Search Results (436)

Background: While Bacillus Calmette-Guérin (BCG) remains the first-line therapy for high-risk bladder cancer, 30–40% of patients develop treatment resistance necessitating radical cystectomy, some are not suitable candidates for this procedure. This underscores the critical need for novel therapeutic approaches. Emerging clinical evidence has increasingly supported the therapeutic potential of oncolytic viruses in bladder cancer treatment. Based on this clinical foundation, we investigated the anti-tumor effects of KD01, a novel type 5 recombinant oncolytic adenovirus previously developed by our team engineered to express truncated BID (tBID), in bladder cancer. Methods: The cytotoxic effects and anti-tumor efficacy of KD01 were systematically evaluated across human bladder cancer cell lines, and cell death pathways were investigated by RNA sequencing and validated. Combination therapy studies with cisplatin employed cytotoxic testing. In the final stage, the safety of KD01 bladder instillation was evaluated. Results: KD01 induced bladder cancer cell death through multiple mechanisms, including oncolysis, immunogenic cell death, and mitochondrial apoptosis. At higher doses, KD01 combined with cisplatin synergistically inhibited cancer cell proliferation and induced apoptosis. Additionally, KD01 amplified damage-associated molecular patterns (DAMPs) release and immune activation; the combination with cisplatin further enhanced the process. Safety evaluations showed favorable tolerance to intravesical perfusion with KD01. Conclusions: The dual action of KD01 in directly killing tumor cells and activating anti-tumor immunity underscores its potential as a therapeutic agent. These findings highlight the preclinical efficacy and safety of KD01, informing the design of clinical trials. Full article

Parvoviruses are small, single-stranded DNA viruses that have evolved sophisticated mechanisms to hijack host cell machinery for replication and persistence. One critical aspect of this interaction involves the manipulation of the host’s DNA Damage Response (DDR) pathways. While the viral genome is comparatively simple, parvoviruses have developed strategies that cause significant DNA damage, activate DDR pathways, and disrupt the host cell cycle. This review will explore the impact of parvovirus infections on host genome stability, focusing on key viral species such as Adeno-Associated Virus (AAV), Minute Virus of Mice (MVM), and Human Bocavirus (HBoV), and their interactions with DDR proteins. Since parvoviruses are used as oncolytic agents and gene therapy vectors, a better understanding of cellular DDR pathways will aid in engineering potent anti-cancer agents and gene therapies for chronic diseases. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, characterized by rapid growth, invasive infiltration into surrounding brain tissue, and resistance to conventional therapies. Despite advancements in surgery, radiotherapy, and chemotherapy, median survival remains approximately 15 months, underscoring the urgent need for innovative treatments. Key considerations informing treatment development include oncogenic genetic and epigenetic alterations that may dually serve as therapeutic targets and facilitate treatment resistance. Various immunotherapeutic strategies have been explored and continue to be refined for their anti-tumor potential. Technical aspects of drug delivery and blood–brain barrier (BBB) penetration have been addressed through novel vehicles and techniques including the incorporation of nanotechnology. Molecular profiling has emerged as an important tool to individualize treatment where applicable, and to identify patient populations with the most drug sensitivity. The goal of this review is to describe the spectrum of potential GBM therapeutic targets, and to provide an overview of key trial outcomes. Altogether, the progress of clinical and preclinical work must be critically evaluated in order to develop therapies for GBM with the strongest therapeutic efficacy. Full article

Due to the minimal survival benefits of existing therapies for pediatric diffuse midline glioma (DMG) patients, new therapeutic modalities are being investigated. Immunotherapies such as CAR-T cells and oncolytic viruses (OVs) are part of these efforts, as evidenced by the increasing number of clinical trials. αβ T cells engineered with a high-affinity γ9δ2 T-cell receptor (TEGs) are immune cells designed to target metabolic changes in malignant or virally infected cells via BTN2A1 and BTN3A. Because the expression of BTN2A1 and BTN3A can be altered in tumor and infected cells, combining TEGs and OVs could potentially enhance the anti-tumor response. We investigated this hypothesis in the following study. We demonstrate that TEGs can indeed target DMG, which expresses BTN2A1 and BTN3A at varying levels, and that OVs can further enhance the expression of BTN3A—but not BTN2A1—in DMG. Functionally, TEGs killed DMG cell cultures, and this killing was further increased after OV infection of the DMGs with either adenovirus Δ24-RGD or reovirus R124 under suboptimal conditions. However, this additive effect was lost when γ9δ2 TCR–ligand interaction was boosted by pamidronate. This study demonstrates the additive effect of combining OVs and Vγ9Vδ2 TCR-engineered immune cells under suboptimal conditions and supports a combination strategy to enhance the efficacy of both therapeutic modalities. Full article

