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1.
Viruses ; 13(10)2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34696348

RESUMO

The coxsackievirus B3 strain PD-0 has been proposed as a new oncolytic virus for the treatment of colorectal carcinoma. Here, we generated a cDNA clone of PD-0 and analyzed the virus PD-H, newly generated from this cDNA, in xenografted and syngenic models of colorectal cancer. Replication and cytotoxic assays revealed that PD-H replicated and lysed colorectal carcinoma cell lines in vitro as well as PD-0. Intratumoral injection of PD-H into subcutaneous DLD-1 tumors in nude mice resulted in strong inhibition of tumor growth and significantly prolonged the survival of the animals, but virus-induced systemic infection was observed in one of the six animals. In a syngenic mouse model of subcutaneously growing Colon-26 tumors, intratumoral administration of PD-H led to a significant reduction of tumor growth, the prolongation of animal survival, the prevention of tumor-induced cachexia, and the elevation of CD3+ and dendritic cells in the tumor microenvironment. No virus-induced side effects were observed. After intraperitoneal application, PD-H induced weak pancreatitis and myocarditis in immunocompetent mice. By equipping the virus with target sites of miR-375, which is specifically expressed in the pancreas, organ infections were prevented. Moreover, employment of this virus in a syngenic mouse model of CT-26 peritoneal carcinomatosis resulted in a significant reduction in tumor growth and an increase in animal survival. The results demonstrate that the immune status of the host, the route of virus application, and the engineering of the virus with target sites of suitable microRNAs are crucial for the use of PD-H as an oncolytic virus.


Assuntos
Infecções por Coxsackievirus/imunologia , Enterovirus/fisiologia , Vírus Oncolíticos/fisiologia , Animais , Células CHO , Neoplasias Colorretais , Cricetulus , Enterovirus/classificação , Células HEK293 , Células HeLa , Humanos , Camundongos , Camundongos Nus , MicroRNAs , Miocardite , Neoplasias , Vírus Oncolíticos/classificação
2.
Viruses ; 13(6)2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204248

RESUMO

Despite advances in surgical resection and chemoradiation, high-grade brain tumors continue to be associated with significant morbidity/mortality. Novel therapeutic strategies and approaches are, therefore, desperately needed for patients and their families. Given the success experienced in treating multiple other forms of cancer, immunotherapy and, in particular, immunovirotherapy are at the forefront amongst novel therapeutic strategies that are currently under investigation for incurable brain tumors. Accordingly, herein, we provide a focused mini review of pertinent oncolytic herpes viruses (oHSV) that are being investigated in clinical trials.


Assuntos
Neoplasias Encefálicas/terapia , Herpesvirus Humano 1/fisiologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/fisiologia , Ensaios Clínicos como Assunto , Glioblastoma/terapia , Herpes Simples , Humanos , Vírus Oncolíticos/classificação
3.
Viruses ; 13(7)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209584

RESUMO

Glioblastoma multiforme (GBM) is a universally lethal cancer of the central nervous system. Patients with GBM have a median survival of 14 months and a 5-year survival of less than 5%, a grim statistic that has remained unchanged over the last 50 years. GBM is intransigent for a variety of reasons. The immune system has a difficult time mounting a response against glioblastomas because they reside in the brain (an immunologically dampened compartment) and generate few neoantigens relative to other cancers. Glioblastomas inhabit the brain like sand in the grass and display a high degree of intra- and inter-tumoral heterogeneity, impeding efforts to therapeutically target a single pathway. Of all potential therapeutic strategies to date, virotherapy offers the greatest chance of counteracting each of the obstacles mounted by GBM. Virotherapy can xenogenize a tumor that is deft at behaving like "self", triggering adaptive immune recognition in an otherwise immunologically quiet compartment. Viruses can also directly lyse tumor cells, creating damage and further stimulating secondary immune reactions that are detrimental to tumor growth. In this review, we summarize the basic immune mechanisms underpinning GBM immune evasion and the recent successes achieved using virotherapies.


