (19F-NMR) spectroscopy. Animal survival data were plotted on Kaplan-Meier survival curves. Finally, the biodistribution of RCR was determined using quantitative real-time polymerase chain reaction (RT-PCR) for the detection of retroviral env gene. There was no evidence of viral transduction in normal brain cells. Neither severe inflammation nor immunoreaction occurred after intracranial injection of RCR-green fluorescent protein compared with phosphate-buffered saline (PBS). The 19F-NMR spectroscopy studies demonstrated that RCR-CD was able to convert 5-FC to 5-FU effectively in vitro. The infection of RG2 brain tumors with RCR-CD and their subsequent treatment with 5-FC significantly prolonged survival compared with that in animals with RG2 transduced tumors treated with PBS. In contrast to the nude mouse model, evidence of virus dissemination to the systemic organs after intracranial injection was not detected using RT-PCR. CONCLUSIONS The RCR-mediated suicide gene therapy described in this paper effectively transduced malignant gliomas in an immunocompetent in vivo rodent model, prolonging survival, without evidence of severe intracranial inflammation, and without local transduction of normal brain cells or systemic organs.
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Affiliation(s)
- Weijun Wang
- Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
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Abstract
For the minority of patients with hepatocellular carcinoma (HCC), surgical or locally ablative therapies may offer the prospect of cure. However, the majority of patients present with advanced disease, such that treatment with curative intent is no longer possible. For some of these patients, with good hepatic reserve and a patent portal venous system, chemoembolisation may afford a modest survival benefit. The remainder of patients are frequently treated with systemic therapies with palliative intent. However, no drug treatment has yet clearly demonstrated a significant beneficial effect on survival or quality of life. Thus, there is an urgent need for novel approaches. Gene- and immunotherapy approaches using a variety of strategies are in development at present. HCC possesses several characteristics that make it an attractive target for these therapies. This review aims to summarise the approaches to gene- and immunotherapy for HCC, with particular reference to strategies that are entering clinical trials. It will then describe some of the obstacles to the success of these new approaches and provide opinion regarding ongoing and future developments. The challenge remains to design clinical trials to optimally evaluate these agents and allow feedback to the laboratory for their ongoing development.
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Affiliation(s)
- Daniel H Palmer
- CR UK Institute for Cancer Studies, Clinical Research Block, University of Birmingham, Birmingham, B15 2TT, UK.
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Abstract
Gastric cancer is one of the most common tumors worldwide. The therapeutic outcome of conventional therapies is inefficient. Thus, new therapeutic strategies are urgently needed. Gene therapy is a promising molecular alternative in the treatment of gastric cancer, including the replacement of defective tumor suppressor genes, the inactivation of oncogenes, the introduction of suicide genes, genetic immunotherapy, anti-angiogenetic gene therapy, and virotherapy. Improved molecular biological techniques and a better understanding of gastric carcinogenesis have allowed us to validate a variety of genes as molecular targets for gene therapy. This review provides an update of the new developments in cancer gene therapy, new principles, techniques, strategies and vector systems, and shows how they may be applied in the treatment of gastric cancer.
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Affiliation(s)
- Andreas P Sutter
- Department of Gastroenterology/Infectious Diseases/Rheumatology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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Sonabend AM, Ulasov IV, Lesniak MS. Conditionally replicative adenoviral vectors for malignant glioma. Rev Med Virol 2006; 16:99-115. [PMID: 16416455 DOI: 10.1002/rmv.490] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
High-grade gliomas constitute an important challenge to modern medicine, and although great effort has been made to prolong patient survival, the prognosis for this disease remains poor. Due to recent discoveries in the molecular basis of gliomas, gene therapy is becoming a promising alternative. In this review, we discuss the use of conditionally replicative adenoviral vectors (CRAd) and their applications in neuro-oncology. Such vectors, when rendered conditionally replicative via transductional and transcriptional modifications, offer great promise for patients with malignant brain tumours. We review data from preclinical and clinical studies utilising such vectors and discuss the limitations and future perspectives of CRAd oncolytic therapy for malignant glioma.
