Search Results (613)

Senecavirus A (SVA), an emerging causative agent of porcine vesicular disease, belongs to the genus Senecavirus of the family Picornaviridae. The virus has been circulating in pig herds in the USA dating back to 1988, evolved into clinically significant pathogenic SVA variants causing a pandemic in the USA and Canada since 2014, and thereafter gradually spread to the Americas and Asia. To date, most studies have illustrated the infection dynamics, epidemiology, diagnostic methods, and vaccine development, yet the molecular pathogenesis of SVA remains incompletely characterized. As a novel picornavirus capable of establishing persistent subclinical infections, SVA has been detected in tissues such as tonsils and testicles for up to 156 days post-infection, posing a substantial challenge to swine health and production systems. In parallel, SVA has gained attention as an oncolytic virotherapy candidate for neuroendocrine tumors due to its tumor-selective tropism. Therefore, elucidating the mechanisms underlying SVA pathogenesis will not only support the development of effective countermeasures for swine but also inform the engineering of recombinant variants with enhanced therapeutic potential for human oncology. This review comprehensively summarizes the current knowledge on viral and host determinants of SVA pathogenesis, from the viral genome, evolution, and recombination to ANTXR1 host immunity, and programmed cell death, and presents future research directions, aiming to identify key knowledge gaps to guide future studies on SVA. Full article

Immunotherapy delivers a fundamental shift in the treatment of multiple cancers, offering hope for patients with cancer. Unlike conventional therapies, it leverages the patient’s immune system to precisely identify and destroy cancer cells. The remarkable journey of immunotherapy’s has revolutionized oncology and paved the way for the development of modern immunotherapies. Several approaches are applied for immunotherapy, including immune checkpoint inhibitors, adoptive cell therapies, cancer vaccines, tumor microenvironment reprogramming, monoclonal antibodies, cytokine therapies, oncolytic virus therapy and combination strategies. Various immunotherapies are being used for different types of cancers like skin, lung, bladder, kidney, liver, breast and blood cancers. Despite providing an effective cancer treatment, immunotherapies face some challenges in their clinical implementation. To overcome these limitations, future directions emphasize the development of personalized and combination therapies, the incorporation of AI and a good delivery system. The main aim of this review is to give an overview of the journey of evolution, different approaches, limitations, advances and future development for immunotherapy in cancer treatment. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a five-year survival rate of less than 12%. Oncolytic viruses are considered a promising immunotherapeutic approach, but their effectiveness is often limited by the innate interferon response, which is the main antiviral barrier in resistant tumors. A combination of an oncolytic virus with JAK/STAT pathway inhibitors has been proposed to overcome this resistance. Methods: In this study, we investigated the oncolytic and immunotherapeutic potential of the attenuated yellow fever vaccine strain YFV 17D in combination with the JAK1/JAK2 inhibitor ruxolitinib in a panel of six PDAC cell lines with diverse genetic profiles and JAK/STAT signaling activities and in a syngeneic immunocompetent PAN02 mouse model. Results: In vitro, we identified three distinct response patterns: synergistic enhancement of viral replication and cytopathic effect, lack of synergism due to absent interferon signaling, and increased viral replication without cytopathic effect. Despite different cell mutation profiles, the cell response patterns were determined by the basal JAK/STAT activity of each cell line rather than by specific KRAS or TP53 mutation. In vivo, the combination therapy significantly extended median survival compared to YFV 17D monotherapy and the control group and induced tumor regression in 62.5% of animals. Since no difference in intratumoral viral RNA was detected between the combination and monotherapy groups, we suggest that the antitumor effect in vivo was mediated not by enhanced viral replication, but by activation of adaptive immunity. This is indirectly suggested by increased intratumoral IL-12, a fourfold increase in CD8⁺ T cell infiltration, a reduction in CD4⁺ cells, and the generation of virus-neutralizing antibodies. No systemic cytokine surge, neurovirulence, or viral dissemination was observed, suggesting the safety of the proposed regimen. Conclusions: These findings clarify the immune mechanisms determining the efficacy of YFV 17D combined with ruxolitinib and establish the basis for personalized patient stratification by tumor interferon signaling status. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, and durable benefit from immune checkpoint inhibitors is limited by immune exclusion, microenvironmental immunosuppression, and toxicity. This narrative translational review evaluates whether endobronchial intratumoral delivery of immuno- and gene-based therapies can transform bronchoscopic access into a therapeutic platform linking local tumour intervention with systemic antitumour immunity. We synthesise evidence on endobronchial ultrasound, electromagnetic navigation bronchoscopy, and robotic-assisted bronchoscopy, together with local checkpoint blockade, cytokine and mRNA-lipid nanoparticle constructs, oncolytic virotherapy, dendritic-cell approaches, viral and non-viral gene transfer, and enzyme- or metabolite-based strategies. Current clinical evidence remains preliminary, consisting mainly of Phase I trials, small prospective cohorts, and case-based signals, with feasibility and safety observations but no completed randomised trial demonstrating efficacy against standard-of-care systemic therapy. The most plausible candidates are patients with advanced or recurrent NSCLC, bronchoscopically accessible lesions, inadequate response to systemic immunotherapy, and immune-excluded or locally immunosuppressed tumours. Biomarkers such as PD-L1, tumour mutational burden, CD8+ infiltration, tertiary lymphoid structures, radiomics, and circulating tumour DNA require validation. This review integrates delivery technology, immune mechanisms, statistical evidence appraisal, biomarker limitations, AI-guided planning, and global feasibility. Full article

