scholarly journals Optimization of Early Steps in Oncolytic Adenovirus ONCOS-401 Production in T-175 and HYPERFlasks

2019 ◽  
Vol 20 (3) ◽  
pp. 621 ◽  
Author(s):  
Lukasz Kuryk ◽  
Anne-Sophie Møller ◽  
Antti Vuolanto ◽  
Sari Pesonen ◽  
Mariangela Garofalo ◽  
...  
Keyword(s):  
Scale Up ◽  
A549 Cells ◽  
Oncolytic Adenovirus ◽  
Oncolytic Viruses ◽  
Oncolytic Adenoviruses ◽  
Combination Strategies ◽  
Viral Particles ◽  
Advanced Therapy ◽  
Viral Yield ◽  
Harvesting Method

Oncolytic adenoviruses can trigger lysis of tumor cells, induce an antitumor immune response, bypass classical chemotherapeutic resistance strategies of tumors, and provide opportunities for combination strategies. A major challenge is the development of scalable production methods for viral seed stocks and sufficient quantities of clinical grade viruses. Because of promising clinical signals in a compassionate use program (Advanced Therapy Access Program) which supported further development, we chose the oncolytic adenovirus ONCOS-401 as a testbed for a new approach to scale up. We found that the best viral production conditions in both T-175 flasks and HYPERFlasks included A549 cells grown to 220,000 cells/cm2 (80% confluency), with ONCOS-401 infection at 30 multiplicity of infection (MOI), and an incubation period of 66 h. The Lysis A harvesting method with benzonase provided the highest viral yield from both T-175 and HYPERFlasks (10,887 ± 100 and 14,559 ± 802 infectious viral particles/cell, respectively). T-175 flasks and HYPERFlasks produced up to 2.1 × 109 ± 0.2 and 1.75 × 109 ± 0.08 infectious particles of ONCOS-401 per cm2 of surface area, respectively. Our findings suggest a suitable stepwise process that can be applied to optimizing the initial production of other oncolytic viruses.

CGTG-102 (Ad5/3-D24-GMCSF), a novel oncolytic adenovirus, in patients with refractory solid tumors: Experience from an advanced therapy access program.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13035-e13035
Author(s):  
Mikael Von Euler ◽  
Anna Kanerva ◽  
Petri Nokisalmi ◽  
Anniina Koski ◽  
Iulia Diaconu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Oncolytic Adenovirus ◽  
Eligibility Criteria ◽  
Minor Response ◽  
Preclinical Testing ◽  
Viral Particles ◽  
Advanced Therapy ◽  
Wide Range ◽  
Major Organ ◽  
Tumor Types

e13035 Background: Following preclinical testing CGTG-102, a 5/3 chimeric oncolytic adenovirus armed with human GMCSF, has been used to treat 115 refractory cancer patients. Methods: Eligibility criteria included refractory advanced solid tumors, no major organ deficiencies and written informed consent. Patients were treated with either a single treatment or serial treatments with one or more viruses. Intra tumoral administration was performed under ultrasound guidance. The initial dose, 8 x 1010 Viral Particles (VP), was based on published safety results and preclinical testing and escalated in later patients. A routinely tolerated dose of 3 x 1011 VP was deemed optimal and is the target dose for clinical development. To reduce regulatory T-cells, low-dose cyclophosphamide 50 mg/day was given. Adverse Reactions (AR) were scored according to CTCAE 3.0. Imaging was done by CT before and ~2 months after treatment. Response was scored according to RECIST 1.1, including injected and non-injected lesions. Decrease not fulfilling PR was scored as minor response (MR). Results: The most common ARs were pain (82%), fever (81%), fatigue (79%), nausea (54%) and hemoglobin decrease (48%). Pain is mostly tumor pain or pain in the injected tumor, which may be causally related to the MOA of the therapy. Most ARs were G1 or G2; 6 were G4: 2 Hb decrease, 2 pulmonary embolism and single reports of thrombocytopenia and pericardial effusion, most probably due to the underlying disease.Imaging was performed when clinically useful. 65/115 are evaluable by imaging: 3% PR, 11% MR, 40% SD and 46% PD. Best results were obtained in Breast Cancer, Melanoma, Soft Tissue Sarcoma, Mesothelioma and Ovarian Cancer. Median survival in this heavily pre-treated refractory population is 164d, 95% CI 122d – 206d. Mean survival is 281d reflecting that approx. 30% survive more than 300d and 15% up to 600d. A wide range of samples are being analyzed to further characterize the viral and immunological aspects of the therapy. Conclusions: CGTG-102 is a novel oncolytic adenovirus with good safety profile and encouraging signs of efficacy. Formal clinical studies are underway in several tumor types in both US and EU.

