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1.
Cell ; 170(6): 1109-1119.e10, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28886381

RESUMO

Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression, as well as IFN-γ gene expression on several cell subsets in tumors after talimogene laherparepvec treatment. Response to combination therapy did not appear to be associated with baseline CD8+ T cell infiltration or baseline IFN-γ signature. These findings suggest that oncolytic virotherapy may improve the efficacy of anti-PD-1 therapy by changing the tumor microenvironment. VIDEO ABSTRACT.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Melanoma/terapia , Terapia Viral Oncolítica/efeitos adversos , Terapia Combinada , Herpesviridae/genética , Humanos , Imunoterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral
2.
J Virol ; 98(3): e0189723, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38411946

RESUMO

Ferroptosis, a form of programmed cell death characterized by iron-dependent lipid peroxidation, has recently gained considerable attention in the field of cancer therapy. There is significant crosstalk between ferroptosis and several classical signaling pathways, such as the Hippo pathway, which suppresses abnormal growth and is frequently aberrant in tumor tissues. Yes-associated protein 1 (YAP), the core effector molecule of the Hippo pathway, is abnormally expressed and activated in a variety of malignant tumor tissues. We previously proved that the oncolytic Newcastle disease virus (NDV) activated ferroptosis to kill tumor cells. NDV has been used in tumor therapy; however, its oncolytic mechanism is not completely understood. In this study, we demonstrated that NDV exacerbated ferroptosis in tumor cells by inducing ubiquitin-mediated degradation of YAP at Lys90 through E3 ubiquitin ligase parkin (PRKN). Blocking YAP degradation suppressed NDV-induced ferroptosis by suppressing the expression of Zrt/Irt-like protein 14 (ZIP14), a metal ion transporter that regulates iron uptake. These findings demonstrate that NDV exacerbated ferroptosis in tumor cells by inducing YAP degradation. Our study provides new insights into the mechanism of NDV-induced ferroptosis and highlights the critical role that oncolytic viruses play in the treatment of drug-resistant cancers.IMPORTANCEThe oncolytic Newcastle disease virus (NDV) is being developed for use in cancer treatment; however, its oncolytic mechanism is still not completely understood. The Hippo pathway, which is a tumor suppressor pathway, is frequently dysregulated in tumor tissues due to aberrant yes-associated protein 1 (YAP) activation. In this study, we have demonstrated that NDV degrades YAP to induce ferroptosis and promote virus replication in tumor cells. Notably, NDV was found to induce ubiquitin-mediated degradation of YAP at Lys90 through E3 ubiquitin ligase parkin (PRKN). Our study reveals a new mechanism by which NDV induces ferroptosis and provides new insights into NDV as an oncolytic agent for cancer treatment.


Assuntos
Ferroptose , Neoplasias , Vírus da Doença de Newcastle , Terapia Viral Oncolítica , Proteínas de Sinalização YAP , Animais , Humanos , Proteínas Adaptadoras de Transdução de Sinal , Linhagem Celular Tumoral , Ferro , Neoplasias/terapia , Vírus Oncolíticos/fisiologia , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases , Ubiquitinas
3.
Breast Cancer Res ; 26(1): 78, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750591

RESUMO

BACKGROUND: Metastatic breast cancer is a leading cause of cancer death in woman. Current treatment options are often associated with adverse side effects and poor outcomes, demonstrating the need for effective new treatments. Immunotherapies can provide durable outcomes in many cancers; however, limited success has been achieved in metastatic triple negative breast cancer. We tested whether combining different immunotherapies can target metastatic triple negative breast cancer in pre-clinical models. METHODS: Using primary and metastatic 4T1 triple negative mammary carcinoma models, we examined the therapeutic effects of oncolytic vesicular stomatitis virus (VSVΔM51) engineered to express reovirus-derived fusion associated small transmembrane proteins p14 (VSV-p14) or p15 (VSV-p15). These viruses were delivered alone or in combination with natural killer T (NKT) cell activation therapy mediated by adoptive transfer of α-galactosylceramide-loaded dendritic cells. RESULTS: Treatment of primary 4T1 tumors with VSV-p14 or VSV-p15 alone increased immunogenic tumor cell death, attenuated tumor growth, and enhanced immune cell infiltration and activation compared to control oncolytic virus (VSV-GFP) treatments and untreated mice. When combined with NKT cell activation therapy, oncolytic VSV-p14 and VSV-p15 reduced metastatic lung burden to undetectable levels in all mice and generated immune memory as evidenced by enhanced in vitro recall responses (tumor killing and cytokine production) and impaired tumor growth upon rechallenge. CONCLUSION: Combining NKT cell immunotherapy with enhanced oncolytic virotherapy increased anti-tumor immune targeting of lung metastasis and presents a promising treatment strategy for metastatic breast cancer.