Most patients with solid tumors do not respond to immune checkpoint blockade, and inadequate T cell infiltration of the tumor parenchyma is the dominant mechanism of primary resistance. Oncolytic viruses address this problem by a distinct route: they replicate selectively within tumor cells, produce immunogenic cell death, and convert infected cells into local sources of any encoded transgene. Most armed designs to date have carried cytokine or checkpoint-antibody payloads, and chemokines have attracted comparatively little attention despite bearing directly on the trafficking bottleneck. This review synthesizes the preclinical literature on chemokine-armed oncolytic viruses across three receptor axes: CXCR3 (CXCL9, CXCL10, CXCL11), CCR5 (CCL5/RANTES), and CCR7 (CCL19). The accumulated evidence indicates that therapeutic outcome depends less on the chemokine payload itself than on the interaction between payload and viral backbone. CXCL11 outperforms its sister CXCR3 ligands not through intrinsic potency but because it is non-redundant with the endogenous chemokines induced by vesicular stomatitis virus and vaccinia, and because it largely escapes proteolytic cleavage by dipeptidyl peptidase 4 (DPP4). CCL5 has shown the most consistent activity in dual-payload designs that pair chemotaxis with a T cell survival cytokine such as IL-15. CCL19, which addresses lymphoid organization rather than effector recruitment, rests on a single published construct. One evidence gap is central: no head-to-head comparison of chemokine payloads within a single viral platform has been published. We therefore propose a translational decision framework that aligns chemokine selection with the immune contexture of the target tumor. Full article

Virus-based cancer therapy (virotherapy) is currently being researched as a novel form of immunotherapy and has already entered the clinical application phase. Among various types of virotherapy, oncolytic virotherapy involves infecting tumors with tumor-selective viruses, such as herpes simplex virus, adenoviruses, and vaccinia virus, and utilizing their replicative capacity to induce cell destruction within tumors. In addition, this therapy aims to enhance tumor immunity by changing the tumor microenvironment through viral infection. Genetic deletion in viruses is used to reduce their virulence and confer tumor selectivity, while the expression of foreign genes is utilized to enhance antitumor effects. Oncolytic viruses for head and neck cancer (HNC) are administered locally or systemically and are sometimes used as adjuvant therapy or in combination with immune checkpoint inhibitors. Another form of virotherapy involves non-replicating viruses, which are used to produce antitumor cytokines or as cancer vaccines expressing tumor antigens. Research on the efficacy of cancer vaccines in preventing postoperative recurrence is currently underway. A number of challenges have yet to be overcome for further advances in virotherapy, including the efficient delivery of viruses to tumor cells, avoiding viral inactivation in the bloodstream, ensuring efficient replication of the virus, and enhancing antitumor immunity. The development of effective strategies based on the findings of clinical studies will lead to improvements in virotherapy for HNC. Full article

