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1.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802281

RESUMO

Many immuno-therapeutic strategies are currently being developed to fight cancer. In this scenario, oncolytic adenoviruses (Onc.Ads) have an interesting role for their peculiar tumor selectivity, safety, and transgene-delivery capability. The major strength of the Onc.Ads is the extraordinary immunogenicity that leads to a strong T-cell response, which, together with the possibility of the delivery of a therapeutic transgene, could be more effective than current strategies. In this review, we travel in the adenovirus (Ads) and Onc.Ads world, focusing on a variety of strategies that can enhance Onc.Ads antitumoral efficacy, passing through tumor microenvironment modulation. Onc.Ads-based therapeutic strategies constitute additional weapons in the fight against cancer and appear to potentiate conventional and immune checkpoint inhibitors (ICIs)-based therapies leading to a promising scenario.


Assuntos
Adenoviridae/genética , Neoplasias/terapia , Neoplasias/virologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Animais , Terapia Genética/métodos , Humanos , Linfócitos T/virologia , Microambiente Tumoral/genética
2.
Nat Commun ; 12(1): 1930, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33772027

RESUMO

In our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNß), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFNß-escape tumors predictably express a point-mutated CSDE1P5S form of the RNA-binding Cold Shock Domain-containing E1 protein, which promotes escape as an inhibitor of VSV replication by disrupting viral transcription. Given time, VSV-IFNß evolves a compensatory mutation in the P/M Inter-Genic Region which rescues replication in CSDE1P5S cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1P5S also generates a neo-epitope recognized by non-tolerized T cells. We exploit this predictable neo-antigenesis to drive, and trap, tumors into an escape phenotype, which can be ambushed by vaccination against CSDE1P5S, preventing tumor escape. Combining frontline therapy with escape-targeting immunotherapy will be applicable across multiple therapies which drive tumor mutation/evolution and simultaneously generate novel, targetable immunopeptidomes associated with acquired treatment resistance.


Assuntos
Proteínas de Ligação a DNA/imunologia , Interferon beta/imunologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Proteínas de Ligação a RNA/imunologia , Vírus da Estomatite Vesicular Indiana/imunologia , Replicação Viral/imunologia , Animais , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Imunoterapia/métodos , Interferon beta/metabolismo , Camundongos Endogâmicos C57BL , Mutação , Vírus Oncolíticos/metabolismo , Vírus Oncolíticos/fisiologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vírus da Estomatite Vesicular Indiana/metabolismo , Vírus da Estomatite Vesicular Indiana/fisiologia
3.
Viruses ; 13(2)2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525628

RESUMO

Cells are continually exposed to stressful events, which are overcome by the activation of a number of genetic pathways. The integrated stress response (ISR) is a large component of the overall cellular response to stress, which ultimately functions through the phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF2α) to inhibit the energy-taxing process of translation. This response is instrumental in the inhibition of viral infection and contributes to evolution in viruses. Mammalian orthoreovirus (MRV), an oncolytic virus that has shown promise in over 30 phase I-III clinical trials, has been shown to induce multiple arms within the ISR pathway, but it successfully evades, modulates, or subverts each cellular attempt to inhibit viral translation. MRV has not yet received Food and Drug Administration (FDA) approval for general use in the clinic; therefore, researchers continue to study virus interactions with host cells to identify circumstances where MRV effectiveness in tumor killing can be improved. In this review, we will discuss the ISR, MRV modulation of the ISR, and discuss ways in which MRV interaction with the ISR may increase the effectiveness of cancer therapeutics whose modes of action are altered by the ISR.


Assuntos
Vírus Oncolíticos/fisiologia , Orthoreovirus de Mamíferos/fisiologia , Infecções por Reoviridae/virologia , Estresse Fisiológico , Fator de Iniciação 2 em Eucariotos/metabolismo , Humanos , Terapia Viral Oncolítica , Fosforilação , Biossíntese de Proteínas , Capuzes de RNA/metabolismo , Infecções por Reoviridae/metabolismo
4.
Adv Exp Med Biol ; 1295: 317-325, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33543466

