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Molecular Therapy. Oncology Mar 2024Viruses are able to efficiently penetrate cells, multiply, and eventually kill infected cells, release tumor antigens, and activate the immune system. Therefore, viruses...
Viruses are able to efficiently penetrate cells, multiply, and eventually kill infected cells, release tumor antigens, and activate the immune system. Therefore, viruses are highly attractive novel agents for cancer therapy. Clinical trials with first generations of oncolytic viruses (OVs) are very promising but show significant need for optimization. The aim of TheraVision was to establish a broadly applicable engineering platform technology for combinatorial oncolytic virus and immunotherapy. Through genetic engineering, an attenuated herpes simplex virus type 1 (HSV1) was generated that showed increased safety compared to the wild-type strain. To demonstrate the modularity and the facilitated generation of new OVs, two transgenes encoding retargeting as well as immunomodulating single-chain variable fragments (scFvs) were integrated into the platform vector. The resulting virus selectively infected epidermal growth factor receptor (EGFR)-expressing cells and produced a functional immune checkpoint inhibitor against programmed cell death protein 1 (PD-1). Thus, both viral-mediated oncolysis and immune-cell-mediated therapy were combined into a single viral vector. Safety and functionality of the armed OVs have been shown in novel preclinical models ranging from patient-derived organoids and tissue-engineered human 3D tumor models to complex humanized mouse models. Consequently, a novel and proprietary engineering platform vector based on HSV1 is available for the facilitated preclinical development of oncolytic virotherapy.
PubMed: 38596296
DOI: 10.1016/j.omton.2024.200784 -
Molecular Therapy. Oncology Mar 2024Oncolytic herpes simplex viruses (oHSVs) have emerged as leading cancer therapeutic agents. Effective oHSV virotherapy may ultimately require both intratumoral and...
Oncolytic herpes simplex viruses (oHSVs) have emerged as leading cancer therapeutic agents. Effective oHSV virotherapy may ultimately require both intratumoral and systemic vector administration to target the primary tumor and distant metastases. An attractive approach to enhancing oHSV tumor specificity is engineering the virus envelope glycoproteins for selective recognition of and infection via tumor-specific cell surface proteins. We previously demonstrated that oHSVs could be retargeted to EGFR-expressing cells by the incorporation of a single-chain antibody (scFv) at the N terminus of glycoprotein D (gD). Here, we compared retargeted oHSVs generated by the insertion of scFv, affibody molecule, or VHH antibody ligands at different positions within the N terminus of gD. When compared to the scFv-directed oHSVs, VHH and affibody molecules mediated enhanced EGFR-specific tumor cell entry, spread and cell killing , and enabled long-term tumor-specific virus replication following intravenous delivery . Moreover, oHSVs retargeted via a VHH ligand reduced tumor growth upon intravenous injection and achieved complete tumor destruction after intratumoral injection. Systemic oHSV delivery is important for the treatment of metastatic disease, and our enhancements in targeted oHSV design are a critical step in creating an effective tumor-specific oHSVs for safe administration via the bloodstream.
PubMed: 38596286
DOI: 10.1016/j.omton.2024.200761 -
Frontiers in Immunology 2024Oncolytic virus (OV) therapy has emerged as a promising frontier in cancer treatment, especially for solid tumours. While immunotherapies like immune checkpoint... (Review)
Review
Oncolytic virus (OV) therapy has emerged as a promising frontier in cancer treatment, especially for solid tumours. While immunotherapies like immune checkpoint inhibitors and CAR-T cells have demonstrated impressive results, their limitations in inducing complete tumour regression have spurred researchers to explore new approaches targeting tumours resistant to current immunotherapies. OVs, both natural and genetically engineered, selectively replicate within cancer cells, inducing their lysis while sparing normal tissues. Recent advancements in clinical research and genetic engineering have enabled the development of targeted viruses that modify the tumour microenvironment, triggering anti-tumour immune responses and exhibiting synergistic effects with other cancer therapies. Several OVs have been studied for breast cancer treatment, including adenovirus, protoparvovirus, vaccinia virus, reovirus, and herpes simplex virus type I (HSV-1). These viruses have been modified or engineered to enhance their tumour-selective replication, reduce toxicity, and improve oncolytic properties.Newer generations of OVs, such as Oncoviron and Delta-24-RGD adenovirus, exhibit heightened replication selectivity and enhanced anticancer effects, particularly in breast cancer models. Clinical trials have explored the efficacy and safety of various OVs in treating different cancers, including melanoma, nasopharyngeal carcinoma, head and neck cancer, and gynecologic malignancies. Notably, Talimogene laherparepvec (T-VEC) and Oncorine have. been approved for advanced melanoma and nasopharyngeal carcinoma, respectively. However, adverse effects have been reported in some cases, including flu-like symptoms and rare instances of severe complications such as fistula formation. Although no OV has been approved specifically for breast cancer treatment, ongoing preclinical clinical trials focus on four groups of viruses. While mild adverse effects like low-grade fever and nausea have been observed, the effectiveness of OV monotherapy in breast cancer remains insufficient. Combination strategies integrating OVs with chemotherapy, radiotherapy, or immunotherapy, show promise in improving therapeutic outcomes. Oncolytic virus therapy holds substantial potential in breast cancer treatment, demonstrating safety in trials. Multi-approach strategies combining OVs with conventional therapies exhibit more promising therapeutic effects than monotherapy, signalling a hopeful future for OV-based breast cancer treatments.
