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1.
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
2.
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
3.
Medicine (Baltimore) ; 98(45): e17883, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702662

RESUMO

RATIONALE: Of all the parts of the larynx, the glottis has the highest frequency of cancer. With disease progression, the vocal cord movement is affected and for advanced stages its anatomical and functional preservation is rarely achievable, if at all. PATIENT CONCERNS: Here we describe a 72-year-old patient who presented with hoarseness for a year and was only able to whisper. DIAGNOSIS: A computed tomography (CT) scan of the vocal cords (without contrast) showed higher density tissue. Histological examination disclosed a well-differentiated verrucous squamous cell carcinoma of the glottis. INTERVENTIONS: The patient was treated with the oncolytic ECHO-7 virus Rigvir without any of the standard treatments. OUTCOMES: As shown by CT scans, the patient has been stabilized, and the laryngeal functions are preserved with the virotherapy still ongoing. The patient was diagnosed over 4.2 years ago. LESSONS: Considering the present patient being treated with Rigvir without any standard treatment, the results suggest that Rigvir therapy could be a possible treatment for glottic cancer.


Assuntos
Neoplasias Laríngeas/terapia , Terapia Viral Oncolítica/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Idoso , Glote/diagnóstico por imagem , Glote/patologia , Humanos , Neoplasias Laríngeas/diagnóstico por imagem , Neoplasias Laríngeas/patologia , Masculino , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
4.
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
5.
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
6.
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
7.
J Exp Clin Cancer Res ; 38(1): 408, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533779

RESUMO

BACKGROUND: Replication-competent oncolytic viruses (OVs) have been proven to be a potent anticancer weapon for clinical therapy. The preexisting neutralizing antibody in patients is a big challenge for oncolytic efficacy of OVs. Graphene oxide sheets (GOS) possess excellent biological compatibility and are easy to decorate for targeted delivery. METHODS: We generated PEI-GOS-PEG-FA (Polyethyleneimine-Graphene oxide sheets-Polyethylene glycol-Folic acid). After intravenous injection, the distribution of PEI-GOS-PEG-FA in tumor-bearing mice was visualized by the IVIS Lumina XR system. Then, the oncolytic measles virus (MV-Edm) was coated with PEI-GOS-PEG-FA to form a viral-GOS complex (GOS/MV-Edm). The oncolytic effects of GOS/MV-Edm were investigated both in vitro and in vivo. RESULTS: GOS/MV-Edm exhibited higher infectivity and enhanced oncolysis. In tumor-bearing mice, GOS/MV-Edm had significantly elevated viral replication within the tumor mass, and achieved an improved antitumor effect. Then, we confirmed that GOS/MV-Edm entered cancer cells via the folate receptor instead of CD46, a natural cognate receptor of MV-Edm. GOS/MV-Edm remained the infectivity in murine cells that lack CD46. Finally, we found that GOS/MV-Edm was effectively protected from neutralization in the presence of antiserum both in vitro and in vivo. In passively antiserum immunized tumor-bearing mice, the survival was remarkably improved with intravenous injection of GOS/MV-Edm. CONCLUSION: Our findings demonstrate that GOS/MV-Edm displays significantly elevated viral replication within the tumor mass, leading to an improved antitumor effect in solid tumor mouse model. Our study provided a novel strategy to arm OVs for more efficient cancer therapy. That may become a promising therapeutic strategy for cancer patients.


Assuntos
Grafite/química , Vírus do Sarampo , Nanopartículas/administração & dosagem , Nanopartículas/química , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Células A549 , Animais , Ácido Fólico/química , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Nus , Polietilenoglicóis/química , Ensaios Antitumorais Modelo de Xenoenxerto
8.
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
9.
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
10.
World J Gastroenterol ; 25(29): 3920-3928, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31413527

RESUMO

In contrast to other tumor types, immunotherapy has not yet become a relevant part of the treatment landscape of unselected colorectal cancer. Beside the small subgroup of deficient mismatch repair or microsatellite instable tumors (about 5%) as a surrogate for high mutational burden and subsequently high neoantigen load and immunogenicity, inhibitors of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) and/or cytotoxic T lymphocyte-associated antigen-4 were not or only modestly effective in metastatic colorectal cancer. Thus, a variety of combination approaches with chemotherapy, targeted therapy, toll-like receptor agonists, local ablation or oncolytic viruses is currently being evaluated in different disease settings. Despite several encouraging single arm data already presented or published, available randomized data are unimpressive. Adding PD-1/PD-L1 inhibitors to fluoropyrimidines and bevacizumab maintenance showed no beneficial impact on delaying progression. In refractory disease, the combination of PD-1/PD-L1 and MEK inhibitor was not different from regorafenib, whereas a PD-1/PD-L1 and cytotoxic T lymphocyte-associated antigen-4 inhibitor combination demonstrated better overall survival compared to supportive care alone. Clinical trials in all disease settings applying different combination approaches are ongoing and may define the role of immunotherapy in colorectal cancer.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/terapia , Imunoterapia/métodos , Terapia Viral Oncolítica/métodos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Ensaios Clínicos como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Terapia Combinada/métodos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Instabilidade de Microssatélites , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptores Toll-Like/agonistas , Receptores Toll-Like/imunologia , Resultado do Tratamento
11.
World J Gastroenterol ; 25(24): 2977-2989, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31293335

RESUMO

Hepatocellular carcinoma (HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However, there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy, either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.