Assuntos
Células T Matadoras Naturais , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Feminino , Camundongos , Células T Matadoras Naturais/imunologia , Terapia Viral Oncolítica/métodos , Humanos , Linhagem Celular Tumoral , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Imunoterapia/métodos , Vírus da Estomatite Vesicular Indiana/genética , Vírus da Estomatite Vesicular Indiana/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Terapia Combinada , Metástase Neoplásica , Vesiculovirus/genética , Células Dendríticas/imunologia , Neoplasias da Mama/terapia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Modelos Animais de Doenças
4.
Curr Issues Mol Biol ; 46(6): 5582-5594, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38921005

RESUMO

The recent success of cancer immunotherapies, such as immune checkpoint inhibitor (ICIs), monoclonal antibodies (mAbs), cancer vaccines, and adoptive cellular therapies (ACTs), has revolutionized traditional cancer treatment. However, these immunotherapeutic modalities have variable efficacies, and many of them exhibit adverse effects. Oncolytic viral Immunotherapy (OViT), whereby viruses are used to directly or indirectly induce anti-cancer immune responses, is emerging as a novel immunotherapy for treating patients with different types of cancer. The herpes simplex virus type-1 (HSV-1) possesses many characteristics that inform its use as an effective OViT agents and remains a leading candidate. Its recent clinical success resulted in the Food and Drug Administration (FDA) approval of Talimogene laherparevec (T-VEC or Imlygic) in 2015 for the treatment of advanced melanoma. In this review, we discuss recent advances in the development of oncolytic HSV-1-based OViTs, their anti-tumor mechanism of action, and efficacy data from recent clinical trials. We envision this knowledge may be used to inform the rational design and application of future oHSV in cancer treatment.

5.
J Virol ; 97(2): e0000923, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36744961

RESUMO

Mammalian orthoreovirus serotype 3 Dearing is an oncolytic virus currently undergoing multiple clinical trials as a potential cancer therapy. Previous clinical trials have emphasized the importance of prescreening patients for prognostic markers to improve therapeutic success. However, only generic cancer markers such as epidermal growth factor receptor (EGFR), Hras, Kras, Nras, Braf, and p53 are currently utilized, with limited benefit in predicting therapeutic efficacy. This study aimed to investigate the role of p38 mitogen-activated protein kinase (MAPK) signaling during reovirus infection. Using a panel of specific p38 MAPK inhibitors and an inactive inhibitor analogue, p38 MAPK signaling was found to be essential for establishment of reovirus infection by enhancing reovirus endocytosis, facilitating efficient reovirus uncoating at the endo-lysosomal stage, and augmenting postuncoating replication steps. Using a broad panel of human breast cancer cell lines, susceptibility to reovirus infection corresponded with virus binding and uncoating efficiency, which strongly correlated with status of the p38ß isoform. Together, results suggest p38ß isoform as a potential prognostic marker for early stages of reovirus infection that are crucial to successful reovirus infection. IMPORTANCE The use of Pelareorep (mammalian orthoreovirus) as a therapy for metastatic breast cancer has shown promising results in recent clinical trials. However, the selection of prognostic markers to stratify patients has had limited success due to the fact that these markers are upstream receptors and signaling pathways that are present in a high percentage of cancers. This study demonstrates that the mechanism of action of p38 MAPK signaling plays a key role in establishment of reovirus infection at both early entry and late replication steps. Using a panel of breast cancer cell lines, we found that the expression levels of the MAPK11 (p38ß) isoform are a strong determinant of reovirus uncoating and infection establishment. Our findings suggest that selecting prognostic markers that target key steps in reovirus replication may improve patient stratification during oncolytic reovirus therapy.