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Affiliation(s)
- Adam M Sonabend
- Division of Neurosurgery, The University of Chicago, Chicago, IL 60637, USA
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Abstract
Molecular research has vastly advanced our understanding of the mechanism of cancer growth and spread. Targeted approaches utilizing molecular science have yielded provocative results in the treatment of cancer. Oncolytic viruses genetically programmed to replicate within cancer cells and directly induce toxic effect via cell lysis or apoptosis are currently being explored in the clinic. Safety has been confirmed and despite variable efficacy results several dramatic responses have been observed with some oncolytic viruses. This review summarizes results of clinical trials with oncolytic viruses in cancer.
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Affiliation(s)
- Eugene Lin
- Mary Crowley Medical Research Center, Dallas, Texas, USA
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Li G, Sham J, Yang J, Su C, Xue H, Chua D, Sun L, Zhang Q, Cui Z, Wu M, Qian Q. Potent antitumor efficacy of an E1B 55kDa-deficient adenovirus carrying murine endostatin in hepatocellular carcinoma. Int J Cancer 2005; 113:640-8. [PMID: 15389517 DOI: 10.1002/ijc.20581] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Data from clinical trails have shown that the antitumoral effect of ONYX-015, an E1B 55kDa-deficient adenovirus, as monotherapy is insufficient. To enhance its efficiency, CNHK200-mE, another E1B 55kDa-deficient adenovirus armed with a mouse endostatin gene was constructed and its antitumoral activities against hepatocellular carcinoma (HCC) in vitro and in vivo were investigated. The selective replication and cytotoxicity of CNHK200-mE in Hep3B and HepGII cells independent of p53 status were confirmed via TCID50 and 3-(4,5dimetylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assays. Potent tumor growth suppression on SMMC-7721 xenografts in nude mice was observed and a synergistic effect of the carrier virus and the therapeutic gene was suggested. Moreover, in comparison with the nonreplicative adenovirus carrying the same therapeutic gene, amplified transgene expression of mouse endostatin in vitro and in vivo were confirmed by Western blotting and ELISA assay. The effective angiogenesis inhibition and replication of CNHK200-mE in nude mice xenografts were demonstrated by immunohistochemistry. In conclusion, the recombinant adenovirus CNHK200-mE is a replication-competent oncolytic virus mediating high expression of therapeutic gene. Because CNHK200-mE is capable of replicating in and lysing HCC cells selectively with effective tumor growth suppression and antiangiogenic activity on HCC xenografts in nude mice, it holds good potential for the treatment of HCC.
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Affiliation(s)
- Gencong Li
- Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China
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Lu W, Zheng S, Li XF, Huang JJ, Zheng X, Li Z. Intra-tumor injection of H101, a recombinant adenovirus, in combination with chemotherapy in patients with advanced cancers: A pilot phase II clinical trial. World J Gastroenterol 2004; 10:3634-8. [PMID: 15534920 PMCID: PMC4612006 DOI: 10.3748/wjg.v10.i24.3634] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: H101, an E1B 55 kD gene deleted adenovirus, has been shown to possess oncolysis activity experimentally and proved to be safe in preliminary phase I study. The current study was designed to evaluate its anti-tumor activity and toxicity in combination with chemotherapy in patients with late stage cancers.
METHODS: H101 5.0 × 1011 virus particles were given by intra-tumor injection daily for five consecutive days at every three-week cycle, combined with routine chemotherapy, to one of the tumor lesions of 50 patients with different malignant tumors. Tumor lesions without H101 injection in the same individuals were used as controls. The efficacy and toxicity were recorded.
RESULTS: Forty-six patients were evaluable with a 30.4% response rate. H101 injection in combination with chemotherapy induced three complete response (CR) and 11 partial response (PR), giving an overall response rate of 28.0% (14/50) among intention-to-treat patients. The response rate for the control lesions was 13.0%, including one case with CR and five cases with PR, which was significantly lower than that for the injected lesions (P < 0.05). Main side effects were fever (30.2%) and pain at the injected sites (26.9%). Grade 1 hepatic dysfunction was found in four patients, grade 2 in one patient, and grade 4 in one patient. Hematological toxicity (grade 4) was found in four patients.
CONCLUSION: Intra-tumor injection of the genetically engineered adenovirus H101 exhibits potential anti-tumor activity to refractory malignant tumors in combination with chemotherapy. Low toxicity and good tolerance of patients to H101were observed.