Assuntos
Carcinoma Hepatocelular/terapia , Imunoterapia/métodos , Neoplasias Hepáticas/terapia , Antineoplásicos Imunológicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Carcinoma Hepatocelular/imunologia , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Terapia Combinada/tendências , Humanos , Imunoterapia/tendências , Neoplasias Hepáticas/imunologia , Terapia Viral Oncolítica/métodos , Terapia Viral Oncolítica/tendências , Resultado do Tratamento
12.
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
13.
Nat Rev Drug Discov ; 18(9): 689-706, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31292532

RESUMO

In the wake of the success of modern immunotherapy, oncolytic viruses (OVs) are currently seen as a potential therapeutic option for patients with cancer who do not respond or fail to achieve durable responses following treatment with immune checkpoint inhibitors. OVs offer a multifaceted therapeutic platform because they preferentially replicate in tumour cells, can be engineered to express transgenes that augment their cytotoxic and immunostimulatory activities, and modulate the tumour microenvironment to optimize immune-mediated tumour eradication, both at locoregional and systemic sites of disease. Lysis of tumour cells releases tumour-specific antigens that trigger both the innate and adaptive immune systems. OVs also represent attractive combination partners with other systemically delivered agents by virtue of their highly favourable safety profiles. Rational combinations of OVs with different immune modifiers and/or antitumour agents, based on mechanisms of tumour resistance to immune-mediated attack, may benefit the large, currently underserved, population of patients who respond poorly to immune checkpoint inhibition.


Assuntos
Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Neoplasias/tratamento farmacológico
14.
J Surg Oncol ; 120(3): 558-564, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31264725

RESUMO

BACKGROUND AND OBJECTIVES: Patients with in-transit or limited cutaneous metastatic melanoma may benefit from intralesional injections with talimogene laherparepvec (TVEC), a modified oncolytic herpesvirus. However, its use in patients with adverse prognostic scores in a real-life clinical setting has not been studied. METHODS: We performed a two-center retrospective analysis of 40 patients with metastatic melanoma treated with TVEC from 2015-2017. Demographics, overall response, and survival after therapy were noted. RESULTS: Overall, there was a durable response rate of 40%; median progression-free survival (PFS) was 10.5 months and median overall survival (OS) was not reached. Bulky disease was associated with decreased OS (15.7 months vs not reached, P < .05) and mPFS (2.3 months vs not reached, P < .05), when compared with smaller tumors. Poor performance status (ECOG 2-3) was associated with worse OS (10.2 months vs not reached, P < .05) and PFS (2.1 months vs not reached, P < .05) compared to patients with ECOG 0-1. There was no difference in the outcomes with age greater than 75 or with prior therapies. Adverse events were relatively tolerable. CONCLUSIONS: These findings demonstrate that TVEC is an effective and safe treatment for metastatic melanoma in a real-life clinical setting, and suggest parameters to aid in appropriate therapy selection for optimal response.


Assuntos
Herpesviridae/fisiologia , Melanoma/terapia , Terapia Viral Oncolítica/métodos , Neoplasias Cutâneas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Melanoma/virologia , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Cutâneas/virologia , Taxa de Sobrevida
15.
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
16.
BioDrugs ; 33(5): 485-501, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321623

RESUMO

New immuno-oncology therapies are improving cancer treatments beyond the former standard of care, as evidenced by the recent and continuing clinical approvals for immunotherapies in a broad range of indications. However, a majority of patients (particularly those with immunologically cold tumors) still do not benefit, highlighting the need for rational combination approaches. Oncolytic viruses (OV) both directly kill tumor cells and inflame the tumor microenvironment. While OV spread can be limited by the generation of antiviral immune responses, the initial local tumor cell killing can reverse the immunosuppressive tumor microenvironment, resulting in more effective release of tumor-associated antigens (TAAs), cross-presentation, and antitumoral effector T cell recruitment. Moreover, many OVs can be engineered to express immunomodulatory genes. Rational combination approaches to cancer immunotherapy include the use of OVs in combination with immune checkpoint inhibitors (ICIs) or adoptive T cell therapy (ACT) to promote sustained antitumoral immune responses. OV combinations have additive or synergistic efficacy in preclinical tumor models with ICIs or ACT. Several preclinical studies have confirmed systemic reactivation and proliferation of adoptively transferred antitumoral T cells in conjunction with oncolytic OVs (expressing cytokines or TAAs) resulting from the specific tumor cell killing and immunostimulation of the tumor microenvironment which leads to increased tumor trafficking, activity, and survival. Recent clinical trials combining OVs with ICIs have shown additive effects in melanoma. Additional clinical data in an expanded range of patient indications are eagerly awaited. The relative timings of OV and ICI combination remains under-studied and is an area for continued exploration. Studies systematically exploring the effects of systemic ICIs prior to, concomitantly with, or following OV therapy will aid in the future design of clinical trials to enhance efficacy and increase patient response rates.


