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Semireplication-competent vesicular stomatitis virus as a novel platform for oncolytic virotherapy

世界最新医学信息文摘 2015年第5期 245-245页

作者： Alexander Muik Catherine Dold Yvonne Gei Andreas Volk Marina Werbizki Ursula Dietrich Dorothee von Laer

Among oncolytic viruses, the vesicular stomatitis virus(VSV) is especially potent and a highly promising agent for the treatment of cancer. But, even though effective against multiple tumor entities in preclinical animal models, replicationcompetent VSV exhibits inherent neurovirulence, which has so far hindered clinical development. To overcome this limitation,replication-defective VSV vectors for cancer gene therapy have been tested and proven to be safe. However, gene delivery was inefficient and only minor antitumor efficacy was observed. Here, we present semireplicationcompetent vector systems for VSV(sr VSV), composed of two trans-complementing, propagation-deficient VSV vectors. The de novo generated deletion mutants of the two VSV polymerase proteins P(phosphoprotein) and L(large catalytic subunit), VSVΔP and VSVΔL respectively, were used mutually or in combination with VSVΔG vectors. These sr VSV systems copropagated in vitro and in vivo without recombinatory reversion to replication-competent virus. The sr VSV systems were highly lytic for human glioblastoma cell lines,spheroids, and subcutaneous xenografts. Especially the combination of VSVΔG/VSVΔL vectors was as potent as wild-type VSV(VSV-WT) in vitro and induced long-term tumor regression in vivo without any associated adverse effects. In contrast, 90% of VSV-WT-treated animals succumbed to neurological disease shortly after tumor clearance. Most importantly, even when injected into the brain, VSVΔG/VSVΔL did not show any neurotoxicity. In conclusion, sr VSVis a promising platform for virotherapeutic approaches and also for VSV-based vector vaccines, combining improved safety with an increased coding capacity for therapeutic transgenes, potentially allowing for multipronged approaches.

关键词： Vesicular stomatitis virus Oncolytic virus virotherapy Malignant glioma

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Synergistic Antitumor Efficacy of Oncolytic Adenovirus Combined with Chemotherapy

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Chinese Journal of Cancer Research 2007年第2期19卷 76-81页

作者：李月敏宋三泰江泽飞张琪曲怡梅苏长青赵传华李志强葛飞娇钱其军 Clinical Cancer Center Affiliated Hospital the Academy of Military Medical Science Beijing 100039 Laboratory of Viral and Gene Therapy Eastern Hepatobiliary Surgery hospital Second Military MedicalUniversity Shanghai 200438 Cancer Center the second affiliated Hospital PLA General HospitalBeijing 100091

Objective： Chemotherapy is an effective means of treating breast cancer, and cancer-specific replicative adenovirus is also a promising antitumor agent in recent years. Our investigation aims to demonstrate that CNHK300 can mediate selective antitumor efficacy and produce synergistic cytotoxicity with chemotherapy on HER-2 over-expressing breast cancer. Methods： We engineered the telomerase-dependent replicative adenovirus CNHK300 by placing the E1A gene under the control of the human hTERT promoter. By analysis of E1A expression, we proved the fidelity of hTERT promoter in adenovirus genome and the selective expression of E1A in telomerase-positive breast cancer cells but not in normal fibroblast cells. By proliferation test, we further showed efficient replication of CNHK300 in breast cancer cells with apparently attenuated proliferation in normal fibroblast cells. Finally, we demonstrated by MTT methods that CNHK300 virus caused potent cytolysis and produced synergistic cytotoxicity with chemotherapy in breast cancer cells with attenuated cytotoxicity on normal cells. Results： In this virus, the E1A gene is successfully placed under the control of the human hTERT promoter. CNHK300 virus replicated as efficiently as the wild-type adenovirus and caused intensive cell killing in HER-2 over-expressing breast cancer cells in vitro. In contrast, telomerase-negative normal fibroblast cells, which expressed no hTERT activity, were not able to support CNHK300 replication. Combined treatment of CNHK300 with paclitaxel improved cytotoxicity on cancer cells. Conclusion： We conclude that CNHK300 can produce selective antitumor efficacy and enhance the in vitro response of chemotherapy on HER-2 overexpressing breast cancer.