RESUMO

In the last decades, viruses have gained great interest in the field of immuno-oncology (I-O) for their ability of interacting both with the immune system and the tumour microenvironment. Those pathogens have naturally evolved and been evolutionary to specifically infect hosts, replicate, deliver their genome, and spread. These properties, initially considered a disadvantage, have been investigated and edited to turn viruses into precious allies for molecular biology serving as gene therapy vectors, adjuvants for the immune system, drug cargos, and, lately, anticancer therapeutics. As anticancer drug, one interesting option is viral engineering. Modification of either the viral genome or the outer shell of viruses can change infectivity and tissue targeting and add new functions to the viral particle. Remarkably, in the field of cancer virotherapy, scientists realized that a specific viral genomic depletion would turn the normal tropism of viruses to conditionally replicate in cancer cells only. This category of viruses, named 'Oncolytic viruses', have been investigated and used for cancer treatment in the past decades resulting in the approval of the first oncolytic virus, a herpes simplex virus expressing a stimulating factor, named T-Vec, in 2015. As such, oncolytic viruses achieved positive outcome but still are not able to completely eradicate the disease. This has brought the scientific community to edit those agents, adding to their ability to directly lysate cancer cells, few modifications to mainly boost their interaction with the immune system. Viruses experienced then a renaissance not only as infecting agent but as nanoparticle and cancer vaccines too. These strategies bring new life to the concept of using viruses as viral particles for therapeutic applications.


Assuntos
Vacinas Anticâncer , Nanopartículas , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Vacinas Anticâncer/uso terapêutico , Humanos , Neoplasias/terapia , Vírus Oncolíticos/genética , Simplexvirus , Microambiente Tumoral
5.
Adv Exp Med Biol ; 1290: 67-80, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33559855

RESUMO

The great hopes raised by the discovery of the immunoregulatory cytokine interleukin 12 (IL-12) as an anticancer agent were marred during early clinical experimentation because of severe adverse effects, which prompted a search for alternative formulations and routes of administration. Onco-immunotherapeutic viruses (OIVs) are wild-type or genetically engineered viruses that exert antitumor activity by causing death of the tumor cells they infect and by overcoming a variety of immunosuppressive mechanisms put in place by the tumors. OIVs have renewed the interest in IL-12, as they offer the opportunity to encode the cytokine transgenically from the viral genome and to produce it at high concentrations in the tumor bed. A large body of evidence indicates that IL-12 serves as a potent adjuvant for the immunotherapeutic response elicited by OIVs in murine tumor models. The list of OIVs includes onco-immunotherapeutic herpes simplex, adeno, measles, Newcastle disease, and Maraba viruses, among others. The large increase in IL-12-mediated adjuvanticity was invariably observed for all the OIVs analyzed. Indirect evidence suggests that locally delivered IL-12 may also increase tumor antigenicity. Importantly, the OIV/IL-12 treatment was not accompanied by adverse effects and elicited a long-lasting immune response capable of halting the growth of distant tumors. Thus, OIVs provide an avenue for reducing the clinical toxicity associated with systemic IL-12 therapy, by concentrating the cytokine at the site of disease. The changes to the tumor microenvironment induced by the IL-12-armed OIVs primed the tumors to an improved response to the checkpoint blockade therapy, suggesting that the triple combination is worth pursuing in the future. The highly encouraging results in preclinical models have prompted translation to the clinic. How well the IL-12-OIV-checkpoint inhibitors' combination will perform in humans remains to be fully investigated.


Assuntos
Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Humanos , Imunoterapia , Interleucina-12/genética , Camundongos , Vírus Oncolíticos/genética , Microambiente Tumoral
6.
Anticancer Res ; 41(2): 773-782, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517282

RESUMO

BACKGROUND/AIM: Oncolytic adenoviruses (OAds) have attracted much attention as novel anticancer therapeutics. The proper design of an expression cassette containing the E1A gene, which is indispensable for self-replication of the Ad genome, is crucial for efficient tumor cell-specific infection of an OAd. Various types of oncolytic adenoviruses (OAds) possessing different types of the E1A gene expression cassettes have been developed, but their oncolytic activities and safety profiles have not been systematically evaluated. Herein we examined the oncolytic activities and safety profiles of five types of OAds possessing different types of the E1A gene expression cassette in order to optimize the E1A gene expression cassette for development of an efficient and safe OAd. MATERIALS AND METHODS: We prepared five types of OAds containing different types of E1 gene expression cassettes, and examined the oncolytic activities and safety profiles of the OAds. RESULTS: Among the OAds examined, OAd-Δ24, which had a 24-bp deletion in the E1A gene, mediated the most efficient oncolytic activities against the human tumor cell lines, although OAd-Δ24 showed slightly higher cytotoxicity to normal human cells than the other OAds. CONCLUSION: These results provide important clues for the development of safe and efficient OAds.


