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1.
Anticancer Res ; 40(1): 161-168, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892564

RESUMO

BACKGROUND: Arming of an oncolytic adenovirus (OAd) by inserting expression cassettes of therapeutic transgenes into the OAd genome is a promising approach to enhance the therapeutic effects of an OAd. Ideally, this approach would simultaneously promote the replication of an OAd in tumor cells and transgene product-mediated antitumor effects by expressing therapeutic transgenes. We previously demonstrated that knockdown of cullin 4A (CUL4A), which is an E3 ubiquitin ligase, significantly promoted adenovirus replication by increasing the c-JUN protein level. In addition, previous studies reported that CUL4A was highly expressed in various types of tumor, and was involved in tumor growth and metastasis. MATERIALS AND METHODS: In this study, we developed a novel OAd expressing a short-hairpin RNA (shRNA) against CUL4A (OAd-shCUL4A). RESULTS: OAd-shCUL4 mediated higher levels of cytotoxic effects on various types of human tumor cell than a conventional OAd. Higher levels of OAd genome copy numbers were found in the tumor cells for OAd-shCUL4A, compared with a conventional OAd. CONCLUSION: OAd-shCUL4A showed efficient antitumor effects by both enhancing OAd replication and inhibiting tumor cell growth.


Assuntos
Adenoviridae/genética , Proteínas Culina/genética , Vetores Genéticos/genética , Vírus Oncolíticos/genética , RNA Interferente Pequeno/genética , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Terapia Viral Oncolítica , Interferência de RNA , Transdução Genética
2.
J Surg Res ; 245: 127-135, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415934

RESUMO

BACKGROUND: The purpose of this study was to analyze the oncolytic and immunomodulatory functions of an M protein mutant of vesicular stomatitis virus (M51R VSV) in a murine model of peritoneal surface dissemination from colon cancer (PSD from CRC). METHODS: Luciferase-expressing CT26 peritoneal tumors were established in Balb/c mice to evaluate the impact of M51R VSV treatment on intraperitoneal tumor growth and overall survival. The mice were treated with either intraperitoneal phosphate buffered saline (n = 10) or 5 × 106 PFU M51R VSV (n = 10) at 5 d after tumor implantation. Tumor bioluminescence was measured every 3 d during the 60-day study period. The immunomodulatory effect of M51R VSV treatment was evaluated in mice treated with either intraperitoneal phosphate buffered saline (n = 21) or M51R VSV (n = 21). Peritoneal lavages were collected at days 1, 3, and 7 after M51R VSV treatment for flow cytometry and multiplex cytokine bead analysis. RESULTS: A single, intraperitoneal treatment with M51R VSV inhibited the growth of PSD from CRC as evidenced by decreased bioluminescence and improved survival. This treatment approach also resulted in significantly higher frequencies of peritoneal CD4+ T (10.95 ± 1.17 versus 6.19 ± 0.44, P = 0.004) and B1b cells (5.01 ± 0.97 versus 2.20 ± 0.2, P = 0.024). On the other hand, treatment with M51R VSV resulted in fewer myeloid-derived suppressor cells relative to controls (10.66 ± 1.48 versus 14.47 ± 1.06, P = 0.035). M51R-treated peritoneal cavities also contained lower concentrations of immunosuppressive monocyte chemoattractant protein-1 and interleukin 6 cytokines relative to controls. CONCLUSIONS: Our findings suggest that M51R VSV alters the innate and adaptive immune responses in PSD from CRC. Future studies will delineate specific components of antitumor immunity that result in its therapeutic effect.