关键词： virotherapy Oncolytic adenovirus hTERT CNHK300

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Antitumor activity of an hTERT promoter-regulated tumor-selective oncolytic adenovirus in human hepatocellular carcinoma

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World Journal of Gastroenterology 2006年第47期12卷 7613-7620页

作者： Chang-Qing Su Xing-Hua Wang Jie Chen Yong-Jing Liu Wei-Guo Wang Lin-Fang Li Meng-Chao Wu Qi-Jun Qian Laboratory of Viral and Gene Therapy Eastern Hepatobiliary Surgery Hospital Second Military Medical University Shanghai 200438 China Xinyuan Institute of Medicine and Biotechnology College of Life Science Zhcjiang Sci-T~ch University Hangzhou 310018 Zhejiang Province China Changhai Hospital Second Military Medical University Shanghai 200438 China Jiangsu Key Laboratory for Molecular and Medical Bioteclmology Life Science College Nanjing Normal University Nanjing 210097 Jiangsu Province China

AIM: To construct a tumor-selective replication-competent adenovirus (RCAd), SG300, using a modified promoter of human telomerase reverse transcriptase (hTERT). METHODS: The antitumor efficacy of SG300 in hepatocellular carcinoma was assessed in vitro and in vivo. In vitro cell viability by MTT assay was used to assess the tumor-selective oncolysis and safety features of SG300, and in vivo antitumor activity of SG300 was assessed in established hepatocellular carcinoma models in nude mice. RESULTS: SG300 could lyse hepatocellular carcinoma cells at a low multiplicity of infection (MOI), but could not affect growth of normal cells even at a high MOI. Both in Hep3B and SMMC-7721 xenograft models of hepatocellular carcinoma, SG300 had an obvious antitumor effect, resulting in a decrease in tumor volume. Its selective oncolysis to tumor cells and safety to normal cells was also superior to that of ONYX-015. Pathological examination of tumor specimens showed that SG300 replicated selectively in cancer cells and resulted in apoptosis and necrosis of cancer cells. CONCLUSION: hTERT promoter-regulated replicativeadenovirus SG300 has a better cancer-selective replication-competent ability, and can specifically kill a wide range of cancer cells with positive telomerase activity, and thus has better potential for targeting therapy of hepatocellular carcinoma.

关键词： virotherapy Oncolytic adenovirus Human telomerase reverse transcriptase Hepatocellular carcinoma Animal tumor model

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Gene therapy for gastric cancer:Is it promising?

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World Journal of Gastroenterology 2006年第3期12卷 380-387页

作者： AndreasPSutter HenryFechner Department of Gastroenterology/Infectious Diseases/Rheumatology and Department of Cardiologyand Pneumology Charité-Universittsmedizin BerlinCampus Benjamin FranklinHindenburgdamm 3012200 BerlinGermany

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.

关键词： Gene therapy Gastric cancer virotherapy

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Oncolytic viruses:A novel treatment strategy for breast cancer

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Genes & Diseases 2023年第2期10卷 430-446页

作者： Mohammad Javanbakht Sanaz Tahmasebzadeh Luca Cegolon Nasrin Gholami Mandana Kashaki Hassan Nikoueinejad Mohamad Mozafari Mahsa Mozaffari Shi Zhao Mostafa Khafaei Morteza Izadi Saeid Fathi Reza Akhavan-Sigari Nephrology and Urology Research Center Baqiyatallah University of Medical SciencesTehran ***Iran Mehrestan Health Network Iranshahr University of Medical SciencesIranshahr ***Iran University of Trieste Department of MedicalSurgical & Health SciencesTrieste 34128Italy University Health Agency Giuliano-Isontina (ASUGI) Public Health DepartmentTriesteItaly Hematology and Oncology Research Center Tabriz University of Medical SciencesTabriz ***Iran Shahid Akbarabadi Clinical Research Development Unit (ShACRDU) Iran University of Medical Sciences (IUMS)Tehran ***Iran Department of General Surgery Urmia University of Medical ScienceUrmia 57147Iran Department of Pediatrics Iran University of Medical SciencesTehran ***Iran JC School of Public Health and Primary Care Chinese University of Hong KongHong Kong Special Administrative Region 999077China Human Genetics Research Center Baqiyatallah University of Medical SciencesTehran 169875931Iran Health Research Center Baqiyatallah University of Medical SciencesTehran ***Iran Razi Vaccine and Serum Research Institute Agriculture ResearchEducation and Extension Organization (AREEO)Karaj 11365-1558Iran Department of Neurosurgery University Medical CenterTuebingen 72076Germany