Background: Glioblastoma (GBM) is characterised by therapeutic resistance and high invasiveness, so the development of new treatments is essential. Oncolytic virotherapy using the vesicular stomatitis virus (VSV) is a promising approach as it is inherently tumour-selective and immunostimulatory. This study evaluated the antitumour efficacy of a recombinant VSV engineered to co-express mouse interleukin-12 and granulocyte-macrophage colony-stimulating factor (rVSV-dM51-mIL12-mGMCSF) using in vitro and in vivo U-87 MG models. Methods: The oncolytic activity of rVSV-dM51-mIL12-mGMCSF was evaluated in vitro against human U-87 MG and mouse GL-261 glioblastoma cells using flow cytometry (MOI 0.1) and MTT assays (MOIs 0.1 and 0.001). In vivo, tumour progression was monitored in U-87 MG xenograft mice for 30 days after inoculation. At the study endpoint, tumour tissues from treated and control animals were subjected to immunohistochemical (IHC) analysis; the H-score method was used to quantify expression of the Ki-67 proliferation marker, VSV glycoprotein (VSV-G), and mIL-12. Results: rVSV-dM51-mIL12-mGMCSF demonstrated oncolytic activity against both cell lines in vitro; however, its cytotoxicity was lower compared to the parental control virus (rVSV-dM51-GFP). In contrast, treatment in vivo resulted in greater tumour growth inhibition. IHC analysis revealed a significant reduction in the Ki-67 H-score alongside high levels of VSV glycoprotein and mIL-12 expression. These results confirm that, although the payloads do not enhance direct viral oncolysis in vitro, they significantly improve antitumour efficacy in vivo. Conclusions: rVSV-dM51-mIL12-mGMCSF effectively inhibited tumour growth in the U-87 MG xenograft model, supporting further evaluation of glioblastoma-directed oncolytic virotherapy. Full article

Background: Oncolytic viruses (OVs), a promising anti-cancer therapeutic, replicate more efficiently in cancer cells rather than in healthy cells due to the alterations in antiviral response mechanisms and dysregulation of signaling pathways. Vesicular stomatitis virus (VSV) is known for low pathogenicity, tropism to various cancer cells, and the ability to lyse cells in the hypoxic tumor microenvironment (TME). Targeted delivery of immune checkpoint and co-stimulatory molecules can enhance the anti-tumor immune response and remodel the immunosuppressive TME. The aim of this study was to compare the activity of rVSV-GFP with rVSV, encoding the programmed cell death protein 1 (PD-1) and tumor necrosis factor ligand superfamily member 9 (4-1BBL). Methods: The oncolytic efficacy of these rVSV variants used at 10⁵, 10⁶, and 10⁷ TCID50 was evaluated at 24 and 48 h post-infection by flow cytometry in a panel of mouse and human cancer cell lines. Quantitative real-time polymerase chain reaction (qPCR) was used to evaluate mRNA expression levels of certain genes at 12 and 48 h post-infection. Results: Murine hepatocellular carcinoma (H22) and human melanoma (A375) or human lung carcinoma (A549) were the most sensitive to rVSV therapy cell lines. The higher relative expression of the antiviral response genes RIG-I and IFIT1 within each biological species (mouse or human) correlated with lower sensitivity to rVSV. No such effect was observed for the type I interferons (IFNs), despite their proposed key role in resistance to OV therapy. Conclusions: H22, A375, and A549 are more susceptible to the oncolytic activity of the novel rVSV-PD-1-4-1BBL. Full article

Oncolytic virotherapy offers a promising avenue for solid tumor treatment, yet single-agent approaches are frequently limited by insufficient tumor lysis and inadequate immune activation. Here we report that combined therapy with two recombinant variants of the oncolytic vaccinia virus, armed with either herpes simplex virus thymidine kinase (VV-HSVtk) or the interleukin 15 receptor subunit alpha (VV-mIL15Rα), leads to enhanced cytotoxicity and immune stimulation in a murine mammary adenocarcinoma model (4T1). In vitro, VV-HSVtk exhibited dose-dependent cytotoxicity markedly potentiated by ganciclovir (GCV) through HSVtk-mediated phosphorylation into a cytotoxic nucleoside analog, and co-culture of VV-infected tumor cells with donor-derived NK cells further increased oncolytic efficiency. In vivo, combined treatment with VV-HSVtk, VV-mIL15Rα, and GCV resulted in significant tumor regression and extended survival relative to monotherapy controls in 4T1 syngeneic mice. Histological examination revealed increased lymphocytic infiltration at tumor sites and absence of hepatic or splenic toxicity. Together, these data indicate that integrating direct viral cytotoxicity, HSVtk/GCV-mediated suicide gene therapy, and IL-15-pathway-targeted immunomodulation within an oncolytic vaccinia platform can improve antitumor efficacy in a stringent breast cancer model. Full article