Assuntos
Glioblastoma/terapia , Terapia Viral Oncolítica/métodos , Animais , Ensaios Clínicos como Assunto , Feminino , Humanos , Imunoterapia/métodos , Masculino , Camundongos , Vírus Oncolíticos/classificação , Vírus Oncolíticos/patogenicidade , Microambiente Tumoral
4.
Int J Mol Sci ; 21(20)2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33053757

RESUMO

Leveraging the immune system to thwart cancer is not a novel strategy and has been explored via cancer vaccines and use of immunomodulators like interferons. However, it was not until the introduction of immune checkpoint inhibitors that we realized the true potential of immunotherapy in combating cancer. Oncolytic viruses are one such immunotherapeutic tool that is currently being explored in cancer therapeutics. We present the most comprehensive systematic review of all oncolytic viruses in Phase 1, 2, and 3 clinical trials published to date. We performed a systematic review of all published clinical trials indexed in PubMed that utilized oncolytic viruses. Trials were reviewed for type of oncolytic virus used, method of administration, study design, disease type, primary outcome, and relevant adverse effects. A total of 120 trials were found; 86 trials were available for our review. Included were 60 phase I trials, five phase I/II combination trials, 19 phase II trials, and two phase III clinical trials. Oncolytic viruses are feverously being evaluated in oncology with over 30 different types of oncolytic viruses being explored either as a single agent or in combination with other antitumor agents. To date, only one oncolytic virus therapy has received an FDA approval but advances in bioengineering techniques and our understanding of immunomodulation to heighten oncolytic virus replication and improve tumor kill raises optimism for its future drug development.


Assuntos
Vetores Genéticos/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Gerenciamento Clínico , Técnicas de Transferência de Genes , Humanos , Neoplasias/etiologia , Neoplasias/terapia , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/classificação , Resultado do Tratamento
5.
Virology ; 548: 109-116, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32838931

RESUMO

One of the emerging technologies to fight against cancer is oncolytic virus-based immunotherapy. Recently, the FDA approved an oncolytic virus T-vec for the treatment of melanoma. To facilitate the scientific community, we build a manually-curated repository of oncolytic viruses called OvirusTdb (https://webs.iiitd.edu.in/raghava/ovirustdb/). The repository maintains comprehensive information on therapeutically important oncolytic viruses with 5927 records where each record has 25 fields such as the virus species, cancer cell line, synergism with anti-cancer drugs, and many more. It stores information on 09 types of DNA, 15 types of RNA; 300 recombinant and 09 wild-type viral strains; tested against 124 cancer types and 427 cancer cell lines. Approximately, 1047 records suggest improved anti-cancer response using the combinatorial approach with chemotherapeutic agents. Nearly, 3243 and 1506 records indicate cancer cell death via apoptosis induction and immune activation, respectively. OvirusTdb may facilitate researchers in designing and discovering new oncolytic viruses for effective cancer treatment.


Assuntos
Bases de Dados Genéticas , Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Linhagem Celular , Humanos , Imunoterapia , Neoplasias/imunologia , Neoplasias/virologia , Vírus Oncolíticos/classificação , Vírus Oncolíticos/fisiologia
6.
Thorac Cancer ; 10(5): 1031-1035, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30900824

RESUMO

Oncolytic viruses (OVs) are promising new therapeutic agents in the field of malignant tumor treatment. OVs can achieve the goal of targeted therapy by selectively killing tumor cells and inducing specific antitumor immunity. The key roles of OVs are tumor targeting and tumor killing mechanisms. Recently, molecular biotechnology has been used to optimize the transformation of wild virus strains in order to ensure a stronger oncolytic effect and lower adverse reactions, to enable testing in clinical trials as an antitumor drug. The main purpose of this review is to provide a description of oncolytic mechanisms, clinical studies, combination therapies, current challenges, and future prospects of OVs.


Assuntos
Vetores Genéticos/genética , Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Animais , Biomarcadores Tumorais , Estudos Clínicos como Assunto , Terapia Combinada , Suscetibilidade a Doenças , Humanos , Imunoterapia , Neoplasias/genética , Neoplasias/patologia , Vírus Oncolíticos/classificação , Resultado do Tratamento
7.
J Immunother Cancer ; 6(1): 140, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514385