Assuntos
Neoplasias do Colo/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Neoplasias Peritoneais/terapia , Vesiculovirus/imunologia , Imunidade Adaptativa , Animais , Linhagem Celular Tumoral/transplante , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Inata , Injeções Intraperitoneais , Camundongos , Mutação , Vírus Oncolíticos/genética , Neoplasias Peritoneais/secundário , Resultado do Tratamento , Vesiculovirus/genética , Proteínas da Matriz Viral/genética
3.
Int J Cancer ; 146(2): 531-541, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31584185

RESUMO

We have developed an oncolytic Newcastle disease virus (NDV) that has potent in vitro and in vivo anti-tumor activities and attenuated pathogenicity in chickens. In this ex vivo study using the same recombinant NDV backbone with GFP transgene (NDV-GFP, designated as rNDV), we found that rNDV induces maturation of monocyte-derived immature dendritic cells (iDCs) by both direct and indirect mechanisms, which promote development of antigen-specific T cell responses. Addition of rNDV directly to iDCs culture induced DC maturation, as demonstrated by the increased expression of costimulatory and antigen-presenting molecules as well as the production of type I interferons (IFNs). rNDV infection of the HER-2 positive human breast cancer cell line (SKBR3) resulted in apoptotic cell death, release of proinflammatory cytokines, and danger-associated molecular pattern molecules (DAMPs) including high-mobility group protein B1 (HMGB1) and heat shock protein 70 (HSP70). Addition of rNDV-infected SKBR3 cells to iDC culture resulted in greatly enhanced upregulation of the maturation markers and release of type I IFNs by DCs than rNDV-infected DCs only. When co-cultured with autologous T cells, DCs pre-treated with rNDV-infected SKBR3 cells cross-primed T cells in an antigen-specific manner. Altogether, our data strongly support the potential of oncolytic NDV as efficient therapeutic agent for cancer treatment.


Assuntos
Apresentação Cruzada , Células Dendríticas/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Animais , Técnicas de Cocultura , Células Dendríticas/metabolismo , Feminino , Células HeLa , Humanos , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Neoplasias/imunologia , Vírus da Doença de Newcastle/genética , Vírus da Doença de Newcastle/imunologia , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , RNA/administração & dosagem , RNA/genética , RNA Viral/administração & dosagem , RNA Viral/genética , Linfócitos T/imunologia , Células Vero
4.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(5): 649-653, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31762232

RESUMO

OBJECTIVE: To investigate the molecular mechanism of apoptosis of HL60 cells induced by oncolytic virus Reovirus type 3 (Reo3). METHODS: HL60 cells were infected with Reo3 at different multiplicity of infection (MOI) with the uninfected HL60 cells as control group. After 48 h of infection, the activity of HL60 cells infected with virus at different MOI was detected by CCK8 method to investigate the influence of MOI to cell activity. Simultaneously, the apoptotic rate of HL60 cells was detected by flow cytometry, and the activation level of double-stranded RNA-dependent protein kinase (PKR) and the expression of apoptotic-related protein in HL60 cells were detected by Western blot. Before infection with Reo3 for 48 h, HL60 cells were treated with 2-aminopurine (2-AP), a specific inhibitor of PKR, for 24 h. Afterward, the apoptotic level and expression of apoptotic related proteins were detected. RESULTS: Activity of HL60 cells was obviously inhibited after infected with Reo3 with a MOI of 1 for 48 h. The cell survival rate was (24.333±3.396)% and the apoptotic rate was (29.96±2.06)%. Both rates were all higher than those in the control group (P < 0.05). Western blot results showed that the expression levels of PKR, p-PKR, Bax, Caspase3 and cleaved Caspase3 in HL60 cells infected with Reo3 were higher than those in the control group (P < 0.05), while the expression level of Bcl-2 was lower (P < 0.05). Compared with the group without inhibitor, the apoptotic rate of HL60 cells pretreated with 2-AP decreased (P < 0.05), the phosphorylation level of PKR and the expression level of apoptotic-related protein also decreased (P < 0.05). CONCLUSION: Oncolytic virus Reo3 could activate PKR in HL60 cells and thus induce apoptosis of HL60 cells.