Breast cancer,an unceasingly occurring neoplasm,is one of the major determinants of mortality in *** ineffective attempts have been pursued using with conventional therapies against breast *** to existing therapies and their respective debilitating adverse effects have led research toward a new era of cancer treatment using *** constitutes a developing treatment modality with multiple mechanisms of therapeutic activity in which the viruses can be directly oncolyticand can express transgenes or induce host immune response against tumor *** different DNA-and RNA-containing viruses have been considered for virotherapy of breast cancer including adenovirus,herpes virus,vaccinia,reovirus,Newcastle Disease virus,measles virus and vesicular stomatitis *** review aims to summarize the viro-therapeutical agents against breast *** Scientific Concepts of Review:In this review paper,we proposed a new strategy to virus's combinatorial treatments using several kinds of transgenes and *** recombinant viruses have provided evidence of treatment efficacy against human breast cancer.

关键词： Adenovirus Breast cancer Herpes virus Measles virus Newcastle disease virus Reovirus Vaccinia Vesicular stomatitis virus virotherapy

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Immune responses elicited by ssRNA(-) oncolytic viruses in the host and in the tumor microenvironment

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Journal of Cancer Metastasis and Treatment 2023年第1期9卷 285-306页

作者： Yonina Bykov Gloria Dawodu Aryana Javaheri Adolfo Garcia-Sastre Sara Cuadrado-Castano Department of Microbiology Icahn School of Medicine at Mount SinaiNew YorkNY 10029USA Department of Medicine Icahn School of Medicine at Mount SinaiNew YorkNY 10029USA Global Health and Emerging Pathogens Institute Icahn School of Medicine at Mount SinaiNew YorkNY 10029USA The Tisch Cancer Institute Icahn School of Medicine at Mount SinaiNew YorkNY 10029USA Department of Pathology Molecular and Cell-Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNY 10029USA

Oncolytic viruses(OVs)are at the forefront of biologicals for cancer *** represent a diverse landscape of naturally occurring viral strains and genetically modified viruses that,either as single agents or as part of combination therapies,are being evaluated in preclinical and clinical *** the field gains momentum,the research on OVs has been shifting efforts to expand our understanding of the complex interplay between the virus,the tumor and the immune system,with the aim of rationally designing more efficient therapeutic ***,the potential of an OV platform is no longer defined exclusively by the targeted replication and cancer cell killing capacities of the virus,but by its contribution as an immunostimulator,triggering the transformation of the immunosuppressive tumor microenvironment(TME)into a place where innate and adaptive immunity players can efficiently engage and lead the development of tumor-specific long-term memory *** we review the immune mechanisms and host responses induced by ssRNA(-)(negative-sense single-stranded RNA)viruses as OV *** focus on two ssRNA(-)OV candidates:Newcastle disease virus(NDV),an avian paramyxovirus with one of the longest histories of utilization as an OV,and influenza A(IAV)virus,a well-characterized human pathogen with extraordinary immunostimulatory capacities that is steadily advancing as an OV candidate through the development of recombinant IAV attenuated platforms.

关键词： Oncolytic virus NDV IAV virotherapy paramyxovirus orthomyxovirus ssRNA(-) immunotherapy cancer vaccine ICD in situ vaccination tumor microenvironment

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Advance in herpes simplex viruses for cancer therapy

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Science China(Life Sciences) 2013年第4期56卷 298-305页

作者： LIU ShangLong DAI MeiHua YOU Lei ZHAO YuPei Department of General Surgery Peking Union Medical College Hospital Chinese Academy of Medical Sciences &Peking Union Medical College

Oncolytic virotherapy is an attractive approach that uses live viruses to selectively kill cancer cells. Oncolytic viruses can be genetically engineered to induce cell lyses through virus replication and cytotoxic protein expression. Herpes simplex virus (HSV) has become one of the most widely clinically used oncolytic agent. Various types of HSV have been studied in basic or clinical research. Combining oncolytic virotherapy with chemotherapy or radiotherapy generally produces synergic action with unclear molecular mechanisms. Arming HSV with therapeutic transgenes is a promising strategy and can be used to complement conventional therapies. As an efficient gene delivery system, HSV has been successfully used to deliver various immuno-modulatory molecules. Arming HSV with therapeutic genes merits further investigation for potential clinical application.

