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![VCN-01 antisarcoma effect in the orthotopic osteosarcoma model with the 531MII cell line. Tumors were developed by orthotopic injection of 500,000 531MII cells in the tibial tuberosity of female nude mice and were sacrificed 90 days later. A, analyses of tumor burden development. Tumor volume in the mice tibias was measured at different days until the end of experiment. B, PET images of tumor burden. Representative images of PET analyses of control mice or treated with VCN-01 (10 7 or 10 8 pfu). C, quantification of tumor burden by PET with the radiotracer 18 F-FDG. SUVmax was calculated using the formula SUV ¼ [tissue activity concentration (Bq/cm 3 )/injected dose (Bq)]  body weight. Represented are the mean AE SD, SUV values of the tumors of all animals in the same group (Wilcoxon test). D, representative macroscopic images of mice tibias from all treated groups. E, tumor volume evaluation. Quantification of tumor volume was calculated by the formula: volume (mm 3 ) ¼ [(long diameter  perpendicular diameter 2 )/2]. Represented](profile/Arlet-Acanda/publication/284709311/figure/fig2/AS:406480206483457@1473923841502/VCN-01-antisarcoma-effect-in-the-orthotopic-osteosarcoma-model-with-the-531MII-cell-line.png)
VCN-01 antisarcoma effect in the orthotopic osteosarcoma model with the 531MII cell line. Tumors were developed by orthotopic injection of 500,000 531MII cells in the tibial tuberosity of female nude mice and were sacrificed 90 days later. A, analyses of tumor burden development. Tumor volume in the mice tibias was measured at different days until the end of experiment. B, PET images of tumor burden. Representative images of PET analyses of control mice or treated with VCN-01 (10 7 or 10 8 pfu). C, quantification of tumor burden by PET with the radiotracer 18 F-FDG. SUVmax was calculated using the formula SUV ¼ [tissue activity concentration (Bq/cm 3 )/injected dose (Bq)]  body weight. Represented are the mean AE SD, SUV values of the tumors of all animals in the same group (Wilcoxon test). D, representative macroscopic images of mice tibias from all treated groups. E, tumor volume evaluation. Quantification of tumor volume was calculated by the formula: volume (mm 3 ) ¼ [(long diameter  perpendicular diameter 2 )/2]. Represented
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Purpose:
Osteosarcoma is the most common malignant bone tumor in children and adolescents. Despite aggressive chemotherapy more than 30% of patients do not respond and develop bone or lung metastasis. Oncolytic adenoviruses engineered to specifically destroy cancer cells are one feasible option for osteosarcoma treatment. VCN-01 is a replication c...
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... staining of liver sections did not reveal morphologic alterations associated with hepatotoxicity ( Fig. 2B and C). We observed no Councilman bodies, macrosteatosis, or necrotic areas. IHC did not detect expression of E1A and hexon (Supplementary Fig. S2A and S2B) in the liver, indicating absence of virus (Fig. 3B). Thus, in mice, locally or systemically administrated VCN-01 was not significantly toxic and was well ...
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... that purpose, we inoculated 531MII cells in the tibial tuberosity of nude mice followed by VCN-01 injection at days 7 and 21 administered at two different dosages (10 7 pfu/animal or 10 8 pfu/animal). PBS was adminis- tered to the control group ( Supplementary Fig. S3A). Tumor development was monitored every week until the end of the experiment (day 90 after cell implantation), and mice were then sacrificed. ...
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... the end of the experiment, there were clearly visible differ- ences in tumors in the three groups of mice (Fig. 3A). PET imaging also showed that tumor volumes were significantly bigger in the control group relative to those in the 10 8 pfu group (Fig. 3B and C). All control mice (5 mice  10 tibias) developed visible tibial tumors, whereas only 3 out of 10 tibias in the group treated with 10 7 pfu VCN-01 and none of the mice in the group treated ...
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... the end of the experiment, there were clearly visible differ- ences in tumors in the three groups of mice (Fig. 3A). PET imaging also showed that tumor volumes were significantly bigger in the control group relative to those in the 10 8 pfu group (Fig. 3B and C). All control mice (5 mice  10 tibias) developed visible tibial tumors, whereas only 3 out of 10 tibias in the group treated with 10 7 pfu VCN-01 and none of the mice in the group treated with 10 8 pfu VCN-01 did ( Fig. 3D and E). Tumor volumes of control mice ranged between 100 and 500 mm 3 ; volumes for mice in the 10 7 pfu group ...