This article is concerned with the mathematical modeling of cancer virotherapy, emphasizing the impact of Allee effects on tumor cell growth. We propose a modeling framework that describes the complex interaction between tumor cells and oncolytic viruses. The efficacy of this therapy against cancer is mathematically investigated. The analysis involves linear and logistic growth scenarios coupled with different Allee effects, including weak, strong, and hyper Allee forms. Critical points are identified, and their existence and stability are analyzed using dynamical system theories and bifurcation techniques. Also, bifurcation diagrams and numerical simulations are utilized to verify and extend analytical results. It is observed that Allee effects significantly influence the stability of the system and the conditions necessary for tumor control and eradication. Full article

Skin cancer, including melanoma and non-melanoma types, presents a significant and growing global health challenge due to its increasing incidence and mortality rates. While conventional treatments such as surgical excision, immunotherapy, and targeted therapies are well-established, microorganism-based approaches represent an innovative and promising alternative. These therapies employ live, genetically engineered, or commensal bacteria, viral vectors, or bacterial components to achieve various therapeutic mechanisms, including tumor targeting, immune system modulation, vascular disruption, competitive exclusion, drug delivery, and direct oncolysis. Despite their potential, these approaches require further investigation to address safety concerns, optimize treatment protocols, and gain a comprehensive understanding of their long-term outcomes. Full article

In this study, we present an oncolytic virus (OV) evaluation system established using microfluidic organ-on-a-chip (OOC) systems and patient-derived organoids (PDOs), which was used in the development of a novel oncolytic virus, AD4-GHPE. An OV offers advantages such as good targeting ability and minimal side effects, and it has achieved significant breakthroughs when combined with immunotherapy in recent clinical trials. The development of OVs has become an emerging research focus. PDOs can preserve the heterogeneity of in situ tumor tissues, whereas microfluidic OOC systems can automate and standardize various experimental procedures. These systems have been applied in cutting-edge drug screening and cell therapy experiments; however, their use in functionally complex oncolytic viruses remains to be explored. In this study, we constructed a novel recombinant oncolytic adenovirus, AD4-GHPE, and evaluated OOC systems and PDOs through various functional validations in hypopharyngeal and breast cancer organoids. The results confirmed that AD4-GHPE exhibits three antitumor mechanisms, namely, tumor-specific cytotoxicity, a reduction in programmed death ligand 1 (PD-L1) expression in tumor cells to increase CD8⁺ T-cell activity, and granulocyte–macrophage colony-stimulating factor (GM-CSF) secretion. The evaluation system combining OOC systems and PDOs was efficient and reliable, providing personalized OV treatment recommendations for patients and offering industrialized and standardized research ideas for the development of OVs. Full article

Ovarian cancer (OC) remains the most lethal gynecologic malignancy with limited effective treatment options. Oncolytic viruses (OVs) have emerged as a promising therapeutic approach for cancer treatment, capable of selectively infecting and lysing cancer cells while stimulating anti-tumor immune responses. Preclinical studies have demonstrated significant tumor regression and prolonged survival in OC models using various OVs, such as herpes simplex. Early-phase clinical trials have shown a favorable safety profile, though the impact on patient survival has been modest. Current research focuses on combining OVs with other treatments like immune checkpoint inhibitors to enhance their efficacy. We provide a comprehensive overview of the current understanding and future directions for utilizing OVs in the management of OC. Full article

Oncolytic adenoviruses derived from human serotype 5 (Ad5) are being developed to treat cancer. Treatment efficacy could be affected by pre-existing or induced neutralizing antibodies (NAbs), in particular in repeat administration strategies. Several oncolytic adenoviruses that are currently in clinical development have modified fiber proteins to increase their infectivity. One example is Ad5-∆24.RGD, which carries a cyclic RGD peptide insert in the fiber protein to allow cell entry via integrins. The effect of anti-Ad5 NAbs on anticancer efficacy could be different for oncolytic adenoviruses with RGD-modified fibers than for unmodified Ad5-based viruses. Here, we determine pre-existing and elicited NAb titers in the serum of patients with glioblastoma who were treated by delivering Ad5-∆24.RGD to the tumor and to the surrounding tumor-infiltrated brain. We show that intracranial infusion of Ad5-∆24.RGD induced mainly neutralization of adenovirus native tropism. Infection of cells with RGD-modified virus was significantly less affected. In cerebrospinal fluid, neutralizing activity against RGD-mediated infection remained very low. Thus, the RGD-mediated alternative cell entry route allowed to bypass pre-existing and induced anti-Ad5 neutralization. Interestingly, in the course of these experiments, we discovered that the serum of most humans promotes the uptake of RGD-modified adenovirus in human cells. The until now unidentified infection-stimulating factor seems distinct from serum proteins known to promote Ad5 infection. Together, our work supports the utility of RGD-modified oncolytic adenoviruses for the treatment of cancer in humans. Since these viruses hardly induced neutralization, they seem particularly suitable for repeat administration treatments. Full article