Assuntos
Apoptose , Orthoreovirus Mamífero 3/fisiologia , eIF-2 Quinase/metabolismo , 2-Aminopurina/farmacologia , Caspase 3/metabolismo , Citometria de Fluxo , Células HL-60 , Humanos , Vírus Oncolíticos/fisiologia , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
5.
PLoS Comput Biol ; 15(11): e1007495, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31774808

RESUMO

Oncolytic virotherapies, including the modified herpes simplex virus talimogene laherparepvec (T-VEC), have shown great promise as potent instigators of anti-tumour immune effects. The OPTiM trial, in particular, demonstrated the superior anti-cancer effects of T-VEC as compared to systemic immunotherapy treatment using exogenous administration of granulocyte-macrophage colony-stimulating factor (GM-CSF). Theoretically, a combined approach leveraging exogenous cytokine immunotherapy and oncolytic virotherapy would elicit an even greater immune response and improve patient outcomes. However, regimen scheduling of combination immunostimulation and T-VEC therapy has yet to be established. Here, we calibrate a computational biology model of sensitive and resistant tumour cells and immune interactions for implementation into an in silico clinical trial to test and individualize combination immuno- and virotherapy. By personalizing and optimizing combination oncolytic virotherapy and immunostimulatory therapy, we show improved simulated patient outcomes for individuals with late-stage melanoma. More crucially, through evaluation of individualized regimens, we identified determinants of combination GM-CSF and T-VEC therapy that can be translated into clinically-actionable dosing strategies without further personalization. Our results serve as a proof-of-concept for interdisciplinary approaches to determining combination therapy, and suggest promising avenues of investigation towards tailored combination immunotherapy/oncolytic virotherapy.


Assuntos
Terapia Combinada/métodos , Biologia Computacional/métodos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Simulação por Computador , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Imunoterapia/métodos , Melanoma/patologia , Modelos Teóricos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/patogenicidade , Medicina de Precisão/métodos , Estudo de Prova de Conceito
6.
Expert Opin Investig Drugs ; 28(12): 1041-1049, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31726894

RESUMO

Introduction: High-grade gliomas (HGG) are extremely aggressive brain malignancies that are fatal. Despite maximal resection, chemotherapy, and radiation, these tumors inevitably recur and present a poor median overall survival (mOS); hence a pressing need for improved treatments.Areas covered: This review assesses DNX-2401 as a treatment of recurrent HGG. Phase I data on efficacy, safety, and tolerability are examined while insights and perspectives on future directions are offered.Expert opinion: This phase I study assessed DNX-2401 in two study groups; one received an intratumoral injection without tumor resection while the second received an intratumoral injection followed by surgical resection 14 days later with a second injection into the resection cavity. In patients that did not receive resection, the mOS was 9.5 months while patients in the resection group had a mOS of 13 months, a promising extension of survival compared to historical controls. Furthermore, this study had numerous long-term survivors living for greater than 2 years. DNX-2401 was well tolerated with no Grade 3/4 adverse events; it provoked an immunologic response to the tumor which may contribute to the complete responses in some patients. Randomized-control trials are necessary and further studies are warranted to identify patients who will benefit most.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Terapia Viral Oncolítica/métodos , Adenoviridae , Animais , Neoplasias Encefálicas/patologia , Drogas em Investigação/administração & dosagem , Glioblastoma/patologia , Humanos , Recidiva Local de Neoplasia , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos , Taxa de Sobrevida
8.
Nat Commun ; 10(1): 4801, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641136

RESUMO

Improving efficacy of oncolytic virotherapy remains challenging due to difficulty increasing specificity and immune responses against cancer and limited understanding of its population dynamics. Here, we construct programmable and modular synthetic gene circuits to control adenoviral replication and release of immune effectors selectively in hepatocellular carcinoma cells in response to multiple promoter and microRNA inputs. By performing mouse model experiments and computational simulations, we find that replicable adenovirus has a superior tumor-killing efficacy than non-replicable adenovirus. We observe a synergistic effect on promoting local lymphocyte cytotoxicity and systematic vaccination in immunocompetent mouse models by combining tumor lysis and secretion of immunomodulators. Furthermore, our computational simulations show that oncolytic virus which encodes immunomodulators can exert a more robust therapeutic efficacy than combinatorial treatment with oncolytic virus and immune effector. Our results provide an effective strategy to engineer oncolytic adenovirus, which may lead to innovative immunotherapies for a variety of cancers.