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... also showed that tumor volumes were significantly bigger in the control group relative to those in the 10 8 pfu group (Fig. 3B and C). All control mice (5 mice  10 tibias) developed visible tibial tumors, whereas only 3 out of 10 tibias in the group treated with 10 7 pfu VCN-01 and none of the mice in the group treated with 10 8 pfu VCN-01 did ( Fig. 3D and E). Tumor volumes of control mice ranged between 100 and 500 mm 3 ; volumes for mice in the 10 7 pfu group were between 50 and 400 mm 3 ...
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... at the end of the experiment, tumors had the characteristic morphology of osteosarcoma and a notable pro- duction of malignant osteoid (Fig. 3F). In some control mice, tumors had grown such that they had crossed the epiphysis of the tibiae, resulting in transarticular tumors. In the VCN-01 lower dose treated group, there was evidence of a certain tumoral burden in some tibiae. Mice in the higher dose treated group showed no evidence of ...
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... the end of the experiment, approximately 70% of control mice presented lung metastases derived from the primary osteo- sarcoma tumor (Supplementary Fig. S4B). Of mice treated with VCN-01, only one in the 10 7 pfu-treated group developed lung metastasis ( Fig. 3E and F and Supplementary Figs S4B and ...
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... to express PH20, and that this PH20 was functional at digesting hyaluronic acid ( Supplementary Fig. S4A). RNA extracted from tibial sections was used to assess the expression of fiber and PH20. Expression of fiber and hyal- uronidase mRNA was higher in mice treated with VCN-01- 10 8 pfu group relative to those in the VCN-0 10 7 pfu-treated group (Fig. 3G). As in the in vitro experiments, there was a significant correlation between the levels of expression of hyaluronidase PH20 and fiber ...
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... administrated 2 Â 10 6 cells in the tail vein of athymic nude mice and, seven days later, mice were treated with four intravenous injections at doses of 10 7 pfu/animal of VCN-01 or 10 8 pfu/animal of VCN-01. Mice were sacrificed at day 60 ( Supplementary Fig. S3B). The objective of this experiment was the assessment of tumor burden in mice lungs and the evaluation of the capacity of VCN-01 to reach the tumors and to replicate in tumor cells after systemic adminis- tration. ...
Citations
... Several studies have modified adenovirus to encode relaxin to degrade the matrix metalloproteinases (MMPs), which in turn degrade the ECM [43,44]. To increase tissue permeability, oncolytic adenovirus was modified to encode hyaluronidase to target hyaluronan in the ECM [45]. Other strategies by which the oncolytic virus can alter the mechanism, such as adding endonuclease DNase I into the oncolytic adenovirus, could eliminate the free DNA and enhance virus spread [46]. ...
Oncolytic viruses have positively impacted cancer immunotherapy over the past 20 years. Both natural and genetically modified viruses have shown promising results in treating various cancers. Various regulatory authorities worldwide have approved four commercial oncolytic viruses, and more are being developed to overcome this limitation and obtain better anti-tumor responses in clinical trials at various stages. Faster advancements in translating research into the commercialization of cancer immunotherapy and a comprehensive understanding of the modification strategies will widen the current knowledge of future technologies related to the development of oncolytic viruses. In this review, we discuss the strategies of virus engineering and the progress of clinical trials to achieve virotherapeutics.
... VCN-01 is a replication-competent adenovirus with enhanced infectivity through a modified fibre specifically engineered to replicate in tumours with a defective Rb pathway, encoding a soluble hyaluronidase [215]. The anti-tumour effect of VCN-01 was evaluated in vitro in osteosarcoma patient-derived cell lines and in vivo in orthotopic intratibial and lung metastatic osteosarcoma murine models. ...