RESUMO

BACKGROUND: Immunotherapy is at the forefront of modern oncologic care. Various novel therapies have targeted all three layers of tumor biology: tumor, niche, and immune system with a range of promising results. One emerging class in both primary and salvage therapy is oncolytic viruses. This therapy offers a multimodal approach to specifically and effectively target and destroy malignant cells, though a barrier oncoviral therapies have faced is a limited therapeutic response to currently delivery techniques. MAIN BODY: The ability to deliver therapy tailored to specific cellular targets at the precise locus in which it would have its greatest impact is a profound development in anti-cancer treatment. Although immune checkpoint inhibitors have an improved tolerability profile relative to cytotoxic chemotherapy and whole beam radiation, severe immune-related adverse events have emerged as a potential limitation. These include pneumonitis, pancreatitis, and colitis, which are relatively infrequent but can limit therapeutic options for some patients. Intratumor injection of oncolytic viruses, in contrast, has a markedly lower rate of serious adverse effects and perhaps greater specificity to target tumor cells. Early stage clinical trials using oncolytic viruses show induction of effector anti-tumor immune responses and suggest that such therapies could also morph and redefine both the local target cells' niche as well as impart distant effects on remote cells with a similar molecular profile. CONCLUSION: It is imperative for the modern immuno-oncologist to understand the biological processes underlying the immune dysregulation in cancer as well as the effects, uses, and limitations of oncolytic viruses. It will be with this foundational understanding that the future of oncolytic viral therapies and their delivery can be refined to forge future horizons in the direct modulation of the tumor bed.


Assuntos
Vetores Genéticos , Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Vacinas Anticâncer/imunologia , Terapia Combinada , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Humanos , Vigilância Imunológica , Imunomodulação , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias/patologia , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/classificação , Vírus Oncolíticos/genética , Resultado do Tratamento , Evasão Tumoral/imunologia
8.
Ther Innov Regul Sci ; 52(4): 430-437, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29714547

RESUMO

Oncolytic virus therapy (OVT) represents a new class of therapeutic agents in cancer treatment. The molecular and cellular mechanisms of action of OVTs have been evaluated in nonclinical/clinical phase trials. Various genetically modified viruses have been developed as oncolytic agents, and the first approval of an OVT for clinical use was issued by the US Food and Drug Administration in 2015. In this context, more and more clinical development of OVTs is anticipated in the future. This article provides a risk assessment of OVT based on the safety data obtained from all clinical trials to date using a publicly available database. The most common adverse events (AEs) observed in clinical trials have been infection-related symptoms such as fatigue, chills, fever, and nausea; few serious AEs have been observed, regardless of the kind of virus or transfected genes. In vivo systemic infusion of OVTs demonstrated a high percentage of AEs, but most AEs were manageable using common drugs. This paper describes OVTs' specific safety/toxicity profiles and encourages the performance of further clinical trials of OVTs to address the most serious challenges anticipated in the development of OVTs as a new class of drugs for the treatment of cancer.


Assuntos
Neoplasias/terapia , Terapia Viral Oncolítica/efeitos adversos , Ensaios Clínicos como Assunto , Aprovação de Drogas , Humanos , Vírus Oncolíticos/classificação , Medição de Risco , Estados Unidos , United States Food and Drug Administration
9.
Viruses ; 9(6)2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28587298

RESUMO

Reovirus is under development as a therapeutic for numerous types of cancer. In contrast to other oncolytic viruses, the safety and efficacy of reovirus have not been improved through genetic manipulation. Here, we tested the oncolytic capacity of recombinant strains (rs) of prototype reovirus laboratory strains T1L and T3D (rsT1L and rsT3D, respectively) in a panel of non-small cell lung cancer (NSCLC) cell lines. We found that rsT1L was markedly more cytolytic than rsT3D in the large cell carcinoma cell lines tested, whereas killing of adenocarcinoma cell lines was comparable between rsT1L and rsT3D. Importantly, non-recombinant T1L and T3D phenocopied the kinetics and magnitude of cell death induced by recombinant strains. We identified gene segments L2, L3, and M1 as viral determinants of strain-specific differences cell killing of the large cell carcinoma cell lines. Together, these results indicate that recombinant reoviruses recapitulate the cell killing properties of non-recombinant, tissue culture-passaged strains. These studies provide a baseline for the use of reverse genetics with the specific objective of engineering more effective reovirus oncolytics. This work raises the possibility that type 1 reoviruses may have the capacity to serve as more effective oncolytics than type 3 reoviruses in some tumor types.