Assuntos
Adenoviridae/fisiologia , Proteínas E1A de Adenovirus/genética , Deleção de Sequência , Survivina/genética , Telomerase/genética , Adenoviridae/genética , Apoptose , Linhagem Celular Tumoral , Expressão Gênica , Células HCT116 , Células HEK293 , Células HeLa , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Células MCF-7 , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Vírus Oncolíticos/fisiologia , Regiões Promotoras Genéticas , Replicação Viral
7.
Anticancer Res ; 41(2): 999-1004, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517307

RESUMO

BACKGROUND/AIM: Identification of predictors of survival of patients with lower genital tract melanoma (LGTM) and evaluation of the effectiveness of immunotherapy. PATIENTS AND METHODS: Data of twenty women with LGTM were retrospectively collected. Survival outcomes were evaluated using the Kaplan-Meier method. Survival distributions were analyzed using the Log rank test. RESULTS: Twenty patients with LGTM (6 vaginal/14 vulvar) were evaluated. Factors significantly affecting Five-year OS was the stage of the American Joint Committee on Cancer (AJCC 2017) (I+II: 55.6% vs. III+IV: 25.9%; p=0.030) and the T-Stage (I+II: 100% vs. III+IV: 7.5%; p=0.280). Factors negatively affecting Five-year PFS was T-Stage >II (p=0.005), AJCC stage >II (p<0.001), depth of tumor infiltration >3 mm (p=0.008), nodal involvement (p=0.013), distant disease (p=0.002), and resection margins <10 mm (p=0.024). Nine patients received immunotherapy [median duration of response (DOR)=4 months]. Three patients received immuno- and radiation therapy (median DOR of 5 months). Two patients received T-VEC, only one responded. CONCLUSION: Surgery has a therapeutic effect in early stage LGTM. Advanced stages may be treated with immunotherapy, radiation therapy, a combination of both, and oncolytic viral immunotherapy.


Assuntos
Terapia Combinada/métodos , Melanoma/terapia , Neoplasias Vaginais/terapia , Neoplasias Vulvares/terapia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Terapia Combinada/mortalidade , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Imunoterapia , Estimativa de Kaplan-Meier , Margens de Excisão , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Vírus Oncolíticos/fisiologia , Radioterapia , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias Vaginais/mortalidade , Neoplasias Vaginais/patologia , Neoplasias Vulvares/mortalidade , Neoplasias Vulvares/patologia
8.
Int J Mol Sci ; 22(2)2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33477279

RESUMO

Oncolytic virotherapy is one of the most promising, emerging cancer therapeutics. We generated three types of telomerase-specific replication-competent oncolytic adenovirus: OBP-301; a green fluorescent protein (GFP)-expressing adenovirus, OBP-401; and Killer-Red-armed OBP-301. These oncolytic adenoviruses are driven by the human telomerase reverse transcriptase (hTERT) promoter; therefore, they conditionally replicate preferentially in cancer cells. Fluorescence imaging enables visualization of invasion and metastasis in vivo at the subcellular level; including molecular dynamics of cancer cells, resulting in greater precision therapy. In the present review, we focused on fluorescence imaging applications to develop precision targeting for oncolytic virotherapy. Cell-cycle imaging with the fluorescence ubiquitination cell cycle indicator (FUCCI) demonstrated that combination therapy of an oncolytic adenovirus and a cytotoxic agent could precisely target quiescent, chemoresistant cancer stem cells (CSCs) based on decoying the cancer cells to cycle to S-phase by viral treatment, thereby rendering them chemosensitive. Non-invasive fluorescence imaging demonstrated that complete tumor resection with a precise margin, preservation of function, and prevention of distant metastasis, was achieved with fluorescence-guided surgery (FGS) with a GFP-reporter adenovirus. A combination of fluorescence imaging and laser ablation using a KillerRed-protein reporter adenovirus resulted in effective photodynamic cancer therapy (PDT). Thus, imaging technology and the designer oncolytic adenoviruses may have clinical potential for precise cancer targeting by indicating the optimal time for administering therapeutic agents; accurate surgical guidance for complete resection of tumors; and precise targeted cancer-specific photosensitization.