Assuntos
Neoplasias da Mama , Orthoreovirus Mamífero 3 , Infecções por Reoviridae , Internalização do Vírus , Proteínas Quinases p38 Ativadas por Mitógeno , Feminino , Humanos , Capsídeo/metabolismo , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Orthoreovirus Mamífero 3/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Replicação Viral , Linhagem Celular Tumoral
6.
J Med Virol ; 96(7): e29748, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38975633

RESUMO

Prostate cancer is a prevalent carcinoma among males, and conventional treatment options are often limited. Cytotoxic chemotherapy, despite its drawbacks, remains a mainstay. We propose a targeted co-delivery approach using nanoscale delivery units for Oncolytic measles virus (OMV) and vincristine (VC) to enhance treatment efficacy. The HA-coated OMV + VC-loaded TCs nanoformulation is designed for targeted oncolytic activity in prostate cancer. The CD44 expression analysis in prostate cancer cell lines indicates a significantly high expression in PC3 cells. The optimization of nanoformulations using Design of Expert (DOE) is performed, and the preparation and characterization of HA-coated OMV + VC-loaded TCs nanoformulations are detailed showing average particle size 397.2 ± 0.01 nm and polydispersity index 0.122 with zeta potential 19.7 + 0.01 mV. Results demonstrate successful encapsulation efficiency with 2.4 × 106 TCID50/Ml and sustained release of OMV and VC from the nanoformulation for up to 72 h. In vitro, assays reveal potent anticancer activity at 10 ± 0.71% cell viability in PC3 cells compared to 73 ± 0.66% in HPrEC and significant morphological changes at 90 µg/ml in dose and time-dependent manner. The co-formulation showed positive cell death 49.5 ± 0.02% at 50 µg PI/ml in PBS and 54.3% cell cycle arrest at the G2/M phase, 8.1% G0/G1 and 5.7% at S phase, with significant mitochondrial membrane potential (MMP) at 50 µg/ml, as assessed by flow cytometry (FACS). The surface-integrating ligand approach enhances the targeted delivery of the oncolytic virus and chemotherapeutic drug, presenting a potential alternative for prostate cancer treatment and suggested that co-administering VC and OMV in a nanoformulation could improve therapeutic outcomes while reducing chemotherapeutic drug doses.


Assuntos
Terapia Viral Oncolítica , Vírus Oncolíticos , Neoplasias da Próstata , Vincristina , Humanos , Masculino , Neoplasias da Próstata/terapia , Neoplasias da Próstata/tratamento farmacológico , Vincristina/farmacologia , Vincristina/administração & dosagem , Terapia Viral Oncolítica/métodos , Linhagem Celular Tumoral , Vírus do Sarampo/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Células PC-3
7.
Ann Surg Oncol ; 2024 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-39422848

RESUMO

BACKGROUND: Talimogene laherparapvec (T-VEC) is a modified herpes simplex virus type 1 (HSV-1) and the first oncolytic virus to be approved for the treatment of unresectable melanoma. We assessed whether there are tumor-intrinsic genetic factors that are associated with tumor control. METHODS: A single-institution, retrospective analysis of melanoma patients treated with T-VEC was performed. Demographics, histopathologic reports, treatment history, clinical outcomes, and tumor genomic analysis of approximately 100 genes were collected. RESULTS: Ninety-three patients who had received T-VEC were identified, of whom 84 (91%) were diagnosed with cutaneous melanoma. Sixty-nine (69) patients received more than one dose of T-VEC and had sufficient data available for clinical analysis. Of these patients 30.0% (n = 21) had evidence of a complete response, defined as complete regression of all lesions without the need for additional treatment or procedures. Stage III disease (p < 0.001), absence of macroscopic nodal disease (p < 0.001), and absence of visceral/central nervous system metastases (p = 0.004) were all associated with evidence of any clinical response or local control by univariate analysis. At the time of analysis, 54 patients had tumor genetic data available. Sixty genes were mutated in at least one patient, and all but one patient had at least one gene mutation identified. Presence of TERT promotor mutation was associated with evidence of any clinical response (p = 0.043) or local control (p = 0.039) by multivariate analysis. CONCLUSIONS: This work describes the experience using T-VEC in melanoma at a single institution and highlights the presence of TERT promotor mutations as a possible driver of clinical response.