Assuntos
Neoplasias/imunologia , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Transferência Adotiva , Animais , Ensaios Clínicos como Assunto , Humanos , Imunoterapia/métodos , Vírus Oncolíticos , Linfócitos T/transplante , Microambiente Tumoral/imunologia
17.
Mar Drugs ; 17(6)2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31248066

RESUMO

Lectins display a variety of biological functions including insecticidal, antimicrobial, as well as antitumor activities. In this report, a gene encoding Aphrocallistes vastus lectin (AVL), a C-type lectin, was inserted into an oncolytic vaccinia virus vector (oncoVV) to form a recombinant virus oncoVV-AVL, which showed significant in vitro antiproliferative activity in a variety of cancer cell lines. Further investigations revealed that oncoVV-AVL replicated faster than oncoVV significantly in cancer cells. Intracellular signaling elements including NF-κB2, NIK, as well as ERK were determined to be altered by oncoVV-AVL. Virus replication upregulated by AVL was completely dependent on ERK activity. Furthermore, in vivo studies showed that oncoVV-AVL elicited significant antitumor effect in colorectal cancer and liver cancer mouse models. Our study might provide insights into a novel way of the utilization of marine lectin AVL in oncolytic viral therapies.


Assuntos
Antineoplásicos/farmacologia , Lectinas/genética , Lectinas/farmacologia , Vírus Oncolíticos/genética , Poríferos/genética , Vírus Vaccinia/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Feminino , Células HCT116 , Células HEK293 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia Viral Oncolítica/métodos , Transdução de Sinais/efeitos dos fármacos , Replicação Viral/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
18.
Bull Exp Biol Med ; 167(1): 111-115, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31177454

RESUMO

Rat glioma cell line C6 expressing human poliovirus receptor (PVR) and susceptible to polioviruses (C6-PVR-BFP) was used to produce a clone with knockout of IFNα/ß (Ifnar1) receptor subunit 1 gene (Ifnar1). The sensitivity of C6-PVR-BFP cells to the vaccine strain of poliovirus type 3 (PV3) depended on the signaling pathways of the cell response to type 1 IFN. Using the model of subcutaneous tumor xenografts, we demonstrated oncolytic activity of PV3 against C6-PVR-BFP cells that depended on the expression of PVR and increased considerably upon disturbances in IFN response pathways.


Assuntos
Glioma/terapia , Glioma/virologia , Terapia Viral Oncolítica/métodos , Poliovirus/fisiologia , Animais , Linhagem Celular Tumoral , Glioma/metabolismo , Interferon-alfa/genética , Interferon beta/genética , Camundongos , Vírus Oncolíticos/fisiologia , Ratos , Ratos Mutantes , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo
19.
Mayo Clin Proc ; 94(9): 1834-1839, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31235278

RESUMO

Recent measles epidemics in US and European cities where vaccination coverage has declined are providing a harsh reminder for the need to maintain protective levels of immunity across the entire population. Vaccine uptake rates have been declining in large part because of public misinformation regarding a possible association between measles vaccination and autism for which there is no scientific basis. The purpose of this article is to address a new misinformed antivaccination argument-that measles immunity is undesirable because measles virus is protective against cancer. Having worked for many years to develop engineered measles viruses as anticancer therapies, we have concluded (1) that measles is not protective against cancer and (2) that its potential utility as a cancer therapy will be enhanced, not diminished, by prior vaccination.


Assuntos
Comunicação , Vírus do Sarampo/imunologia , Sarampo/epidemiologia , Sarampo/prevenção & controle , Terapia Viral Oncolítica/métodos , Vacinação/efeitos adversos , Criança , Pré-Escolar , Controle de Doenças Transmissíveis/organização & administração , Europa (Continente) , Feminino , Humanos , Masculino , Prevalência , Medição de Risco , Estados Unidos , Vacinação/métodos
20.
Arch Virol ; 164(7): 1805-1814, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31087190

RESUMO

The recombinant vaccinia virus VG9 and the STAT3 inhibitor Stattic were combined to kill cancer cells via both oncolytic activity and inhibition of STAT3 phosphorylation in cells. The combinatory anti-tumour activity of these compounds was superior to the activity of VG9 or Stattic alone in vivo. The inhibition of tumour growth occurred via increased apoptosis and autophagy pathways. Furthermore, the combinatory anti-tumour activity was more efficient than that of VG9 or Stattic alone on xenografts, especially in nude mice.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Óxidos S-Cíclicos/farmacologia , Neoplasias/terapia , Vírus Oncolíticos/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Vírus Vaccinia/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia Viral Oncolítica/métodos , Fosforilação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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