Topics: Female; Humans; Oncolytic Virotherapy; Melanoma; Oncolytic Viruses; Breast Neoplasms; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Tumor Microenvironment
PubMed: 38576614
DOI: 10.3389/fimmu.2024.1375433 -
Signal Transduction and Targeted Therapy Apr 2024
Topics: Oncolytic Viruses; Oncolytic Virotherapy; Cell Line, Tumor
PubMed: 38565863
DOI: 10.1038/s41392-024-01815-2 -
Molecular Oncology Apr 2024Oncolytic viruses (OVs) are biological therapeutic agents that selectively destroy cancer cells while sparing normal healthy cells. Besides direct oncolysis, OV...
Oncolytic viruses (OVs) are biological therapeutic agents that selectively destroy cancer cells while sparing normal healthy cells. Besides direct oncolysis, OV infection induces a proinflammatory shift in the tumor microenvironment and the release of tumor-associated antigens (TAAs) that might induce an anti-tumor immunity. Due to their immunostimulatory effect, OVs have been explored for cancer vaccination against specific TAAs. However, this approach usually requires genetic modification of the virus and the production of a new viral vector for each target, which is difficult to implement for low prevalent antigens. In a recent study, Chiaro et al. presented an elegant proof of concept on how to implement the PeptiCRAd vaccination platform to overcome this limitation for the treatment of mesothelioma. Authors showed the feasibility of identifying immunogenic TAAs in human mesothelioma and using them to coat oncolytic adenovirus particles. The result was a customized virus-based cancer vaccine that circumvents time and resource-consuming steps incurred from genetically engineering viruses. Although some questions remain to be addressed, this interesting approach suggests novel strategies for personalized cancer medicine using oncolytic virotherapy.
Topics: Humans; Adenoviridae; Marriage; Oncolytic Viruses; Oncolytic Virotherapy; Neoplasms; Mesothelioma; Mesothelioma, Malignant; Antigens, Neoplasm; Tumor Microenvironment
PubMed: 38561242
DOI: 10.1002/1878-0261.13648 -
Heliyon Apr 2024Oncolytic viruses (OV) are part of a burgeoning field of investigational oncolytic therapy (OT), in which lytic viruses dissolve advanced tumors productively and...
Oncolytic viruses (OV) are part of a burgeoning field of investigational oncolytic therapy (OT), in which lytic viruses dissolve advanced tumors productively and specifically. One such OT is a Coxsackievirus A21 (CVA21) based OV that is currently under clinical evaluation. A tissue culture infectious dose (TCID50) assay was used for CVA21 potency release and stability testing in early clinical development. The titer measured in this method was an extrapolated value from cytopathic effect (CPE) observed during the serial dilution but doesn't represent direct viral killing of cells. Moreover, the assay was not deemed to be optimal to carry into late phase clinical development due to limitations in assay precision, turn-around time, and sample throughput. To address these points, we developed a plaque assay to measure viral plaque forming units to measure the potency value for drug substance (DS), drug product (DP) and virus seed (master and working) stocks. In this manuscript, we describe the steps taken to develop this plaque assay for the late-stage clinical development, which include the assay qualification, validation, and robustness protocols, and describe statistical methods for data analysis. Moreover, the method was validated for linearity, accuracy, precision, and specificity. Furthermore, the plaque assay quantifies OV infectivity with better precision (32% vs 58%), with higher sample throughput (22 samples/week vs 3 samples/week) and shorter assay turnaround time (4 days vs 7 days) than the TCID50 method. This assay development strategy can provide guidance for the development of robust cell-based potency methods for OVs and other infectious viral products.
PubMed: 38560158
DOI: 10.1016/j.heliyon.2024.e28414 -
Frontiers in Immunology 2024In recent years, oncolytic viruses have emerged as promising agents for treating various cancers. An oncolytic virus is a non-pathogenic virus that, due to genetic... (Review)
Review
In recent years, oncolytic viruses have emerged as promising agents for treating various cancers. An oncolytic virus is a non-pathogenic virus that, due to genetic manipulation, tends to replicate in and cause lysis of cancerous cells while leaving healthy cells unaffected. Among these viruses, vaccinia virus is an attractive platform for use as an oncolytic platform due to its 190 Kb genome with a high capacity for encoding therapeutic payloads. Combining oncolytic VV therapy with other conventional cancer treatments has been shown to be synergistic and more effective than monotherapies. Additionally, OVV can be used as a vector to deliver therapeutic payloads, alone or in combination with other treatments, to increase overall efficacy. Here, we present a comprehensive analysis of preclinical and clinical studies that have evaluated the efficacy of oncolytic vaccinia viruses in cancer immunotherapy. We discuss the outcomes of these studies, including tumor regression rates, overall survival benefits, and long-term responses. Moreover, we provide insights into the challenges and limitations associated with oncolytic vaccinia virus- based therapies, including immune evasion mechanisms, potential toxicities, and the development of resistance.