关键词： oncolytic viruses herpesvirus virotherapy cancer gene therapy

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Oncoselectivity in Oncolytic Viruses against Colorectal Cancer

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Journal of Cancer Therapy 2014年第13期5卷 1153-1174页

作者： Steven J. Conrad Karim Essani Laboratory of Virology Department of Biological Sciences Western Michigan University Kalamazoo USA

In humans colorectal cancer (CRC) is a significant cause of morbidity and mortality. New treatment options are urgently needed to supplement existing therapies. Replication-competent oncolytic viruses (RCOVs) for the treatment of cancerous tumors?in vivo?is a relatively new therapeutic modality with great but largely unrealized potential against CRC. In the context of oncolytic virus safety, oncoselectivity is an important criterion. It is at the conceptual intersection of viral replication strategy and tumor cell biology that RCOVs acquire their oncoselectivity, and thus their safety. Every aspect of tumor molecular biology which distinguishes it from normal, non-neoplastic cells is a potential target for exploitation. In the first section of this review we will provide an explanation of some of the successful and widely used strategies for improving oncoselectivity in wild-type viruses to make them more suitable as RCOVs. In the second section we will describe some of the characteristics of CRC biology which can be exploited to provide oncoselectivity against CRC. Throughout the review examples of successfully-engineered RCOVs which embody the approach or strategy under discussion are noted. By showing what has been done, we hope to highlight what is possible and what remains to be done to generate oncoselective RCOVs for use against CRC in humans.

关键词： Colorectal Cancer Replication-Competent Oncolytic Virus Oncoselectivity virotherapy

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Immunotherapy for pediatric brain tumors

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Neuroimmunology and Neuroinflammation 2018年第7期5卷 20-35页

作者： Daniel B.Landi Eric M.Thompson David M.Ashley Preston Robert Tisch Brain Tumor Center DurhamNC27710USA Department of Pediatrics Duke University Medical CenterDurhamNC27710USA Department of Neurosurgery Duke University Medical CenterDurhamNC27710USA

Immunotherapy, while effective against lymphoid cancers and some solid tumors, has shown less benefit against pediatric brain tumors. Tumor heterogeneity, a suppressive immune microenvironment, and the blood-brain barrier have the potential to diminish any immune-based approach and limit efficacy. More importantly, most pediatric brain tumors are immunologically quiescent, stemming from a low mutational burden. This review focuses on innate vs. adaptive immunotherapeutic approaches and describes how the immunologic context of pediatric brain tumors can help identify well-suited immunotherapies for our patients. In this framework, we will discuss past and current approaches using virotherapy, immunoconjugates, monoclonal antibodies, active immunization, and adoptive cel-lular therapy, and share our thoughts on how immunotherapy can cure children with brain tumors.

关键词： Immunotherapy brain tumor pediatrics virotherapy active immunization adoptive cellular therapy

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CXCL12 Retargeting of an Oncolytic Adenovirus Vector to the Chemokine CXCR4 and CXCR7 Receptors in Breast Cancer

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Journal of Cancer Therapy 2021年第6期12卷 311-336页

作者： Samia M. O’Bryan J. Michael Mathis Department of Comparative Biomedical Sciences School of Veterinary Medicine Louisiana State University Baton Rouge LA USA University of North Texas Health Science Center Graduate School of Biomedical Sciences Fort Worth TX USA

Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant progress has been made in developing targeted therapies for breast cancer, advanced breast cancer continues to have high mortality, with poor 5-year survival rates. Thus, current therapies are insufficient in treating advanced stages of breast cancer;new treatments are sorely needed to address the complexity of advanced-stage breast cancer. Oncolytic virotherapy has been explored as a therapeutic approach capable of systemic administration, targeting cancer cells, and sparing normal tissue. In particular, oncolytic adenoviruses have been exploited as viral vectors due to their ease of manipulation, production, and demonstrated clinical safety profile. In this study, we engineered an oncolytic adenovirus to target the chemokine receptors CXCR4 and CXCR7. The overexpression of CXCR4 and CXCR7 is implicated in the initiation, survival, progress, and metastasis of breast cancer. Both receptors bind to the ligand, CXCL12 (SDF-1), which has been identified to play a crucial role in the metastasis of breast cancer cells. This study incorporated a T4 fibritin protein fused to CXCL12 into the tail domain of an adenovirus fiber to retarget the vector to the CXCR4 and CXCR7 chemokine receptors. We showed that the modified virus targets and infects CXCR4- and CXCR7-overexpressing breast cancer cells more efficiently than a wild-type control vector. In addition, the substitution of the wild-type fiber and knob with the modified chimeric fiber did not interfere with oncolytic capability. Overall, the result

关键词： Adenovirus Breast Cancer Cancer Chemokine CXCL12 CXCR4 CXCR7 Oncolytic Preclinical Receptor virotherapy Virus

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