scholarly journals Oncolytic Adenovirus: Prospects for Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yaqi Zhao ◽  
Zheming Liu ◽  
Lan Li ◽  
Jie Wu ◽  
Huibo Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Cancer Immunotherapy ◽  
Checkpoint Inhibitors ◽  
Oncolytic Adenovirus ◽  
Oncolytic Viruses ◽  
Engineering Technology ◽  
Antiviral Immune Response ◽  
Oncolytic Adenoviruses ◽  
Genetic Engineering Technology ◽  
Oncologic Treatment

Immunotherapy has moved to the forefront of modern oncologic treatment in the past few decades. Various forms of immunotherapy currently are emerging, including oncolytic viruses. In this therapy, viruses are engineered to selectively propagate in tumor cells and reduce toxicity for non-neoplastic tissues. Adenovirus is one of the most frequently employed oncolytic viruses because of its capacity in tumor cell lysis and immune response stimulation. Upregulation of immunostimulatory signals induced by oncolytic adenoviruses (OAds) might significantly remove local immune suppression and amplify antitumor immune responses. Existing genetic engineering technology allows us to design OAds with increasingly better tumor tropism, selectivity, and antitumor efficacy. Several promising strategies to modify the genome of OAds have been applied: capsid modifications, small deletions in the pivotal viral genes, insertion of tumor-specific promoters, and addition of immunostimulatory transgenes. OAds armed with tumor-associated antigen (TAA) transgenes as cancer vaccines provide additional therapeutic strategies to trigger tumor-specific immunity. Furthermore, the combination of OAds and immune checkpoint inhibitors (ICIs) increases clinical benefit as evidence shown in completed and ongoing clinical trials, especially in the combination of OAds with antiprogrammed death 1/programed death ligand 1 (PD-1/PD-L1) therapy. Despite remarkable antitumor potency, oncolytic adenovirus immunotherapy is confronted with tough challenges such as antiviral immune response and obstruction of tumor microenvironment (TME). In this review, we focus on genomic modification strategies of oncolytic adenoviruses and applications of OAds in cancer immunotherapy.

scholarly journals Unleashing the Full Potential of Oncolytic Adenoviruses against Cancer by Applying RNA Interference: The Force Awakens

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 228 ◽  
Author(s):  
Tereza Brachtlova ◽  
Victor van Beusechem
Keyword(s):  
Rna Interference ◽  
Immune Responses ◽  
Oncolytic Viruses ◽  
Full Potential ◽  
Anticancer Efficacy ◽  
Host Interactions ◽  
Oncolytic Adenoviruses ◽  
Cellular Factors ◽  
Immunotherapy Of Cancer ◽  
Cellular Pathways

Oncolytic virus therapy of cancer is an actively pursued field of research. Viruses that were once considered as pathogens threatening the wellbeing of humans and animals alike are with every passing decade more prominently regarded as vehicles for genetic and oncolytic therapies. Oncolytic viruses kill cancer cells, sparing healthy tissues, and provoke an anticancer immune response. Among these viruses, recombinant adenoviruses are particularly attractive agents for oncolytic immunotherapy of cancer. Different approaches are currently examined to maximize their therapeutic effect. Here, knowledge of virus–host interactions may lead the way. In this regard, viral and host microRNAs are of particular interest. In addition, cellular factors inhibiting viral replication or dampening immune responses are being discovered. Therefore, applying RNA interference is an attractive approach to strengthen the anticancer efficacy of oncolytic viruses gaining attention in recent years. RNA interference can be used to fortify the virus’ cancer cell-killing and immune-stimulating properties and to suppress cellular pathways to cripple the tumor. In this review, we discuss different ways of how RNA interference may be utilized to increase the efficacy of oncolytic adenoviruses, to reveal their full potential.