8.
Cancer Cell Int ; 24(1): 50, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38291394

RESUMO

BACKGROUND: Although a combination of immune checkpoint inhibitors (ICIs) is recommended as the first line treatment option for metastatic renal cell carcinoma (mRCC), several immune-related adverse events (irAEs) occur, especially hepatitis. We explored the therapeutic benefits and safety profile of combining oncolytic vaccinia virus, JX-594, with a programmed cell death protein-1 (PD-1) inhibitor. METHODS: We used early-stage and advanced-stage orthotopic murine mRCC models developed by our group. PD-1 inhibitor monotherapy or a PD-1 inhibitor combined with either JX-594 or a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor were systemically injected through the peritoneum. An immunofluorescence analysis was performed to analyze the tumor immune microenvironment (TIME). irAEs were assessed in terms of hepatitis. RESULTS: In the early-stage mRCC model mice, the combination of JX-594 and a PD-1 inhibitor significantly decreased the primary tumor size and number of lung nodules, compared with the ICI combination, but the JX-594 and PD-1 inhibitor combination and ICI combination did not differ significantly in the advanced-stage mRCC model mice. The JX-594 and PD-1 inhibitor combination induced tumor-suppressing TIME changes in both the early- and advanced-stage mRCC models. Furthermore, mice treated with the ICI combination had significantly greater hepatic injuries than those treated with the JX-594 and PD-1 inhibitor combination which was evaluated in early-stage mRCC model. CONCLUSIONS: The JX-594 and PD-1 inhibitor combination effectively reduced primary tumors and the metastatic burden, similar to ICI combination therapy, through dynamic remodeling of the TIME. Furthermore, hepatitis was significantly decreased in the JX-594 and PD-1 inhibitor combination group, suggesting the potential benefit of that combination for reducing ICI-induced toxicity.

9.
Acta Pharmacol Sin ; 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39030309

RESUMO

Recombinant human type 5 adenovirus (H101) is an oncolytic virus used to treat nasopharyngeal carcinoma. Owing to the deletion of the E1B-55kD and E3 regions, H101 is believed to selectively inhibit nasopharyngeal carcinoma. Whether H101 inhibits other type of tumors via different mechanisms remains unclear. In this study we investigated the effects of H101 on melanomas. We established B16F10 melanoma xenograft mouse model, and treated the mice with H101 (1 × 108 TCID50) via intratumoral injection for five consecutive days. We found that H101 treatment significantly inhibited B16F10 melanoma growth in the mice. H101 treatment significantly increased the infiltration of CD8+ T cells and reduced the proportion of M2-type macrophages. We demonstrated that H101 exhibited low cytotoxicity against B16F10 cells, but the endothelial cells were more sensitive to H101 treatment. H101 induced endothelial cell pyroptosis in a caspase-1/GSDMD-dependent manner. Furthermore, we showed that the combination of H101 with the immune checkpoint inhibitor PD-L1 antibody (10 mg/kg, i.p., every three days for three times) exerted synergic suppression on B16F10 tumor growth in the mice. This study demonstrates that, in addition to oncolysis, H101 inhibits melanoma growth by promoting anti-tumor immunity and inducing pyroptosis of vascular endothelial cells.

10.
Mol Ther ; 31(11): 3127-3145, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37735876

RESUMO

In recent years, there has been a surge in the innovative modification and application of the viral vector-based gene therapy field. Significant and consistent improvements in the engineering, delivery, and safety of viral vectors have set the stage for their application as RNA interference (RNAi) delivery tools. Viral vector-based delivery of RNAi has made remarkable breakthroughs in the treatment of several debilitating diseases and disorders (e.g., neurological diseases); however, their novelty has yet to be fully applied and utilized for the treatment of cancer. This review highlights the most promising and emerging viral vector delivery tools for RNAi therapeutics while discussing the variables limiting their success and suitability for cancer therapy. Specifically, we outline different integrating and non-integrating viral platforms used for gene delivery, currently employed RNAi targets for anti-cancer effect, and various strategies used to optimize the safety and efficacy of these RNAi therapeutics. Most importantly, we provide great insight into what challenges exist in their application as cancer therapeutics and how these challenges can be effectively navigated to advance the field.


Assuntos
Vetores Genéticos , Neoplasias , Interferência de RNA , Vetores Genéticos/genética , Terapia Genética , Técnicas de Transferência de Genes , Neoplasias/genética , Neoplasias/terapia
11.
Cell Biochem Funct ; 42(4): e4055, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38856033