Intraocular malignant tumors are rare; however, they can cause serious life-threatening complications. Uveal melanoma (UM) and retinoblastoma (RB) are the most common intraocular tumors in adults and children, respectively, and come with a great disease burden. For many years, several different treatment modalities for UM and RB have been proposed, with chemotherapy for RB cases and plaque radiation therapy for localized UM as first-line treatment options. Extraocular extension, recurrence, and metastasis constitute the major challenges of conventional treatments. To overcome these obstacles, immunotherapy, which encompasses different treatment options such as oncolytic viruses, antibody-mediated immune modulations, and targeted immunotherapy, has shown great potential as a novel therapeutic tool for cancer therapy. These anti-cancer treatment options provide numerous advantages such as selective cancer cell death and the promotion of an anti-tumor immune response, and they prove useful in preventing vision impairment due to macular and/or optic disc involvement. Numerous factors such as the vector choice, route of administration, dosing, and patient characteristics must be considered when engineering an oncolytic virus or other forms of immunotherapy vectors. This manuscript provides an in-depth review of the molecular design of oncolytic viruses (e.g., virus capsid proteins and encapsulation technologies, vectors for delivery, cell targeting) and immunotherapy. The most recent advances in preclinical- and clinical-phase studies are further summarized. The recent developments in virus-like drug conjugates (i.e., AU011), oncolytic viruses for metastatic UM, and targeted immunotherapies have shown great results in clinical trials for the future clinical application of these novel technologies in the treatment algorithm of certain intraocular tumors. Full article

In this paper, the impulsive conformable calculus approach is applied to the introduction of an $M1$ oncolytic virotherapy neural network model. The proposed model extends some existing mathematical models that describe the dynamics of the concentrations of normal cells, tumor cells, nutrients, $M1$ viruses and cytotoxic T lymphocyte (CTL) cells to the impulsive conformable setting. The conformable concept allows for flexibility in the modeling approach, as well as avoiding the complexity of using classical fractional derivatives. The impulsive generalization supports the application of a suitable impulsive control therapy. Reaction–diffusion terms are also considered. We analyze the stable behavior of sets of states, which extend the investigations of the dynamics of separate equilibrium points. By applying the impulsive conformable Lyapunov function technique, sufficient conditions for the uniform global exponential stability of sets of states are established. An example is also presented to illustrate our results. Full article

Background/Objectives: Multiple immune-modulatory strategies have been tested in efforts to mitigate the pro-tumor microenvironment in pediatric high-grade glioma. HSV1716 is an oncolytic virus that previously demonstrated evidence of response in adult and pediatric patients. PBTC-037 was a single-center phase I trial developed and performed by the Pediatric Brain Tumor Consortium (PBTC) to estimate the maximum tolerated dose or recommended phase II dose of HSV1716 administered during surgical resection. Methods: Patients aged 12 to 21 years with recurrent or refractory high-grade glioma for whom surgical resection was clinically indicated were eligible. After maximal tumor resection, patients received one intraoperative dose of HSV1716. Results: Two patients were enrolled; one was later deemed ineligible yet was continued in follow up for safety. Both patients underwent complete tumor resection with the administration of HSV1716. Shortly after the enrollment of the two patients, this study was closed to accrual due to a change in the sponsor’s investment focus. One patient completed the 8-week reporting period without toxicity. The second patient who was later deemed ineligible had no evidence of dose-limiting toxicity. The two patients had progressive disease at 1.9 and 2.9 months after enrollment; both eventually died due to progressive disease at 7.5 months. Conclusion: We describe the administration of HSV1716 to two pediatric patients with recurrent high-grade glioma, without evidence of dose-limiting toxicity. Oncolytic viruses are currently being tested in pediatric patients in larger combinatorial trials. Despite the limited numbers, the data presented here will hopefully provide incremental steps toward improved immunovirotherapy of pediatric brain tumors. Full article