Assuntos
Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Terapia Viral Oncolítica/tendências , Adenoviridae/genética , Animais , Antineoplásicos , Linhagem Celular Tumoral , Fluorescência , Proteínas de Fluorescência Verde/metabolismo , Humanos , Neoplasias/virologia , Vírus Oncolíticos/genética , Imagem Óptica/métodos , Medicina de Precisão/métodos , Regiões Promotoras Genéticas/genética , Telomerase/genética , Telomerase/metabolismo
9.
Anticancer Res ; 41(1): 81-89, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419801

RESUMO

BACKGROUND/AIM: Breast cancer is the most common cancer in women worldwide, and triple-negative breast cancer (TNBC) is highly refractory to current standard therapies. Oncolytic virotherapy has recently gathered attention as a new treatment candidate for refractory cancers. MATERIALS AND METHODS: We previously developed a new Coxsackievirus B3 (CVB3) virotherapy targeting lung cancers, and demonstrated that miRNA target sequence insertion into CVB3 reduced its pathogenicity, retaining its original oncolytic activity. In this study, we examined the oncolytic effects of CVB3 against breast cancer cells including TNBC cells. RESULTS: CVB3 infection killed breast cancer cells in a time- and titer-dependent manner, and induced apoptosis. Nude mice transplanted with human TNBC cells were successfully treated with both CVB3-WT and CVB3-HP. Importantly, mice treated with CVB3-HP showed very few adverse events. CONCLUSION: CVB3-HP is a strong oncolytic virus candidate for breast cancer, including TNBC, due to its remarkable oncolytic efficacy and improved safety profile.


Assuntos
Neoplasias da Mama/genética , Enterovirus Humano B/genética , Terapia Genética , Vetores Genéticos/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Animais , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Células Cultivadas , Efeito Citopatogênico Viral , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Expressão Gênica , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/efeitos adversos , Humanos , Imuno-Histoquímica , Camundongos , Terapia Viral Oncolítica/métodos , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Methods Mol Biol ; 2225: 63-75, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33108657

RESUMO

Myxoma virus (MYXV) has proven to be an effective candidate for oncolytic virotherapy in many preclinical cancer models. As a nonhuman pathogen, MYXV does not need to overcome any preexisting antiviral immunity, and its DNA cannot integrate into the host genome, making it an extremely safe vector. Moreover, the large dsDNA genome of MYXV allows the insertion of multiple transgenes and the design of engineered recombinant oncolytic viruses (OVs) with enhanced immunostimulatory or other desired properties. In this chapter, we describe detailed protocols for the generation and characterization of transgene-armed recombinant MYXV vectors.


Assuntos
Engenharia Genética/métodos , Genoma Viral , Myxoma virus/genética , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Animais , Chlorocebus aethiops , Clonagem Molecular/métodos , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Myxoma virus/metabolismo , Vírus Oncolíticos/metabolismo , Plasmídeos/química , Plasmídeos/metabolismo , Coelhos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Transgenes , Células Vero
11.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333826

RESUMO

The epidermal growth factor receptor (EGFR) plays a central role in the progression of many solid tumors. We used this validated target to analyze the de novo design of EGFR-binding peptides and their application for the delivery of complex payloads via rational design of a viral vector. Peptides were computationally designed to interact with the EGFR dimerization interface. Two new peptides and a reference (EDA peptide) were chemically synthesized, and their binding ability characterized. Presentation of these peptides in each of the 60 capsid proteins of recombinant adeno-associated viruses (rAAV) via a genetic based loop insertion enabled targeting of EGFR overexpressing tumor cell lines. Furthermore, tissue distribution and tumor xenograft specificity were analyzed with systemic injection in chicken egg chorioallantoic membrane (CAM) assays. Complex correlations between the targeting of the synthetic peptides and the viral vectors to cells and in ovo were observed. Overall, these data demonstrate the potential of computational design in combination with rational capsid modification for viral vector targeting opening new avenues for viral vector delivery and specifically suicide gene therapy.