Assuntos
Carcinoma de Células Grandes/virologia , Vírus Oncolíticos/fisiologia , Reoviridae/fisiologia , Replicação Viral , Carcinoma de Células Grandes/terapia , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Vírus Oncolíticos/classificação , Vírus Oncolíticos/genética , Reoviridae/classificação , Reoviridae/genética , Sorogrupo
10.
Virology ; 505: 162-171, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28260622

RESUMO

Enadenotucirev (EnAd) is a group B oncolytic adenovirus developed for systemic delivery and currently undergoing clinical evaluation for advanced cancer therapy. For differentiated carcinomas, systemic delivery would likely expose virus particles to the basolateral surface of cancer cells rather than the apical surface encountered during natural infection. Here, we compare the ability of EnAd and adenovirus type-5 (Ad5) to infect polarised colorectal carcinoma cells from the apical or basolateral surfaces. Whereas Ad5 infection was more efficient via the apical than basolateral surface, EnAd readily infected cells from either surface. Progeny particles from EnAd were released preferentially via the apical surface for all cell lines and routes of infection. These data further support the utility of group B adenoviruses for systemic delivery and suggest that progeny virus are more likely to be released into the tumour rather than back through the basolateral surface into the blood stream.


Assuntos
Adenovírus Humanos/metabolismo , Antineoplásicos/metabolismo , Neoplasias Colorretais/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/metabolismo , Internalização do Vírus , Adenovírus Humanos/classificação , Células CACO-2 , Linhagem Celular Tumoral , Polaridade Celular , Células Epiteliais/virologia , Células HT29 , Humanos , Microscopia Eletrônica de Transmissão , Vírus Oncolíticos/classificação , Receptores Virais/metabolismo , Junções Íntimas/metabolismo
12.
Anticancer Res ; 35(10): 5401-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26408702

RESUMO

BACKGROUND/AIM: Virotherapy may be a promising alternative to chemotherapy of malignant melanoma. In clinical trials using strains of Newcastle disease virus (NDV), only a fraction of patients with cancer responded to virotherapy. In the present study, we tried to find a correlation between the susceptibility of human melanoma cell lines to NDV and growth factor signaling pathways. MATERIALS AND METHODS: Using an ATP assay, cytotoxicity of an NDV strain (MTH-68/H) was tested in 13 human melanoma cell lines. The activation state of growth factor signaling pathways was studied by the analysis of key signaling proteins. RESULTS: MTH-68/H was found to be cytotoxic in all melanoma cells tested, but the IC50 values varied significantly. No correlation between the IC50 values and the rate of extracellular signal-regulated kinase (ERK) and AKT phosphorylation and phosphatase and tensin homologue (PTEN) expression was found. CONCLUSION: Susceptibility of tumor cells to NDV may be affected by alterations other than those of RAS/ERK and phosphatidylinositol 3-kinase (PI3K)/AKT signaling in uninfected cells.


Assuntos
Melanoma/terapia , Vírus da Doença de Newcastle , Terapia Viral Oncolítica , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Concentração Inibidora 50 , Melanoma/patologia , Vírus da Doença de Newcastle/classificação , Vírus Oncolíticos/classificação , Transdução de Sinais
13.
Proc Natl Acad Sci U S A ; 111(42): E4504-12, 2014 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-25288727

RESUMO

Oncolytic virotherapy is a growing treatment modality that uses replicating viruses as selective antineoplastic agents. Safety and efficacy considerations dictate that an ideal oncolytic agent would discriminate between normal and cancer cells on the basis of common genetic abnormalities in human cancers. Here, we identify a naturally occurring alphavirus (M1) as a novel selective killer targeting zinc-finger antiviral protein (ZAP)-deficient cancer cells. In vitro, in vivo, and ex vivo studies showed potent oncolytic efficacy and high tumor tropism of M1. We showed that the selectivity depends on ZAP deficiency by systematic identification. A large-scale multicenter pathology study using tissue microarrays reveals that ZAP is commonly deficient in human cancers, suggesting extensive application prospects for M1. Additionally, M1 killed cancer cells by inducing endoplasmic reticulum stress-mediated apoptosis. Our report provides novel insights into potentially personalized cancer therapy using oncolytic viruses.