Assuntos
Adenoviridae/genética , Genes Sintéticos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Animais , Carcinoma Hepatocelular/terapia , Feminino , Células HEK293 , Células Hep G2 , Humanos , Imunoterapia/métodos , Neoplasias Hepáticas/terapia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Cancer Invest ; 37(8): 393-414, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31502477

RESUMO

Colorectal cancer (CRC) is one of the most common malignancies. In recent decades, early diagnosis and conventional therapies have resulted in a significant reduction in mortality. However, late stage metastatic disease still has very limited effective treatment options. There is a growing interest in using viruses to help target therapies to tumour sites. In recent years the evolution of immunotherapy has emphasised the importance of directing the immune system to eliminate tumour cells; we aim to give a state-of-the-art over-view of the diverse viruses that have been investigated as potential oncolytic agents for the treatment of CRC.


Assuntos
Neoplasias do Colo/terapia , Terapia Viral Oncolítica/tendências , Vírus Oncolíticos/patogenicidade , Neoplasias Retais/terapia , Animais , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias do Colo/virologia , Difusão de Inovações , Previsões , Interações Hospedeiro-Patógeno , Humanos , Terapia Viral Oncolítica/efeitos adversos , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Neoplasias Retais/virologia , Resultado do Tratamento
10.
Nat Rev Cancer ; 19(11): 607, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31527698
11.
Immunity ; 51(3): 548-560.e4, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31471106

RESUMO

Immunotherapy can reinvigorate dormant responses to cancer, but response rates remain low. Oncolytic viruses, which replicate in cancer cells, induce tumor lysis and immune priming, but their immune consequences are unclear. We profiled the infiltrate of aggressive melanomas induced by oncolytic Vaccinia virus using RNA sequencing and found substantial remodeling of the tumor microenvironment, dominated by effector T cell influx. However, responses to oncolytic viruses were incomplete due to metabolic insufficiencies induced by the tumor microenvironment. We identified the adipokine leptin as a potent metabolic reprogramming agent that supported antitumor responses. Leptin metabolically reprogrammed T cells in vitro, and melanoma cells expressing leptin were immunologically controlled in mice. Engineering oncolytic viruses to express leptin in tumor cells induced complete responses in tumor-bearing mice and supported memory development in the tumor infiltrate. Thus, leptin can provide metabolic support to tumor immunity, and oncolytic viruses represent a platform to deliver metabolic therapy.


Assuntos
Leptina/imunologia , Melanoma/imunologia , Vírus Oncolíticos/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Imunoterapia/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microambiente Tumoral/imunologia , Vírus Vaccinia/imunologia
12.
Immunity ; 51(3): 423-425, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533054

RESUMO

Effective anticancer immunosurveillance after oncolytic viral infection is often hindered by the defective metabolic function of tumor-infiltrating lymphocytes (TILs). A recent paper by Rivadeneira et al. demonstrates that intratumoral delivery of leptin by a recombinant oncolytic vaccinia virus can metabolically enhance TIL effector and memory functions through improved mitochondrial oxidative phosphorylation, thereby enhancing therapeutic efficacy.


Assuntos
Neoplasias , Vírus Oncolíticos , Humanos , Leptina , Linfócitos do Interstício Tumoral , Linfócitos T
13.
Biomater Sci ; 7(10): 4195-4207, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31386700

RESUMO

A dual pH- and temperature-responsive physically crosslinked and injectable hydrogel system was developed for efficient and long-term delivery of oncolytic adenoviruses (Ads). Three different types of physically crosslinked hydrogels with different chemical compositions and properties were prepared. These hydrogels with good biocompatibility can be injected at pH 9.0 and room temperature and rapidly form a gel under body or tumor microenvironment conditions. Ads encapsulated in hydrogels were released gradually without burst release. Moreover, these physically crosslinked hydrogels provided a protective environment for Ads and maintained their bioactivity for a long period of time. Compared to naked Ads, Ads protected by these physically crosslinked hydrogels showed strong cytotoxicity to cancer cells even after 11 days. The Ad-loaded hydrogel system also exhibited enhanced and long-term antitumor therapeutic effects in human xenograft tumor models. Due to these outstanding properties, Ad-loaded injectable hydrogels might have potential for long-term cancer treatment.