Viral vectors have been widely investigated as tools for cancer immunotherapy. Although many preclinical studies demonstrate significant virus-mediated tumour inhibition in synergy with immune checkpoint molecules and other drugs, the clinical success of viral vector applications in cancer therapy currently is limited. A number of challenges have to be solved to translate promising vectors to clinics. One of the key elements of successful virus-based cancer immunotherapy is the understanding of the tumour immune state and the development of vectors to modify the immunosuppressive tumour microenvironment (TME). Tumour-associated immune cells, as the main component of TME, support tumour progression through multiple pathways inducing resistance to treatment and promoting cancer cell escape mechanisms. In this review, we consider DNA and RNA virus vectors delivering immunomodulatory genes (cytokines, chemokines, co-stimulatory molecules, antibodies, etc.) and discuss how these viruses break an immunosuppressive cell development and switch TME to an immune-responsive “hot” state. We highlight the advantages and limitations of virus vectors for targeted therapeutic programming of tumour immune cell populations and tumour stroma, and propose future steps to establish viral vectors as a standard, efficient, safe, and non-toxic cancer immunotherapy approach that can complement other promising treatment strategies, e.g., checkpoint inhibitors, CAR-T, and advanced chemotherapeutics.
... Our group has evaluated the antisarcoma effect of the RB pathway-based viruses Delta-24-RGD (57) and VCN-01 (58). Both adenoviruses were able to control tumor volume, and specifically for Delta-24-RGD, the use of cisplatin as a combinatorial treatment improved the antitumor virus response, showing that combination therapies are, in fact, a possible solution. ...
Immunotherapy has seen tremendous strides in the last decade, acquiring a prominent position at the forefront of cancer treatment since it has been proven to be efficacious for a wide variety of tumors. Nevertheless, while immunotherapy has changed the paradigm of adult tumor treatment, this progress has not yet been translated to the pediatric solid tumor population. For this reason, alternative curative therapies are urgently needed for the most aggressive pediatric tumors. In recent years, oncolytic virotherapy has consolidated as a feasible strategy for cancer treatment, not only for its tumor-specific effects and safety profile but also for its capacity to trigger an antitumor immune response. This review will summarize the current status of immunovirotherapy to treat cancer, focusing on pediatric solid malignancies. We will revisit previous basic, translational, and clinical research and discuss advances in overcoming the existing barriers and limitations to translate this promising therapeutic as an every-day cancer treatment for the pediatric and young adult populations.
... The mTOR inhibitor rapamycin improved the survival rate of xenograft and isograft mice bearing pulmonary metastases compared to those treated with vehicle [161]. The oncolytic adenoviruses Delta24-RGD and VCN-01 both reduced the size and number of pulmonary metastases compared to control-treated mice in models of metastatic osteosarcoma using established cell lines and patient-derived cells [162]. Treatment of mice with the CXCR4 antagonist AMD3100 reduced the number of metastatic nodules in the lungs compared to vehicle-treated mice. ...
The survival rate for metastatic osteosarcoma has not improved for several decades, since the introduction and refinement of chemotherapy as a treatment in addition to surgery. Over two thirds of metastatic osteosarcoma patients, many of whom are children or adolescents, fail to exhibit durable responses and succumb to their disease. Concerted efforts have been made to increase survival rates through identification of candidate therapies via animal studies and early phase trials of novel treatments, but unfortunately, this work has produced negligible improvements to the survival rate for metastatic osteosarcoma patients. This review summarizes data from clinical trials of metastatic osteosarcoma therapies as well as pre-clinical studies that report efficacy of novel drugs against metastatic osteosarcoma in vivo. Considerations regarding the design of animal studies and clinical trials to improve survival outcomes for metastatic osteosarcoma patients are also discussed.
... HA has been identified as an obstacle for cancer therapies 7 including OVs, hampering drugs' extravasation and intratumoral spreading. 8 An OAd expressing hyaluronidase, VCN-01, enhanced the spread of tumor lysis in several relevant models, 15,17 which led to the testing of VCN-01 in clinical settings. 16 We hypothesized that a virus expressing higher amounts of hyal (PH20) might improve antitumor efficacy and the translational relevance of a hyaluronidase-expressing adenovirus. ...