Assuntos
Alphavirus/classificação , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/classificação , Animais , Apoptose , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Retículo Endoplasmático/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Transplante de Neoplasias , Neoplasias/metabolismo , Interferência de RNA , Análise Serial de Tecidos , Dedos de Zinco
14.
Mol Ther ; 22(8): 1504-1517, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24791939

RESUMO

We are interested in developing oncolytic adenoviruses for the treatment of prostate cancer (PCa) bone metastases. A key limitation of Adenovirus 5 (Ad5) is that upon systemic administration, it produces major liver and systemic toxicities. To address this issue, a chimaeric Ad5/48 adenovirus mHAd.sTßRFc was created. Seven hypervariable regions of Ad5 hexon present in Ad5-based Ad.sTßRFc expressing soluble transforming growth factor beta receptor II-Fc fusion protein (sTGßRIIFc), were replaced by those of Ad48. mHAd.sTßRFc, like Ad.sTßRFc, was replication competent in the human PCa cells, and produced high levels of sTGßRIIFc expression. Compared to Ad.sTßRFc, the systemic delivery of mHAd.sTßRFc in nude mice resulted in much reduced systemic toxicity, and reduced liver sequestration. Ad.sTßRFc produced significant liver necrosis, and increases in alanine transaminase, aspartate transaminase, lactate dehydrogenase, tumor necrosis factor-α, and interleukin-6 levels, while mHAd.sTßRFc produced much reduced responses of these markers. Intravenous delivery of Ad.sTßRFc or mHAd.sTßRFc (5 × 10(10) viral particles/mouse) in nude mice bearing PC-3-luc PCa bone metastases produced inhibition of bone metastases. Moreover, a larger dose of the mHAd.sTßRFc (4 × 10(11) viral particles /mouse) was also effective in inhibiting bone metastases. Thus, mHAd.sTßRFc could be developed for the treatment of PCa bone metastases.


Assuntos
Neoplasias Ósseas/terapia , Proteínas do Capsídeo/genética , Vetores Genéticos/efeitos adversos , Vírus Oncolíticos/genética , Neoplasias da Próstata/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Animais , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Dependovirus/classificação , Dependovirus/genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/uso terapêutico , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos/classificação , Neoplasias da Próstata/terapia , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo
15.
Surgery ; 152(3): 441-8, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22853858

RESUMO

INTRODUCTION: Pancreatic adenocarcinoma is an aggressive malignancy. Oncolytic adenoviruses (Ads) are modified genetically to target tumor cells while sparing normal cells. We modified the knob domain of the Ad serotype 5 with a serotype 3 knob domain and incorporated the CXCR4 promoter to regulate Ad E1A gene expression (Ad5/3-CXCR4-E1A). These modifications were made to efficiently infect and lyse pancreatic tumors. METHODS: Human pancreatic cancer lines CFPAC-1, PANC-1, AsPC-1, and BxPC-3 were obtained from the American Type Culture Collection. Efficiency of Ad infection in the cells was determined by the use of an Ad construct expressing the green fluorescence protein (GFP) marker in place of the E1A gene (Ad5/3-CXCR4-GFP) and quantified by flow cytometry. Oncolytic activity in the pancreatic cancer cells was determined with the Ad5/3-CXCR4-E1A oncolytic Ad by a crystal violet staining method. To determine the oncolytic effect in vivo, pancreatic cancer cells were implanted on the flanks of 40 SCID mice (4 groups). Tumors were injected intratumorally for 3 days with Ad5/3-CXCR4-E1A, Ad5 wild-type (a positive control), or phosphate-buffered saline (a no virus control). Tumor size, overall survival, and body condition scale score were recorded. Statistical analyses included the Kaplan-Meier survival curve, the log-rank test, and one-way analysis of variance. RESULTS: The serotype 3 fiber-modified Ad with the CXCR4 promoter (Ad5/3-CXCR4-E1A) was most efficient in infecting and lysing pancreatic cancer cells compared with an Ad containing an unmodified fiber knob (Ad5-CXCR4-E1A). Treatment of pancreatic tumor xenografts in vivo with Ad5/3-CXCR4-E1A group resulted in smaller tumors (P = .001), greater body condition scale score (P = .01), and greater survival time (P = .04) than the other treatment groups. CONCLUSION: Ad5/3-CXCR4-E1A treatment significantly prolonged survival in SCID mice pancreatic tumor xenografts. This novel construct represents a potential new therapy against pancreatic cancer.