Assuntos
Dependovirus/metabolismo , Vírus Oncolíticos/química , Peptídeos/química , Engenharia de Proteínas/métodos , Animais , Capsídeo/química , Capsídeo/metabolismo , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Linhagem Celular Tumoral , Embrião de Galinha , Membrana Corioalantoide/metabolismo , Dicroísmo Circular , Biologia Computacional , Dependovirus/química , Dimerização , Receptores ErbB/química , Receptores ErbB/genética , Receptores ErbB/metabolismo , Terapia Genética , Vetores Genéticos , Humanos , Microscopia de Fluorescência , Vírus Oncolíticos/genética , Vírus Oncolíticos/metabolismo , Peptídeos/síntese química , Ligação Proteica , Transplante Heterólogo , Regulação para Cima , Cicatrização/efeitos dos fármacos
12.
Cell Death Dis ; 11(12): 1062, 2020 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-33311488

RESUMO

Reversing the highly immunosuppressive tumor microenvironment (TME) is essential to achieve long-term efficacy with cancer immunotherapy. Despite the impressive clinical response to checkpoint blockade in multiple types of cancer, only a minority of patients benefit from this approach. Here, we report that the oncolytic virus M1 induces immunogenic tumor cell death and subsequently restores the ability of dendritic cells to prime antitumor T cells. Intravenous injection of M1 disrupts immune tolerance in the privileged TME, reprogramming immune-silent (cold) tumors into immune-inflamed (hot) tumors. M1 elicits potent CD8+ T cell-dependent therapeutic effects and establishes long-term antitumor immune memory in poorly immunogenic tumor models. Pretreatment with M1 sensitizes refractory tumors to subsequent checkpoint blockade by boosting T-cell recruitment and upregulating the expression of PD-L1. These findings reveal the antitumor immunological mechanism of the M1 virus and indicated that oncolytic viruses are ideal cotreatments for checkpoint blockade immunotherapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Vírus Oncolíticos/metabolismo , Linfócitos T/imunologia , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Morte Celular Imunogênica/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Inflamação/genética , Injeções Intravenosas , Camundongos Endogâmicos C57BL , Vírus Oncolíticos/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
13.
Anticancer Res ; 40(11): 6319-6325, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109569

RESUMO

BACKGROUND: Attempts have been made to enhance systemic therapy for osteosarcoma. In our previous study, the systemic administration of a vesicular stomatitis virus (VSV) improved the survival rates of mice with osteosarcoma but did not improve the long-term survival of the animals. MATERIALS AND METHODS: In the present study, we developed a novel oncolytic VSV by incorporating tumor-suppressor microRNA143 (rVSV-miR143) to compare the antitumor effects of various doses (10×10-4, 5×10-4, and 1×10-4 multiplicity of infection) of rVSV-miR143 with those of VSV in vitro. RESULTS: The cytotoxicity and migration-inhibitory effects of rVSV-miR143 on the osteosarcoma cells were significantly higher than those of VSV alone at a dose of 5×10-4 multiplicity of infection, indicating that rVSV-miRNA143 enhances the antitumor effect at certain doses. CONCLUSION: VSV incorporating tumor-suppressor miRNA143 demonstrated a synergistic antitumor effect on osteosarcoma cells in vitro.


Assuntos
Genes Supressores de Tumor , MicroRNAs/genética , Vírus Oncolíticos/genética , Recombinação Genética/genética , Vírus da Estomatite Vesicular Indiana/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , MicroRNAs/metabolismo , Terapia Viral Oncolítica , Osteossarcoma/genética , Osteossarcoma/patologia
14.
Sheng Wu Gong Cheng Xue Bao ; 36(7): 1269-1276, 2020 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-32748584

RESUMO

Human adenoviruses are widespread causative agent that induces respiratory diseases, epidemic keratoconjunctivitis and other related diseases. Adenoviruses are commonly used in experimental and clinical areas. It is one of the most commonly used virus vectors in gene therapy, and it has attracted a lot of attention and has a high research potential in tumor gene therapy and virus oncolytic. Here, we summarize the biological characteristics, epidemiology and current application of adenovirus, in order to provide reference for engineering application of adenovirus.