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Affiliation(s)
- Wei Lu
- Cancer Center, Second Affiliated Hospital, Medical College, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China
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Abstract
Treatment of cancer is limited by toxicity to normal tissue with standard approaches (chemotherapy, surgery and radiotherapy). The use of selective replicating viral vectors may enable the targeting of gene-modified viruses to malignant tissue without toxic effect. Studies of these vectors have demonstrated tumour-selective replication and minimal evidence of replication in normal tissue. The most advanced clinical results reported involve gene-modified adenoviral vectors. Several completed, histologically confirmed responses to local/regional injection have been induced, particularly in recurrent squamous cell carcinoma involving the head and neck region. Dose limiting toxicity above 10(13) viral particles per injection has been observed. Anti-tumour effect is demonstrable in animal models without evidence of significant toxicity when these vectors are used alone or in combination with chemotherapy, radiation therapy or as gene delivery vehicles. Preliminary clinical trials, particularly with E1B-deleted adenoviruses, report evidence of clinical activity in comparison with expected historical responses. Enhancement in replication selectivity to malignant tissue is also demonstrated preclinically and clinically with an E1B-deleted adenovirus utilising a prostate-specific antigen promoter. Other selective replicating viral vectors such as herpes simplex virus and vaccinia virus have also been explored clinically and suggest evidence of activity in patients with cancer. Modifications may one day enable more aggressive use of these new and exciting therapeutics as systemic gene delivery vehicles.
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21
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Miller CG, Fraser NW. Requirement of an integrated immune response for successful neuroattenuated HSV-1 therapy in an intracranial metastatic melanoma model. Mol Ther 2003; 7:741-7. [PMID: 12788647 PMCID: PMC2661757 DOI: 10.1016/s1525-0016(03)00120-5] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Neuroattenuated herpes simplex virus ICP34.5 mutants slow progression of preformed tumors and lead to complete regression of some tumors. Although this was previously thought to be due to viral lysis of infected tumor cells, it is now understood that there is an immune component to tumor destruction. We have previously shown that no difference in survival is seen in lymphocyte-depleted mice after viral or mock therapy of syngeneic intracranial melanomas. We have also demonstrated the presence of a wide spectrum of immune cells following viral therapy, including larger percentages of CD4+ T cells and macrophages. In this paper, the contribution of the immune system to tumor destruction has been further delineated. Viral therapy of intracranial melanoma induces a tumor-specific cytotoxic and proliferative T cell response. However, there is no increase following viral therapy in either serum tumor antibody levels or viral-neutralizing antibodies. Thus specific T cell responses appear to mediate viral-elicited prolongation in survival. These data suggest that designing new viruses capable of augmenting T cell responses may induce stronger tumor destruction upon viral therapy.
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MESH Headings
- Animals
- Brain Neoplasms/immunology
- Brain Neoplasms/therapy
- CD4 Antigens/genetics
- CD4 Antigens/metabolism
- CD4-Positive T-Lymphocytes/immunology
- CD8 Antigens/genetics
- CD8 Antigens/metabolism
- CD8-Positive T-Lymphocytes/immunology
- Cancer Vaccines/administration & dosage
- Cancer Vaccines/immunology
- Cell Division/physiology
- DNA-Binding Proteins/deficiency
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Female
- Herpes Simplex/genetics
- Herpes Simplex/immunology
- Herpes Simplex/virology
- Herpes Simplex Virus Vaccines/administration & dosage
- Herpes Simplex Virus Vaccines/immunology
- Herpesvirus 1, Human/genetics
- Herpesvirus 1, Human/immunology
- Herpesvirus 1, Human/physiology
- Injections, Intraperitoneal
- Killer Cells, Natural/immunology
- Macrophages/immunology
- Melanoma, Experimental/immunology
- Melanoma, Experimental/therapy
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neoplasm Transplantation
- T-Lymphocytes, Cytotoxic/immunology
- Vaccines, Attenuated/administration & dosage
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Affiliation(s)
| | - Nigel W. Fraser
- Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6076, USA
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22
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Nemunaitis J, Edelman J. Selectively replicating viral vectors. Cancer Gene Ther 2002; 9:987-1000. [PMID: 12522438 DOI: 10.1038/sj.cgt.7700547] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2002] [Indexed: 01/26/2023]
Affiliation(s)
- John Nemunaitis
- US Oncology, Inc., Collins Building, 5th Floor, Dallas, Texas 75246, USA.
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