Oncolytic viruses represent a promising class of anticancer therapeutics, and rapid, accurate quantification of viral titers is critical for ensuring both efficacy and safety during clinical development. Conventional viral titering methods, such as 50% cell culture infectious dose (CCID₅₀), are time-consuming and limited in sensitivity, thereby restricting their application in real-time clinical monitoring. This study aimed to develop and validate a rapid titer assay for oHSV2-PD-L1/CD3-BsAb, an oncolytic herpes simplex virus expressing a PD-L1/CD3 bispecific antibody, to support preclinical and clinical monitoring. A dual-reporter cell system was established using Vero-PD-L1-GFP (Vero cells expressing PD-L1 and GFP) cells as target cells and Jurkat-NFAT-Fluc (Jurkat cells expressing NFAT and Fluc) cells as effector cells. Viral infection activates the NFAT signaling pathway, driving Fluc expression, thereby enabling rapid quantification of infectious virus. The assay was evaluated for specificity, limit of detection (LOD), and lower limit of quantification (LLOQ), and compared with the conventional CCID₅₀ method. Its applicability was further assessed using clinical simulation samples, including PBMCs and swabs. The rapid titer assay accurately quantified virus at 10³ CCID₅₀/mL after 8 h of incubation, consistent with CCID₅₀ results, while extending the incubation to 18 h improved the LLOQ to 10^2.5 CCID₅₀/mL, demonstrating enhanced sensitivity. The assay exhibited high reproducibility and stability in both PBMC and swab samples, enabling reliable quantification of low-titer virus in complex biological matrices. Compared with CCID₅₀, the method substantially reduced assay time (from 3–5 days to 8–18 h) while improving sensitivity and specificity. The developed rapid titer assay for oHSV2-PD-L1/CD3-BsAb provides a sensitive and specific platform for viral quantification. It offers a valuable tool for oncolytic virus development, production quality control, and clinical monitoring, facilitating efficient safety evaluation and risk management in ongoing and future clinical applications. Full article

We propose a fractional-order cancer virotherapy model based on Caputo derivatives to investigate the temporal interactions among tumor cells, viruses, and immune response components. The existence and uniqueness of the solutions for the proposed model are rigorously studied. The proposed model is capable of tracking the temporal dynamics of uninfected and infected cancer cells, free oncolytic virus, and several components of the immune response. To determine the analytical solutions of the resulting nonlinear fractional-order system, we utilize the Temimi–Ansari method (TAM). The convergence and accuracy of the method are confirmed via error analysis and numerical simulation carried out in MATHEMATICA. It is observed that the fractional order plays a prominent role in controlling the temporal dynamics of the cancer–virus–immune system, leading to a reduction in the number of infected cancer cells due to virotherapy. On the other hand, the immune response is vital for controlling cancer growth. Full article

Glioblastoma multiforme (GBM) is the most aggressive primary brain malignancy with limited treatment options and poor clinical outcomes. There is growing interest in using Zika virus as a treatment for GBM due to its selectivity in finding and killing rapidly proliferating neural cells. Several studies reproducibly show that Zika can effectively kill GBM cells. We sought to uncover the molecular mechanisms driving this cytotoxic effect by performing a meta-analysis of transcriptomic studies in which Zika virus was used to kill GBM cells. We integrated four datasets from studies on GBM and added neuroblastoma (NBM) studies as an outgroup comparator. Our analysis identified a shared molecular signature of the Zika-infected GBM cell. Interestingly, GBM cells killed by the Zika virus showed dysregulation of pathways commonly implicated in proliferation and metastasis, including TNF, NF-κB, and p53 signaling. Using a hypothesis-free design, we found several long non-coding RNAs (lncRNAs) that were consistently dysregulated in Zika-infected GBMs, many of which have previously unrecognized roles in cancer cell death. Among this group, we validated four lncRNAs for a role in Zika-mediated oncolysis. We functionally tested MELTF-AS1, TIPARP-AS1, NR2F1-AS1, and SLC9A3-AS1 in adult GBM cell lines using siRNA-mediated knockdown. Silencing of MELTF-AS1 augmented Zika-induced cell death, while knockdown of TIPARP-AS1, NR2F1-AS1, and SLC9A3-AS1 attenuated oncolysis, identifying lncRNAs whose modulation is associated with altered Zika-mediated cytotoxicity. These findings elucidate candidate mechanisms of Zika oncolysis in GBM cell lines, highlight novel lncRNA targets, and support further exploration of lncRNA modulation as a strategy to enhance oncolytic virotherapy for GBM and related malignancies. Full article