RESUMO

The heterogeneity of the solid tumor microenvironment (TME) impairs the therapeutic efficacy of standard therapies and also reduces the infiltration of antitumor immune cells, all of which lead to tumor progression and invasion. In addition, self-renewing cancer stem cells (CSCs) support tumor dormancy, drug resistance, and recurrence, all of which might pose challenges to the eradication of malignant tumor masses with current therapies. Natural forms of oncolytic viruses (OVs) or engineered OVs are known for their potential to directly target and kill tumor cells or indirectly eradicate tumor cells by involving antitumor immune responses, including enhancement of infiltrating antitumor immune cells, induction of immunogenic cell death, and reprogramming of cold TME to an immune-sensitive hot state. More importantly, OVs can target stemness factors that promote tumor progression, which subsequently enhances the efficacy of immunotherapies targeting solid tumors, particularly the CSC subpopulation. Herein, we describe the role of CSCs in tumor heterogeneity and resistance and then highlight the potential and remaining challenges of immunotherapies targeting CSCs. We then review the potential of OVs to improve tumor immunogenicity and target CSCs and finally summarize the challenges within the therapeutic application of OVs in preclinical and clinical trials.


Assuntos
Imunoterapia , Neoplasias , Células-Tronco Neoplásicas , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Células-Tronco Neoplásicas/imunologia , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Animais
12.
Int J Mol Sci ; 25(4)2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38396720

RESUMO

Glioblastoma is one of the most malignant and aggressive tumors of the central nervous system. Despite the standard therapy consisting of maximal surgical resection and chemo- and radiotherapy, the median survival of patients with this diagnosis is about 15 months. Oncolytic virus therapy is one of the promising areas for the treatment of malignant neoplasms. In this review, we have focused on emphasizing recent achievements in virotherapy, both as a monotherapy and in combination with other therapeutic schemes to improve survival rate and quality of life among patients with glioblastoma.


Assuntos
Glioblastoma , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Glioblastoma/patologia , Vírus Oncolíticos/genética , Qualidade de Vida
13.
Int J Mol Sci ; 25(18)2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39337402

RESUMO

Pancreatic cancer presents formidable challenges due to rapid progression and resistance to conventional treatments. Oncolytic viruses (OVs) selectively infect cancer cells and cause cancer cells to lyse, releasing molecules that can be identified by the host's immune system. Moreover, OV can carry immune-stimulatory payloads such as interleukin-12, which when delivered locally can enhance immune system-mediated tumor killing. OVs are very well tolerated by cancer patients due to their ability to selectively target tumors without affecting surrounding normal tissues. OVs have recently been combined with other therapies, including chemotherapy and immunotherapy, to improve clinical outcomes. Several OVs including adenovirus, herpes simplex viruses (HSVs), vaccinia virus, parvovirus, reovirus, and measles virus have been evaluated in preclinical and clinical settings for the treatment of pancreatic cancer. We evaluated the safety and tolerability of a replication-competent oncolytic adenoviral vector carrying two suicide genes (thymidine kinase, TK; and cytosine deaminase, CD) and human interleukin-12 (hIL12) in metastatic pancreatic cancer patients in a phase 1 trial. This vector was found to be safe and well-tolerated at the highest doses tested without causing any significant adverse events (SAEs). Moreover, long-term follow-up studies indicated an increase in the overall survival (OS) in subjects receiving the highest dose of the OV. Our encouraging long-term survival data provide hope for patients with advanced pancreatic cancer, a disease that has not seen a meaningful increase in OS in the last five decades. In this review article, we highlight several preclinical and clinical studies and discuss future directions for optimizing OV therapy in pancreatic cancer. We envision OV-based gene therapy to be a game changer in the near future with the advent of newer generation OVs that have higher specificity and selectivity combined with personalized treatment plans developed under AI guidance.


Assuntos
Terapia Viral Oncolítica , Vírus Oncolíticos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/imunologia , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Terapia Viral Oncolítica/métodos , Animais , Imunoterapia/métodos , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , Interleucina-12/genética , Terapia Combinada
14.
Int J Mol Sci ; 25(9)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38732225

RESUMO

Oncolytic viruses (OVs) are characterised by their preference for infecting and replicating in tumour cells either naturally or after genetic modification, resulting in oncolysis. Furthermore, OVs can elicit both local and systemic anticancer immune responses while specifically infecting and lysing tumour cells. These characteristics render them a promising therapeutic approach for paediatric brain tumours (PBTs). PBTs are frequently marked by a cold tumour immune microenvironment (TIME), which suppresses immunotherapies. Recent preclinical and clinical studies have demonstrated the capability of OVs to induce a proinflammatory immune response, thereby modifying the TIME. In-depth insights into the effect of OVs on different cell types in the TIME may therefore provide a compelling basis for using OVs in combination with other immunotherapy modalities. However, certain limitations persist in our understanding of oncolytic viruses' ability to regulate the TIME to enhance anti-tumour activity. These limitations primarily stem from the translational limitations of model systems, the difficulties associated with tracking reliable markers of efficacy throughout the course of treatment and the role of pre-existing viral immunity. In this review, we describe the different alterations observed in the TIME in PBTs due to OV treatment, combination therapies of OVs with different immunotherapies and the hurdles limiting the development of effective OV therapies while suggesting future directions based on existing evidence.