Oncolytic viruses (OVs) preferentially infect and selectively replicate in cancer cells. OVs have been tested in clinical trials as monotherapy or in combination with chemotherapy, radiotherapy, and immunotherapy. However, the dense extracellular matrix hampers the intratumoral spreading and efficacy of OVs. Previously we described VCN-01, an oncolytic adenovirus expressing a soluble version of human sperm hyaluronidase PH20, which exhibited enhanced intratumoral distribution and antitumor activity in different models. Here, we present two oncolytic adenoviruses designed to increase the secretion of PH20 compared to VCN-01. ICO15K-40SAPH20, encoding PH20 under an Ad40 splice acceptor, and ICO15K-E1aPH20 expressing PH20 fused to the E1A gene by P2A peptide. We demonstrate that increased hyaluronidase activity improves antitumor efficacy in both a sensitive immunodeficient model and an immunocompetent model. Moreover, we show that hyaluronidase activity impacts T-cell accumulation in tumors, highlighting the value of a hyaluronidase-expressing virus for combinations with other immunotherapies in cancers involving dense stroma.
... identifiers: NCT02045589, NCT02045602). 81,82 Targeting tumor-associated stromal cells is another approach. Puig-Saus et al 83 have demonstrated that the C-terminus truncation of adenovirus i-leader protein leads to a bioselection against cancer-associated fibroblasts. ...
Despite advancements in cancer therapy that have occurred over the past several decades, successful treatment of advanced malignancies remains elusive. Substantial resources and significant efforts have been directed toward the development of novel therapeutic modalities to improve patient outcomes. Oncolytic viruses (OVs) are emerging tools with unique characteristics that have attracted great interest in developing effective anticancer treatment. The original attraction was directed toward selective replication and cell-specific toxicity, two unique features that are either inherent to the virus or could be conferred by genetic engineering. However, recent advancements in the knowledge and understanding of OVs are shifting the therapeutic paradigm toward a greater focus on their immunomodulatory role. Nonetheless, there are still significant obstacles that remain to be overcome to enhance the efficiency of OVs as effective therapeutic modalities and potentially establish them as part of standard treatment regimens. In this review, we discuss advances in the design of OVs, strategies to enhance their therapeutic efficacy, functional translation into the clinical settings, and various obstacles that are still encountered in the efforts to establish them as effective anticancer treatments.
... Cancer associated fibroblasts (CAFs) are key players in orchestrating the deposition of extracellular matrix components [279]. Oncolytic herpesvirus and adenovirus able to efficiently degrade components of the extracellular matrix and enhance viral spread and drug delivery by encoding metalloproteinase 9 (MMP9) and hyaluronidase within viral genome, respectively, were generated, with the latter one (VCN-01) showing to be safe and to induce intravitreous infiltration of CD4+ and CD8 + T cells in patients with refractory retinoblastoma [280][281][282][283] (Fig. 4c). ...
Since the discovery in 1796 by Edward Jenner of vaccinia virus as a way to prevent and finally eradicate smallpox, the concept of using a virus to fight another virus has evolved into the current approaches of viral vectored genetic vaccines. In recent years, key improvements to the vaccinia virus leading to a safer version (Modified Vaccinia Ankara, MVA) and the discovery that some viruses can be used as carriers of heterologous genes encoding for pathological antigens of other infectious agents (the concept of ‘viral vectors’) has spurred a new wave of clinical research potentially providing for a solution for the long sought after vaccines against major diseases such as HIV, TB, RSV and Malaria, or emerging infectious diseases including those caused by filoviruses and coronaviruses. The unique ability of some of these viral vectors to stimulate the cellular arm of the immune response and, most importantly, T lymphocytes with cell killing activity, has also reawakened the interest toward developing therapeutic vaccines against chronic infectious diseases and cancer. To this end, existing vectors such as those based on Adenoviruses have been improved in immunogenicity and efficacy. Along the same line, new vectors that exploit viruses such as Vesicular Stomatitis Virus (VSV), Measles Virus (MV), Lymphocytic choriomeningitis virus (LCMV), cytomegalovirus (CMV), and Herpes Simplex Virus (HSV), have emerged. Furthermore, technological progress toward modifying their genome to render some of these vectors incompetent for replication has increased confidence toward their use in infant and elderly populations. Lastly, their production process being the same for every product has made viral vectored vaccines the technology of choice for rapid development of vaccines against emerging diseases and for ‘personalised’ cancer vaccines where there is an absolute need to reduce time to the patient from months to weeks or days.