Assuntos
Adenocarcinoma/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/classificação , Vírus Oncolíticos/genética , Neoplasias Pancreáticas/terapia , Adenocarcinoma/metabolismo , Adenocarcinoma/virologia , Análise de Variância , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Estimativa de Kaplan-Meier , Camundongos , Camundongos SCID , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/virologia , Ratos , Receptores CXCR4/metabolismo , Sorotipagem , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cancer Gene Ther ; 18(10): 744-50, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21886190

RESUMO

Although there are 55 serotypes of adenovirus (Ad) that infect humans, Ad serotype 5 (Ad5) is the most widely studied because of the availability of commercial kits for its genetic manipulation. In fact, engineered Ad 5 is currently being used in all of the 87 global clinical trials utilizing Ad for the treatment of cancer. Unfortunately, Ad5 is one of the most seroprevalent serotypes, meaning that this virus has to confront additional immunological barriers to be effective in Ad5-immune patients. In this work, we compare Ad5 to 13 other adenoviral serotypes from species B, C, D and E for oncolytic potential in both immunodeficient mouse and immunocompetent hamster models. Our results indicate that species D Ads are not effective oncolytics against most solid tumors. Conversely, lower seroprevalent Ad6 and Ad11 had anti-cancer activity comparable to Ad5. This work strongly supports the consideration of Ad6-based oncolytic therapies for the treatment of breast, ovarian, kidney and liver tumors.


Assuntos
Adenovírus Humanos/imunologia , Neoplasias/imunologia , Terapia Viral Oncolítica , Vírus Oncolíticos/imunologia , Adenovírus Humanos/classificação , Adenovírus Humanos/genética , Animais , Células CHO , Linhagem Celular Tumoral , Sobrevivência Celular , Cricetinae , Efeito Citopatogênico Viral , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Nus , Neoplasias/metabolismo , Neoplasias/terapia , Vírus Oncolíticos/classificação , Vírus Oncolíticos/genética , Filogenia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Virology ; 394(2): 311-20, 2009 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-19765790

RESUMO

Human adenovirus type 5 (Ad5) has been the most popular platform for the development of oncolytic Ads. Alternative Ad serotypes with low seroprevalence might allow for improved anticancer efficacy in Ad5-immune patients. We studied the safety and efficacy of rare serotypes Ad6, Ad11 and Ad35. In vitro cytotoxicity of the Ads correlated with expression of CAR and CD46 in most but not all cell lines. Among CAR-binding viruses, Ad5 was often more active than Ad6, among CD46-binding viruses Ad35 was generally more cytotoxic than Ad11 in cell culture studies. Ad5, Ad6, and Ad11 demonstrated similar anticancer activity in vivo, whereas Ad35 was not efficacious. Hepatotoxicity developed only in Ad5-injected mice. Predosing with Ad11 and Ad35 did not increase infection of hepatocytes with Ad5-based vector demonstrating different interaction of these Ads with Kupffer cells. Data obtained in this study suggest developing Ad6 and Ad11 as alternative Ads for anticancer treatment.


Assuntos
Adenovírus Humanos/classificação , Adenovírus Humanos/fisiologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/classificação , Vírus Oncolíticos/fisiologia , Animais , Neoplasias da Mama/terapia , Carcinoma Hepatocelular/terapia , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Hepatócitos/virologia , Humanos , Células de Kupffer/virologia , Neoplasias Hepáticas/terapia , Masculino , Proteína Cofatora de Membrana/genética , Proteína Cofatora de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Terapia Viral Oncolítica/efeitos adversos , Neoplasias Ovarianas/terapia , Neoplasias da Próstata/terapia , Receptores Virais/metabolismo , Recoverina/metabolismo , Sorotipagem
18.
Structure ; 16(10): 1555-61, 2008 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-18940610

RESUMO

The crystal structure of Seneca Valley Virus-001 (SVV-001), the representative member of a new genus, Senecavirus, is reported at 2.3A resolution. SVV-001 is the first naturally occurring nonpathogenic picornavirus shown to mediate selective cytotoxicity towards tumor cells with neuroendocrine cancer features. The nonsegmented (+) ssRNA genome of SVV-001 shares closest sequence similarity with the genomes of the members of Cardiovirus. The overall tertiary structure of VP1-VP4 subunits is conserved with the exception of loops, especially those of VP1 that show large deviations relative to the members of the cardioviruses. The surface loops of VP1 and VP2 are predicted to mediate cell tropism of SVV-001. In addition, the organization of the packaged nucleic acid density indicates that certain regions of VP2 and VP4 interact closely with the packaged nucleic acid.