Assuntos
Adenoviridae , Hidrogéis/administração & dosagem , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Hidrogéis/química , Injeções , Masculino , Camundongos Nus , Neoplasias/patologia , Neoplasias/terapia , Poliuretanos/administração & dosagem , Poliuretanos/química , Sulfametazina/administração & dosagem , Sulfametazina/química , Carga Tumoral
15.
EBioMedicine ; 47: 89-97, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31409575

RESUMO

BACKGROUND: Talimogene laherparepvec (T-VEC) is an intralesionally delivered, modified herpes simplex virus type-1 oncolytic immunotherapy. The biodistribution, shedding, and potential transmission of T-VEC was systematically evaluated during and after completion of therapy in adults with advanced melanoma. METHODS: In this phase 2, single-arm, open-label study, T-VEC was administered into injectable lesions initially at 106 plaque-forming units (PFU)/mL, 108 PFU/mL 21 days later, and 108 PFU/mL every 14 (±3) days thereafter. Injected lesions were covered with occlusive dressings for ≥1 week. Blood, urine, and swabs from exterior of occlusive dressings, surface of injected lesions, oral mucosa, anogenital area, and suspected herpetic lesions were collected throughout the study. Detectable T-VEC DNA was determined for each sample type; infectivity was determined for all swabs with detectable T-VEC DNA. FINDINGS: Sixty patients received ≥1 dose of T-VEC. During cycles 1-4, T-VEC DNA was detected in blood (98·3% of patients, 36·7% of samples), urine (31·7% of patients, 3·0% of samples) and swabs from injected lesions (100% of patients, 57·6% of samples), exterior of dressings (80% of patients,19·5% of samples), oral mucosa (8·3% of patients, 2·5% of samples), and anogenital area (8·0% of patients, 1·1% of samples). During the safety follow-up period, T-VEC DNA was only detected on swabs from injected lesions (14% of patients, 5.8% of samples). T-VEC DNA was detected in 4/37 swabs (3/19 patients) of suspected herpetic lesions. Among all samples, only those from the surface of injected lesions tested positive for infectivity (8/740 [1·1%]). Three close contacts reported signs and symptoms of suspected herpetic origin; however, no lesions had detectable T-VEC DNA. INTERPRETATION: Using current guidelines, T-VEC can be administered safely to patients with advanced melanoma and is unlikely to be transmitted to close contacts with appropriate use of occlusive dressings. FUND: This study was funded by Amgen Inc.: ClinicalTrials.gov, NCT02014441.


Assuntos
Produtos Biológicos/uso terapêutico , Melanoma/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Produtos Biológicos/farmacocinética , DNA Viral , Esquema de Medicação , Herpesvirus Humano 1 , Humanos , Melanoma/diagnóstico , Melanoma/etiologia , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Estadiamento de Neoplasias , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Distribuição Tecidual , Resultado do Tratamento , Adulto Jovem
16.
Int J Mol Med ; 44(4): 1484-1494, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432139