Assuntos
Adenovírus Humanos , Vetores Genéticos , Terapia Viral Oncolítica , Vírus Oncolíticos , Infecções por Adenovirus Humanos/epidemiologia , Infecções por Adenovirus Humanos/virologia , Adenovírus Humanos/genética , Engenharia Genética/métodos , Engenharia Genética/tendências , Humanos , Terapia Viral Oncolítica/tendências , Vírus Oncolíticos/genética , Replicação Viral
15.
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
16.
PLoS One ; 15(7): e0235356, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628693

RESUMO

As a new class of cancer therapeutic agents, oncolytic viruses (OVs) have gained much attention not only due to their ability to selectively replicate in and lyse tumor cells, but also for their potential to stimulate antitumor immune responses. As a result, there is an increasing need for in vitro modeling systems capable of recapitulating the 3D physiological tumor microenvironment. Here, we investigated the potential of our recently developed microphysiological system (MPS), featuring a vessel-like channel to reflect the in vivo tumor microenvironment and serving as culture spaces for 3D multicellular tumor spheroids (MCTSs). The MCTSs consist of cancer A549 cells, stromal MRC5 cells, endothelial HUVECs, as well as the extracellular matrix. 3D MCTSs residing in the MPS were infected with oncolytic VSV expressing GFP (oVSV-GFP). Post-infection, GFP signal intensity increased only in A549 cells of the MPS. On the other hand, HUVECs were susceptible to virus infection under 2D culture and IFN-ß secretion was quite delayed in HUVECs. These results thus demonstrate that OV antitumoral characteristics can be readily monitored in the MPS and that its behavior therein somewhat differs compared to its activity in 2D system. In conclusion, we present the first application of the MPS, an in vitro model that was developed to better reflect in vivo conditions. Its various advantages suggest the 3D MCTS-integrated MPS can serve as a first line monitoring system to validate oncolytic virus efficacy.


Assuntos
Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/imunologia , Vesiculovirus/imunologia , Células A549 , Técnicas de Cultura de Células/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Matriz Extracelular , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias/imunologia , Vírus Oncolíticos/genética , Esferoides Celulares , Vesiculovirus/genética
17.
Nat Commun ; 11(1): 3187, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581235

RESUMO

The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified T cells, to solid tumors requires combinatorial strategies to overcome immune suppression associated with the tumor microenvironment. Here we test whether the inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment may help to recruit and potentiate the functionality of CAR T cells. Contrary to our hypothesis, VSVmIFNß infection is associated with attrition of murine EGFRvIII CAR T cells in a B16EGFRvIII model, despite inducing a robust proinflammatory shift in the chemokine profile. Mechanistically, type I interferon (IFN) expressed following infection promotes apoptosis, activation, and inhibitory receptor expression, and interferon-insensitive CAR T cells enable combinatorial therapy with VSVmIFNß. Our study uncovers an unexpected mechanism of therapeutic interference, and prompts further investigation into the interaction between CAR T cells and oncolytic viruses to optimize combination therapy.


Assuntos
Imunoterapia Adotiva , Interferon beta/metabolismo , Vírus Oncolíticos/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Terapia Combinada , Feminino , Interferon beta/genética , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Baço/imunologia
20.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188385, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32554098

RESUMO

As a promising area of tumor treatment, immunotherapies, such as immune checkpoint inhibitors, have been applied to various types of cancer. However, many patients do not respond to such therapies. Increasing application of tumor ablation therapy, a minimally invasive treatment, has been observed in the clinic. Although it can boost the anti-tumor immune response of patients in many ways, ablation alone is not sufficient to remove the tumor completely or stop tumor recurrence in the long term. Currently, there is emerging research focusing on ablation in combination with immunotherapy, aiming to confirm the therapeutic value of this treatment for cancer patients. Hence, in this article, we review the classification, guideline recommendations, and immunomodulatory effects of ablation therapy, as well as the pre-clinical and clinical research of this combination therapy.


Assuntos
Técnicas de Ablação/métodos , Antineoplásicos Imunológicos/uso terapêutico , Hipertermia Induzida/métodos , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Técnicas de Ablação/normas , Animais , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Terapia Combinada/normas , Modelos Animais de Doenças , Humanos , Hipertermia Induzida/normas , Neoplasias/imunologia , Terapia Viral Oncolítica/normas , Vírus Oncolíticos/imunologia , Guias de Prática Clínica como Assunto , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento
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