Oncolytic virotherapy has shown great promise in mediating targeted tumor destruction through tumor-selective replication and induction of anti-tumor immunity; however, obstacles remain for virus candidates to reach the clinic. These include avoiding neutralizing antibodies, preventing stimulation of the adaptive immune response during intravenous administration, and inducing sufficient apoptosis and immune activation so that the body’s defense can work to eradicate systemic disease. We have developed a co-formulation of oncolytic viruses (OVs) with Imagent^® lipid-encapsulated, perfluorocarbon microbubbles (MBs) to protect the OVs from the innate and adaptive immune system. Once inside the MB, the viral particles become acoustically active such that external ultrasound can target the delivery of the virus locally within the tumor. Humanized NSG female mice (Hu-CD34⁺ NSG-SGM3) engrafted in their flanks with MDA-MB-231-Luc triple-negative breast cancer (TNBC) cells were transduced with MB/OVs, with or without adjuvant Pembrolizumab treatment, and tumor sizes and tumor necrosis were assessed. The presence of CD8⁺ (cytotoxic T-cells), CD4⁺ (helper T-cells), and CD25⁺ (Tregs) tumor-infiltrating lymphocytes (TILs) was quantified in the tumor samples by immunohistochemistry. In an in vivo model of humanized mice engrafted with a human immune system, we observed significantly greater tumor necrosis and smaller tumor mass in human TNBC xenografts systemically treated with MB/OV complexes in the presence or absence of pembrolizumab adjuvant treatment, compared to controls. Additionally, we observed a low ratio of CD4⁺/CD8⁺ TILs and a high ratio of CD8⁺/CD25⁺ TILs in the MDA-MB-231 xenografts treated with MB/OVs complexes with or without pembrolizumab adjuvant treatment, compared to controls. Our study demonstrated the feasibility of using MBs to target OVs to TNBC through diagnostic ultrasound, which decreased tumor mass by increasing tumor necrosis and stimulated a local and systemic antitumoral immune response by increasing intratumoral CD8⁺ T-cytotoxic lymphocyte infiltration and decreasing CD25⁺ Treg cells. Full article

This study evaluates the oncolytic potential of the Moscow strain of reovirus against human metastatic melanoma and glioblastoma cells. The Moscow strain effectively infects and replicates within human melanoma cell lines and primary glioblastoma cells, while sparing non-malignant human cells. Infection leads to the selective destruction of neoplastic cells, mediated by functional viral replication. A positive correlation was identified between viral RNA accumulation and tumor cell death, with no replication observed in non-malignant cells. This study highlights the critical roles of cathepsins B, L, and S as mediators of the oncolytic process. The pharmacological inhibition of these enzymes significantly attenuated reovirus-induced cytotoxicity in melanoma and glioblastoma cells. Conversely, PKR production analysis revealed minimal activation in reovirus-infected tumor cells, suggesting that the hyperactivation of the RAS-signaling pathway and subsequent PKR inhibition do not directly contribute to the selective efficacy of reovirus. Moreover, infected tumor cells exhibited features of both apoptotic and non-apoptotic death, emphasizing the intricate mechanisms of reovirus-mediated oncolysis. These findings underscore the therapeutic promise of the Moscow strain of reovirus as a selective and potent oncolytic agent for targeting melanoma and glioblastoma cells. Full article

Background/Objectives: Ovarian cancer is the deadliest gynecologic cancer, and with the majority of patients dying within the first five years of diagnosis, new therapeutic options are required. The small guanosine triphosphatase (GTPase) Ras-related nuclear protein (Ran) has been reported to be highly expressed in high-grade serous ovarian cancers (HGSOCs) and associated with poor outcomes. Blocking Ran function or preventing its expression were shown to be promising treatment strategies, however, there are currently no small molecule inhibitors available to specifically inhibit Ran function. Interestingly, a previous study suggested that the Vesicular stomatitis virus (VSV) could inhibit Ran activity. Given that VSV is an oncolytic virus (OV) and, therefore, has anti-cancer activity, we reasoned that oncolytic VSV (oVSV) might be particularly effective against ovarian cancer via Ran inhibition. Methods: We evaluated the sensitivity of patient-derived ovarian cancer cell lines to oVSV, as well as the impact of oVSV on Ran and vice versa, using overexpression systems, small interfering RNAs (siRNAs), and drug inhibition. Results: In this study, we evaluated the interplay between oVSV and Ran and found that, although oVSV does not consistently block Ran, increased Ran activation allows for better oVSV replication and tumor cell killing. Conclusions: Our study reveals a positive impact of Ran on oVSV sensitivity. Given the high expression of Ran in HGSOCs, which are particularly aggressive ovarian cancers, our data suggest that oVSV could be effective against the deadliest form of the disease. Full article