RESUMO

Virotherapy using oncolytic viruses is an upcoming therapy strategy for cancer treatment. A variety of preclinical and clinical trials have indicated that adenoviruses may be used as potent agents in the treatment of a variety of cancers, and also for the treatment of brain tumors. In these studies, it has also been shown that oncovirotherapy is safe in terms of toxicity and side effects. In addition, previous studies have presented evidence for a significant role of oncovirotherapy in the activation of anti­tumor immune responses. With regard to oncolytic adenoviruses, we have demonstrated previously that the multifunctional protein Y­box binding protein­1 (YB­1) is a potent factor that was used to develop an YB­1­dependent oncolytic adenovirus (XVir­N­31). XVir­N­31 provides the opportunity for tumor­selective replication and exhibited marked oncolytic properties in a mouse glioma tumor model using therapy­resistant brain tumor initiating cells (BTICs). In a number of, but not all, patients with glioma, YB­1 is primarily located in the nucleus; this promotes XVir­N­31­replication and subsequently tumor cell lysis. However, in certain BTICs, only a small amount of YB­1 has been identified to be nuclear, and therefore virus replication is suboptimal. YB­1 in BTICs was demonstrated to be translocated into the nucleus following irradiation, which was accompanied by an enhancement in XVir­N­31 production. R28 glioma spheres implanted in living organotypic human brain slices exhibited a significantly delayed growth rate when pre­irradiated prior to XVir­N­31­infection as compared with single treatment methods. Consistent with the in vitro data, R28 glioma­bearing mice exhibited a prolonged mean and median survival following single tumor irradiation prior to intratumoral XVir­N­31 injection, compared with the single treatment methods. In conclusion, the present study demonstrated that in an experimental glioma model, tumor irradiation strengthened the effect of an XVir­N­31­based oncovirotherapy.


Assuntos
Adenoviridae/genética , Neoplasias Encefálicas/terapia , Vetores Genéticos/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Radiação Ionizante , Animais , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Terapia Combinada , Modelos Animais de Doenças , Feminino , Expressão Gênica , Regulação da Expressão Gênica/efeitos da radiação , Terapia Genética , Vetores Genéticos/administração & dosagem , Humanos , Camundongos , Transgenes , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína 1 de Ligação a Y-Box/genética
17.
Medicine (Baltimore) ; 98(35): e16817, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464907

RESUMO

BACKGROUND: Accumulating evidence in the last decade has pointed to the effectiveness of oncolytic virus in the treatment of a variety of cancer types in preclinical or clinical studies, showing high potency and low toxicity compared to conventional treatments. To track this research trend and highlight future directions, we conducted a bibliometric analysis of oncolytic virus research to date. METHODS: Relevant studies were obtained from the Web of Science Core Collection between January 2000 and December 2018. Data were collected in terms of the number of publications, country, journal of publication, journal scope, author, and keywords or topics. Analysis and visual representation of the data were performed with CiteSpace V. RESULTS: The trend in publications related to oncolytic virus showed a dramatic increase, from 10 publications in 2000 to 199 publications in 2018. The United States clearly dominates this field (981 publications, 52.770%), followed by Canada (244, 13.125%) and China (205, 11.027%). The top 15 academic journals account for over one third of the total publications on oncolytic virus research (724, 38.95%). Most of the related papers were published in journals with a focus on biology, medicine, immunology, medicine, molecular biology, and clinical perspectives, as represented by the dual-map overlay. The most highly cited papers were published in journals in the fields of nursing, molecular biology, general biology, genetics, health, and medicine. Over 1300 institutions have focused their attention on oncolytic virus research to date, and cooperation among mainstream institutions is common. CONCLUSION: The global field of oncolytic virus research has expanded at a rapid pace from 2000 to 2018. There is no doubt that North America currently has the most powerful impact on the field with respect to both productivity and contribution. However, European and some East Asian institutions are also prominent in this field. Overall, this bibliometric study identifies the top 4 hotspots in oncolytic virus research: T-cells, vaccinia virus, dendritic cells, and apoptosis. Thus, further research focuses on these topics may be more helpful to promote the clinical translation of this treatment strategy to bring a benefit to cancer patients in the near future.