Topics: Humans; Oncolytic Viruses; Vaccinia virus; Oncolytic Virotherapy; Neoplasms; Immunotherapy
PubMed: 38558795
DOI: 10.3389/fimmu.2024.1272351 -
Mathematical Biosciences and... Feb 2024Bortezomib and oncolytic virotherapy are two emerging targeted cancer therapies. Bortezomib, a proteasome inhibitor, disrupts protein degradation in cells, leading to...
Bortezomib and oncolytic virotherapy are two emerging targeted cancer therapies. Bortezomib, a proteasome inhibitor, disrupts protein degradation in cells, leading to the accumulation of unfolded proteins that induce apoptosis. On the other hand, virotherapy uses genetically modified oncolytic viruses (OVs) to infect cancer cells, trigger cell lysis, and activate anti-tumor response. Despite progress in cancer treatment, identifying administration protocols for therapeutic agents remains a significant concern, aiming to strike a balance between efficacy, minimizing toxicity, and administrative costs. In this work, optimal control theory was employed to design a cost-effective and efficient co-administration protocols for bortezomib and OVs that could significantly diminish the population of cancer cells via the cell death program with the NF$ \kappa $B-BAX-RIP1 signaling network. Both linear and quadratic control strategies were explored to obtain practical treatment approaches by adapting necroptosis protocols to efficient cell death programs. Our findings demonstrated that a combination therapy commencing with the administration of OVs followed by bortezomib infusions yields an effective tumor-killing outcome. These results could provide valuable guidance for the development of clinical administration protocols in cancer treatment.
Topics: Humans; Bortezomib; Oncolytic Virotherapy; Oncolytic Viruses; Neoplasms; Cell Death
PubMed: 38549312
DOI: 10.3934/mbe.2024173 -
Viruses Feb 2024Adenoviruses (Ad) have the potential to induce severe infections in vulnerable patient groups. Therefore, understanding Ad biology and antiviral processes is important... (Review)
Review
Adenoviruses (Ad) have the potential to induce severe infections in vulnerable patient groups. Therefore, understanding Ad biology and antiviral processes is important to comprehend the signaling cascades during an infection and to initiate appropriate diagnostic and therapeutic interventions. In addition, Ad vector-based vaccines have revealed significant potential in generating robust immune protection and recombinant Ad vectors facilitate efficient gene transfer to treat genetic diseases and are used as oncolytic viruses to treat cancer. Continuous improvements in gene delivery capacity, coupled with advancements in production methods, have enabled widespread application in cancer therapy, vaccine development, and gene therapy on a large scale. This review provides a comprehensive overview of the virus biology, and several aspects of recombinant Ad vectors, as well as the development of Ad vector, are discussed. Moreover, we focus on those Ads that were used in preclinical and clinical applications including regenerative medicine, vaccine development, genome engineering, treatment of genetic diseases, and virotherapy in tumor treatment.
Topics: Humans; Adenoviridae; Genetic Vectors; Genetic Therapy; Vaccines; Neoplasms; Oncolytic Virotherapy
PubMed: 38543743
DOI: 10.3390/v16030377 -
Viruses Feb 2024The absence of tumor-infiltrating lymphocytes negatively impacts the response to chemotherapy and prognosis in all subtypes of breast cancer. Therapies that stimulate a...
The absence of tumor-infiltrating lymphocytes negatively impacts the response to chemotherapy and prognosis in all subtypes of breast cancer. Therapies that stimulate a proinflammatory environment may help improve the response to standard treatments and also to immunotherapies such as checkpoint inhibitors. Newcastle disease virus (NDV) shows oncolytic activity, as well as immune modulating potential, in the treatment of breast cancer in vitro and in vivo; however, its potential to enhance tumor-infiltrating immune cells in breast cancer has yet to be evaluated. Since spontaneous canine mammary tumors represent a translational model of human breast cancer, we conducted this proof-of-concept study, which could provide a rationale for further investigating NDV-MLS as immunotherapy for mammary cancer. Six female companion dogs with spontaneous mammary cancer received a single intravenous and intratumoral injection of oncolytic NDV-MLS. Immune cell infiltrates were evaluated by histology and immunohistochemistry in the stromal, intratumoral, and peritumoral compartments on day 6 after viral administration. Increasing numbers of immune cells were documented post-viral treatment, mainly in the peritumoral compartment, where plasma cells and CD3+ and CD3-/CD79- lymphocytes predominated. Viral administration was well tolerated, with no significant adverse events. These findings support additional research on the use of NDV-MLS immunotherapy for mammary cancer.
Topics: Humans; Animals; Female; Dogs; Newcastle disease virus; Oncolytic Virotherapy; Pets; Oncolytic Viruses; Immunotherapy; Cell Line, Tumor; Neoplasms
PubMed: 38543739
DOI: 10.3390/v16030372