Assuntos
Vírus Oncolíticos/química , Vírus Oncolíticos/classificação , Picornaviridae/química , Picornaviridae/classificação , Modelos Moleculares , Conformação de Ácido Nucleico , Estrutura Quaternária de Proteína , Estrutura Secundária de Proteína , RNA Viral/química , Receptores Virais/química , Receptores Virais/metabolismo , Vírion/química
19.
J Natl Cancer Inst ; 99(21): 1623-33, 2007 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-17971529

RESUMO

BACKGROUND: Numerous clinical trials have demonstrated that oncolytic viruses can elicit antitumor responses when they are administered directly into localized cancers. However, the treatment of metastatic disease with oncolytic viruses has been challenging due to the inactivation of viruses by components of human blood and/or to inadequate tumor selectivity. METHODS: We determined the cytolytic potential and selectivity of Seneca Valley Virus-001 (SVV-001), a newly discovered native picornavirus, in neuroendocrine and pediatric tumor cell lines and normal cells. Suitability of the virus for intravenous delivery in humans was assessed by blood inactivation assays. Safety was evaluated in vivo using an immune-competent mouse model, and efficacy was evaluated in vivo in athymic mice bearing tumors derived from human small-cell lung cancer and retinoblastoma cell lines. RESULTS: Cell lines derived from small-cell lung cancers and solid pediatric cancers were at least 10,000-fold more sensitive to the cytolytic activity of SVV-001 than were any of the adult normal human cells tested. Viral infectivity was not inhibited by human blood components. Intravenous doses up to 1 x 10(14) virus particles (vp) per kg were well tolerated, and no dose-limiting toxicity was observed in immune-competent mice. A single intravenous dose of 1 x 10(8) vp per kg into athymic mice bearing preestablished small-cell lung or retinoblastoma tumors resulted in complete, durable responses in ten of ten and five of eight mice, respectively. CONCLUSIONS: SVV-001 has potent cytolytic activity and high selectivity for tumor cell lines having neuroendocrine properties versus adult normal cells. Systemically administered SVV-001 has potential for the treatment of metastatic neuroendocrine cancers.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos , Picornaviridae , Animais , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma de Células Pequenas/terapia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Testes de Hemaglutinação , Humanos , Imuno-Histoquímica , Injeções Intravenosas , Neoplasias Pulmonares/terapia , Camundongos , Camundongos Nus , Vírus Oncolíticos/classificação , Vírus Oncolíticos/patogenicidade , Picornaviridae/classificação , Picornaviridae/patogenicidade , Projetos de Pesquisa , Retinoblastoma/terapia , Transplante Heterólogo
20.
Cancer Lett ; 254(2): 178-216, 2007 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-17383089

RESUMO

Oncolytic virotherapy is a promising form of gene therapy for cancer, employing nature's own agents to find and destroy malignant cells. The purpose of this review is to provide an introduction to this very topical field of research and to point out some of the current observations, insights and ideas circulating in the literature. We have strived to acknowledge as many different oncolytic viruses as possible to give a broader picture of targeting cancer using viruses. Some of the newest additions to the panel of oncolytic viruses include the avian adenovirus, foamy virus, myxoma virus, yaba-like disease virus, echovirus type 1, bovine herpesvirus 4, Saimiri virus, feline panleukopenia virus, Sendai virus and the non-human coronaviruses. Although promising, virotherapy still faces many obstacles that need to be addressed, including the emergence of virus-resistant tumor cells.


Assuntos
Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/fisiologia , Animais , Modelos Animais de Doenças , Terapia Genética/métodos , Humanos , Neoplasias/patologia , Neoplasias/virologia , Vírus Oncolíticos/classificação , Replicação Viral
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