Assuntos
Neoplasias Encefálicas , Terapia Viral Oncolítica , Vírus Oncolíticos , Microambiente Tumoral , Humanos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/imunologia , Terapia Viral Oncolítica/métodos , Microambiente Tumoral/imunologia , Vírus Oncolíticos/fisiologia , Vírus Oncolíticos/genética , Criança , Imunoterapia/métodos , Terapia Combinada/métodos , Animais
15.
Int J Mol Sci ; 25(2)2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38279265

RESUMO

Sarcomas are a group of malignancies of mesenchymal origin with a plethora of subtypes. Given the sheer heterogeneity of various subtypes and the rarity of the disease, the management of sarcomas has been challenging, with poor patient outcomes. Surgery, radiation therapy and chemotherapy have remained the backbone of treatment in patients with sarcoma. The introduction of immunotherapy has revolutionized the treatment of various solid and hematological malignancies. In this review, we discuss the basics of immunotherapy and the immune microenvironment in sarcomas; various modalities of immunotherapy, like immune checkpoint blockade, oncolytic viruses, cancer-targeted antibodies, vaccine therapy; and adoptive cell therapies like CAR T-cell therapy, T-cell therapy, and TCR therapy.


Assuntos
Neoplasias Hematológicas , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Sarcoma/tratamento farmacológico , Imunoterapia , Imunoterapia Adotiva , Microambiente Tumoral
16.
Semin Cancer Biol ; 86(Pt 3): 1143-1157, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-34182141

RESUMO

The intentional use of viruses for cancer therapy dates back over a century. As viruses are inherently immunogenic and naturally optimized delivery vehicles, repurposing viruses for drug delivery, tumor antigen presentation, or selective replication in cancer cells represents a simple and elegant approach to cancer treatment. While early virotherapy was fraught with harsh side effects and low response rates, virus-based therapies have recently seen a resurgence due to newfound abilities to engineer and tune oncolytic viruses, virus-like particles, and virus-mimicking nanoparticles for improved safety and efficacy. However, despite their great potential, very few virus-based therapies have made it through clinical trials. In this review, we present an overview of virus-inspired approaches for cancer therapy, discuss engineering strategies to enhance their mechanisms of action, and highlight their application for overcoming the challenges of traditional cancer therapies.


Assuntos
Nanopartículas , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Vírus Oncolíticos/genética , Imunoterapia
17.
Small ; 19(23): e2206948, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36879416

RESUMO

With advances in cancer biology and an ever-deepening understanding of molecular virology, oncolytic virus (OV)-driven therapies have developed rapidly and become a promising alternative to traditional cancer therapies. In recent years, satisfactory results for oncolytic virus therapy (OVT) are achieved at both the cellular and organismal levels, and efforts are being increasingly directed toward clinical trials. Unfortunately, OVT remains ineffective in these trials, especially when performed using only a single OV reagent. In contrast, integrated approaches, such as using immunotherapy, chemotherapy, or radiotherapy, alongside OVT have demonstrated considerable efficacy. The challenges of OVT in clinical efficacy include the restricted scope of intratumoral injections and poor targeting of intravenous administration. Further optimization of OVT delivery is needed before OVs become a viable therapy for tumor treatment. In this review, the development process and antitumor mechanisms of OVs are introduced. The advances in OVT delivery routes to provide perspectives and directions for the improvement of OVT delivery are highlighted. This review also discusses the advantages and limitations of OVT monotherapy and combination therapy through the lens of recent clinical trials and aims to chart a course toward safer and more effective OVT strategies.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Terapia Viral Oncolítica/métodos , Neoplasias/terapia , Imunoterapia , Terapia Combinada
18.
J Virol ; 96(3): e0082621, 2022 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-34787457