Glioblastoma (GBM) is an aggressive primary brain tumor associated with poor prognosis and resistance to therapy, underscoring the need for reliable preclinical models to evaluate emerging treatments. The orthotopic implantation of GBM stem-like cells (GSCs), combined with the intratumoral delivery of therapeutic agents, represents a widely used approach for modeling GBM tumor growth and studying treatment response. In particular, oncolytic herpes simplex viruses (oHSVs) have emerged as a promising strategy to selectively target malignant cells while inducing antitumor immune responses with minimal systemic toxicity. However, performing repeated survival stereotactic neurosurgeries in the same animal poses significant technical challenges. Here, we describe a comprehensive and reproducible protocol for triple survival stereotactic neurosurgery in mice. This approach involves (i) the intracranial implantation of GSCs to establish orthotopic tumors, (ii) the intratumoral delivery of oHSV using the same stereotactic coordinates, and (iii) contralateral intracranial rechallenge with GSCs to evaluate therapeutic efficacy and resistance to tumor rechallenge as a measure of immune memory. Using this protocol, consistent tumor establishment was achieved, and mice tolerated repeated neurosurgical procedures with stable postoperative recovery. Successful intracranial rechallenge in the same animal demonstrates the technical feasibility of multiple survival surgeries while minimizing procedure-related variability and complications. This method enables longitudinal assessment of tumor progression, therapeutic response, and durable memory protection within a single subject. Furthermore, this protocol provides a versatile platform for evaluating oncolytic virotherapy and other localized treatment strategies for GBM. Full article

Oncolytic viruses (OVs) exploit key hallmarks of cancer to selectively replicate in malignant cells, leading to tumor cell lysis, modulation of the tumor microenvironment, and induction of antitumor immunity. These viral platforms have been engineered to enhance tumor specificity, intratumoral spread, and immunotherapeutic efficacy. Among them, rhabdoviruses, particularly vesiculoviruses, have emerged as promising candidates due to their rapid replication, high titers, and amenability to genetic manipulation. Maraba virus, a recently identified vesiculovirus, is a single-stranded negative-sense RNA virus with a favorable safety profile and minimal pre-existing immunity in humans. It demonstrates selective tumor tropism partly through low-density lipoprotein receptor (LDLR)-mediated entry and impaired antiviral responses in cancer cells. Genetic engineering of the wild-type Maraba virus led to the development of the MG1 strain, characterized by enhanced tumor selectivity, increased replication capacity, and potent cytolytic activity. Preclinical studies have demonstrated its efficacy as a monotherapy, a cancer vaccine vector expressing tumor-associated antigens, and in combination with chemotherapy and immune checkpoint inhibitors. MG1 also reshapes the tumor microenvironment, converting immunologically “cold” tumors into “hot” tumors, thereby enhancing immune-mediated tumor clearance. Compared to vesicular stomatitis virus, Maraba virus exhibits improved safety and reduced neurovirulence while maintaining strong oncolytic potential. This review aims to comprehensively summarize the biological characteristics of the MG1 Maraba virus, its genetic development, mechanisms of action, and current preclinical and clinical applications as a novel oncolytic immunotherapeutic agent. Full article

Glioblastoma (GBM) remains the most aggressive primary malignant brain tumor in adults, with limited survival benefit from the current standard of care consisting of maximal safe resection, radiotherapy, and temozolomide-based chemotherapy. The highly infiltrative growth pattern, profound intratumoral heterogeneity, and strongly immunosuppressive tumor microenvironment together contribute to therapeutic resistance and frequent recurrence. In this context, oncolytic herpes simplex virus (oHSV) has emerged as a promising therapeutic platform for glioblastoma because of its dual capacity to directly lyse tumor cells and stimulate antitumor immune responses. In addition, the large viral genome and well-characterized biology of herpes simplex virus enable extensive genetic engineering to improve tumor selectivity, safety, and immunomodulatory function. In this review, we summarize the molecular design strategies that have driven the development of oHSV for glioblastoma, including attenuation of neurovirulence, enhancement of tumor-selective replication, and arming with immune-stimulatory transgenes. We further discuss the major biological barriers within the GBM tumor microenvironment that continue to limit therapeutic efficacy, with particular attention given to representative engineered oHSV platforms and the lessons learned from preclinical and early-phase clinical studies. A dedicated section examines these barriers in detail, including restricted intratumoral viral spread, antiviral innate immunity, and immunosuppressive myeloid cell dominance. We also review current efforts to improve outcomes through rational combination strategies with radiotherapy, immune checkpoint blockade, cytokine modulation, and other multimodal approaches. Although encouraging advances have been achieved, the clinical translation of oHSV therapy for glioblastoma still faces substantial challenges in patient selection, delivery optimization, response assessment, and treatment integration. A deeper understanding of virus–host–tumor interactions and more precise engineering of viral platforms may help unlock the full potential of oHSV-based therapy. Overall, oHSV represents one of the most compelling translational approaches in glioblastoma and provides a valuable framework for the development of mechanism-driven viro-immunotherapy in neuro-oncology. Full article