Here we review the recent developments in viral vector technologies, focusing on novel vectors based on primate derived Adenoviruses and Poxviruses, Rhabdoviruses, Paramixoviruses, Arenaviruses and Herpesviruses. We describe the rationale for, immunologic mechanisms involved in, and design of viral vectored gene vaccines under development and discuss the potential utility of these novel genetic vaccine approaches in eliciting protection against infectious diseases and cancer.
... The virus was well tolerated and showed a safe profile, but no response was observed (Kolb et al, 2015). The therapeutic effect of several oncolytic viruses in STSs (Leddon et al, 2015;Siurala et al, 2015;Wilkinson et al, 2016;Chen et al, 2017) and bone sarcomas (Witlox et al, 2004;Graat et al, 2006;Hingorani et al, 2014;Martínez-Vélez et al, 2016;Martinez-Velez et al, 2014) was tested in various preclinical studies. Due to their versatility and lack of toxicity, oncolytic Adenoviruses are commonly used (Fig 4). ...
... VCN-01 is an oncolytic Adenovirus where the E1A gene also contains deletions in the pRb binding site, thus rendering its selective replication in Rb-deficient tumor cells (Rodríguez-García et al, 2015). Importantly, both viruses have shown efficacy not only against the primary tumor but also against lung metastases (Martinez-Velez et al, 2014;Martínez-Vélez et al, 2016). It should be noted that most of the oncolytic Adenoviruses are amenable to be used in combination with standard chemotherapy, small molecules, nanoparticles, immunotherapy with immune checkpoint inhibitors, and CAR T cells. ...
Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma. © 2020 The Authors. Published under the terms of the CC BY 4.0 license
... Modifications to the penton base RGD binding domain and serotype switching or modifications of fiber knob proteins are all trying to modify tissue tropism (69). There are many examples like the RGD-4C motif used in DNX-2401, which binds cell adhesion molecules and allows entry through any fibronectin-binding integrin receptor (70); the chimeric ONCOS-102 and LOAd703 viruses, which respectively, incorporate CD46-tropic serotype 3 and 35 fiber knobs into serotype five backbones (71); and inclusion of an RGDK motif in the HS-GAG binding domain of the fiber shaft of VCN-01, which detargets the virus from the liver and enhances tumor selectivity in vivo (72,73). ...
Cancer has always been an enormous threat to human health and survival. Surgery, radiotherapy, and chemotherapy could improve the survival of cancer patients, but most patients with advanced cancer usually have a poor survival or could not afford the high cost of chemotherapy. The emergence of oncolytic viruses provided a new strategy for us to alleviate or even cure malignant tumors. An oncolytic virus can be described as a genetically engineered or naturally existing virus that can selectively replicate in cancer cells and then kill them without damaging the healthy cells. There have been many kinds of oncolytic viruses, such as herpes simplex virus, adenovirus, and Coxsackievirus. Moreover, they have different clinical applications in cancer treatment. This review focused on the clinical application of oncolytic virus and predicted the prospect by analyzing the advantages and disadvantages of oncolytic virotherapy.
... An armed-OAd encoding for relaxin, a peptide hormone able to induce remodeling by degrading collagen and up-regulating matrix metalloproteases, improved the oncolytic potential and tumor spreading in highly metastatic tumor models [106,107]. VCN-01 (Table 1) is an oncolytic adenovirus armed with a soluble version of human hyaluronidase (PH20; SPAM1) to degrade hyaluronic acid from the tumor matrix [69,[108][109][110][111]. VCN-01 is currently in clinical trials in pancreatic, retinoblastoma, and head and neck cancers. ...
Clinical results with oncolytic adenoviruses (OAds) used as antitumor monotherapies show limited efficacy. To increase OAd potency, transgenes have been inserted into their genome, a strategy known as “arming OAds”. Here, we review different parameters that affect the outcome of armed OAds. Recombinant adenovirus used in gene therapy and vaccination have been the basis for the design of armed OAds. Hence, early region 1 (E1) and early region 3 (E3) have been the most commonly used transgene insertion sites, along with partially or complete E3 deletions. Besides transgene location and orientation, transcriptional control elements, transgene function, either virocentric or immunocentric, and even the codons encoding it, greatly impact on transgene levels and virus fitness.