RESUMO

Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HIV-1. However, its primary receptor portfolio remains controversial, potentially including sialic acid, coxsackie and adenovirus receptor (CAR), integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned on the basis of the inability to cocrystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domain CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild-type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (i.m.) injection but not after intranasal (i.n.) administration. Ad26 transduction was 10-fold lower than Ad5 transduction after intratumoral (i.t.) injection of CD46-expressing tumors. Ad26 transduction of liver was 1,000-fold lower than that ofAd5 after intravenous (i.v.) injection. These data demonstrate the use of CD46 by Ad26 in certain situations but also show that the receptor has little consequence by other routes of administration. Finally, i.v. injection of high doses of Ad26 into CD46 mice induced release of liver enzymes into the bloodstream and reduced white blood cell counts but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during coronavirus disease 2019 (COVID-19) vaccination with this serotype of adenovirus. IMPORTANCE The human species D Ad26 is being investigated as a low-seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection and its role in virus biology, vaccine efficacy, and, importantly, vaccine safety.


Assuntos
Infecções por Adenovirus Humanos/metabolismo , Infecções por Adenovirus Humanos/virologia , Adenovírus Humanos/classificação , Adenovírus Humanos/fisiologia , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/metabolismo , Interações Hospedeiro-Patógeno , Proteína Cofatora de Membrana/metabolismo , Adenovírus Humanos/ultraestrutura , Animais , Biomarcadores , Contagem de Células Sanguíneas , Células CHO , Linhagem Celular , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/química , Cricetulus , Modelos Animais de Doenças , Expressão Gênica , Humanos , Proteína Cofatora de Membrana/química , Proteína Cofatora de Membrana/genética , Camundongos Transgênicos , Modelos Biológicos , Modelos Moleculares , Mutagênese , Ligação Proteica , Conformação Proteica , Sorogrupo , Ácidos Siálicos/metabolismo , Ácidos Siálicos/farmacologia , Relação Estrutura-Atividade
19.
J Transl Med ; 21(1): 500, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37491263

RESUMO

BACKGROUND: Oncolytic virotherapy (OVT) is a promising anti-tumor modality that utilizes oncolytic viruses (OVs) to preferentially attack cancers rather than normal tissues. With the understanding particularly in the characteristics of viruses and tumor cells, numerous innovative OVs have been engineered to conquer cancers, such as Talimogene Laherparepvec (T-VEC) and tasadenoturev (DNX-2401). However, the therapeutic safety and efficacy must be further optimized and balanced to ensure the superior safe and efficient OVT in clinics, and reasonable combination therapy strategies are also important challenges worthy to be explored. MAIN BODY: Here we provided a critical review of the development history and status of OVT, emphasizing the mechanisms of enhancing both safety and efficacy. We propose that oncolytic virotherapy has evolved into the fourth generation as tumor immunotherapy. Particularly, to arouse T cells by designing OVs expressing bi-specific T cell activator (BiTA) is a promising strategy of killing two birds with one stone. Amazing combination of therapeutic strategies of OVs and immune cells confers immense potential for managing cancers. Moreover, the attractive preclinical OVT addressed recently, and the OVT in clinical trials were systematically reviewed. CONCLUSION: OVs, which are advancing into clinical trials, are being envisioned as the frontier clinical anti-tumor agents coming soon.


Assuntos
Melanoma , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Melanoma/terapia , Neoplasias/terapia , Imunoterapia , Terapia Combinada
20.
Cancer Cell Int ; 23(1): 1, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604694

RESUMO

Squamous cell carcinomas are the most common head and neck malignancies. Significant progress has been made in standard therapeutic methods combining surgery, radiation, and chemotherapy. Nevertheless, the 5-year survival rate remains at 40-50%. Immune checkpoint inhibitors (ICIs) are a new strategy for treating head and neck squamous cell carcinomas (HNSCCs). Still, the overall response and effective rates are poor, as HNSCCs are 'cold' tumors with an immunosuppressive tumor microenvironment (TME), limiting ICI's beneficial effects. In this case, transforming the tumor suppression microenvironment before using ICIs could be helpful. Oncolytic viruses (OVs) can transform cold tumors into hot tumors, improving the situation. Talimogene laherparepvec (T-VEC), oncolytic immunotherapy authorized for advanced melanoma, also showed good safety and antitumor activity in treating head and neck cancer and pancreatic cancer. In combination with pembrolizumab, T-Vec may have more anticancer efficacy than either drug alone. Therefore, understanding the mechanisms underpinning OVs and their potential synergism with ICIs could benefit patients with HNSCC.

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