Assuntos
Bibliometria , Vírus Oncolíticos , Publicações/tendências , Pesquisa Biomédica , Canadá , China , Humanos , Neoplasias/terapia , Estados Unidos
18.
Oncogene ; 38(34): 6159-6171, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31289361

RESUMO

Malignant tumors of the central nervous system (CNS) continue to be a leading cause of cancer-related mortality in both children and adults. Traditional therapies for malignant brain tumors consist of surgical resection and adjuvant chemoradiation; such approaches are often associated with extreme morbidity. Accordingly, novel, targeted therapeutics for neoplasms of the CNS, such as immunotherapy with oncolytic engineered herpes simplex virus (HSV) therapy, are urgently warranted. Herein, we discuss treatment challenges related to HSV virotherapy delivery, entry, replication, and spread, and in so doing focus on host anti-viral immune responses and the immune microenvironment. Strategies to overcome such challenges including viral re-engineering, modulation of the immunoregulatory microenvironment and combinatorial therapies with virotherapy, such as checkpoint inhibitors, radiation, and vaccination, are also examined in detail.


Assuntos
Neoplasias Encefálicas/terapia , Resistencia a Medicamentos Antineoplásicos , Herpesvirus Humano 1/fisiologia , Terapia Viral Oncolítica/métodos , Terapias em Estudo , Adulto , Neoplasias Encefálicas/genética , Criança , Resistencia a Medicamentos Antineoplásicos/imunologia , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Vetores Genéticos , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/fisiologia , Terapias em Estudo/métodos , Terapias em Estudo/tendências , Resultado do Tratamento
19.
Anticancer Res ; 39(7): 3727-3737, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262899

RESUMO

BACKGROUND/AIM: This study aims to investigate whether the combination of oncolytic viruses with chemoradiotherapy or other therapies is a promising strategy for cancer treatment. MATERIALS AND METHODS: The anticancer effects of measles virus (MeV) in combination with nimotuzumab in the treatment of laryngeal cancer were evaluated in vitro and in nude mice inoculated with Hep2 tumors. MTT assay and flow cytometry were used to examine cell death. RESULTS: Laryngeal cancer cells treated with MeV+nimotuzumab combination had a significantly lower survival rate compared to those treated with MeV or nimotuzumab alone (p<0.0001). In an animal model bearing human laryngeal tumor, the treated group had a higher survival rate (60%) compared to a untreated group (20%) (p<0.05), and the survival rate of the group treated with MeV+nimotuzumab combination was higher compared to the groups received single treatment. CONCLUSION: The MeV+nimotuzumab combination has greater anticancer activities in both laryngeal cancer cells and an animal model.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Laríngeas/terapia , Vírus do Sarampo , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Linhagem Celular Tumoral , Terapia Combinada , Humanos , Vacina contra Sarampo , Camundongos Nus , Células Vero
20.
Nat Commun ; 10(1): 3236, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324774

RESUMO

Virus-neutralizing antibodies are a severe obstacle in oncolytic virotherapy. Here, we present a strategy to convert this unfavorable immune response into an anticancer immunotherapy via molecular retargeting. Application of a bifunctional adapter harboring a tumor-specific ligand and the adenovirus hexon domain DE1 for engaging antiadenoviral antibodies, attenuates tumor growth and prolongs survival in adenovirus-immunized mice. The therapeutic benefit achieved by tumor retargeting of antiviral antibodies is largely due to NK cell-mediated triggering of tumor-directed CD8 T-cells. We further demonstrate that antibody-retargeting (Ab-retargeting) is a feasible method to sensitize tumors to PD-1 immune checkpoint blockade. In therapeutic settings, Ab-retargeting greatly improves the outcome of intratumor application of an oncolytic adenovirus and facilitates long-term survival in treated animals when combined with PD-1 checkpoint inhibition. Tumor-directed retargeting of preexisting or virotherapy-induced antiviral antibodies therefore represents a promising strategy to fully exploit the immunotherapeutic potential of oncolytic virotherapy and checkpoint inhibition.


Assuntos
Adenoviridae/imunologia , Anticorpos/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Adenoviridae/genética , Animais , Anticorpos Neutralizantes/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Células Matadoras Naturais/imunologia , Camundongos , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Vírus Oncolíticos/genética
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