scholarly journals Adenovirus and Immunotherapy: Advancing Cancer Treatment by Combination

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1295 ◽  
Author(s):  
Mizuho Sato-Dahlman ◽  
Christopher J. LaRocca ◽  
Chikako Yanagiba ◽  
Masato Yamamoto
Keyword(s):  
Gene Therapy ◽  
Cancer Treatment ◽  
Viral Vectors ◽  
Therapeutic Strategy ◽  
Tumor Antigens ◽  
Oncolytic Viruses ◽  
The Past ◽  
Oncolytic Adenoviruses ◽  
Gene Therapy Vectors ◽  
Preclinical And Clinical Studies

Gene therapy with viral vectors has significantly advanced in the past few decades, with adenovirus being one of the most commonly employed vectors for cancer gene therapy. Adenovirus vectors can be divided into 2 groups: (1) replication-deficient viruses; and (2) replication-competent, oncolytic (OVs) viruses. Replication-deficient adenoviruses have been explored as vaccine carriers and gene therapy vectors. Oncolytic adenoviruses are designed to selectively target, replicate, and directly destroy cancer cells. Additionally, virus-mediated cell lysis releases tumor antigens and induces local inflammation (e.g., immunogenic cell death), which contributes significantly to the reversal of local immune suppression and development of antitumor immune responses (“cold” tumor into “hot” tumor). There is a growing body of evidence suggesting that the host immune response may provide a critical boost for the efficacy of oncolytic virotherapy. Additionally, genetic engineering of oncolytic viruses allows local expression of immune therapeutics, thereby reducing related toxicities. Therefore, the combination of oncolytic virus and immunotherapy is an attractive therapeutic strategy for cancer treatment. In this review, we focus on adenovirus-based vectors and discuss recent progress in combination therapy of adenoviruses with immunotherapy in preclinical and clinical studies.

scholarly journals Past, Present and Future of Oncolytic Reovirus

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3219
Author(s):  
Louise Müller ◽  
Robert Berkeley ◽  
Tyler Barr ◽  
Elizabeth Ilett ◽  
Fiona Errington-Mais
Keyword(s):  
Immune Responses ◽  
Therapeutic Agent ◽  
Tumour Microenvironment ◽  
Oncolytic Viruses ◽  
Full Potential ◽  
Cellular Mechanisms ◽  
Tumour Immunity ◽  
Combination Strategies ◽  
Significant Attention ◽  
Promising Therapeutic Agent

Oncolytic virotherapy (OVT) has received significant attention in recent years, especially since the approval of talimogene Laherparepvec (T-VEC) in 2015 by the Food and Drug administration (FDA). Mechanistic studies of oncolytic viruses (OVs) have revealed that most, if not all, OVs induce direct oncolysis and stimulate innate and adaptive anti-tumour immunity. With the advancement of tumour modelling, allowing characterisation of the effects of tumour microenvironment (TME) components and identification of the cellular mechanisms required for cell death (both direct oncolysis and anti-tumour immune responses), it is clear that a “one size fits all” approach is not applicable to all OVs, or indeed the same OV across different tumour types and disease locations. This article will provide an unbiased review of oncolytic reovirus (clinically formulated as pelareorep), including the molecular and cellular requirements for reovirus oncolysis and anti-tumour immunity, reports of pre-clinical efficacy and its overall clinical trajectory. Moreover, as it is now abundantly clear that the true potential of all OVs, including reovirus, will only be reached upon the development of synergistic combination strategies, reovirus combination therapeutics will be discussed, including the limitations and challenges that remain to harness the full potential of this promising therapeutic agent.

Intratumoral injection of oncolytic adenovirus H101 in combination with vinorelbine/cisplatin chemotherapy in patients with advanced non-small cell lung cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17082-17082
Author(s):  
C. Zhou ◽  
Y. Xu ◽  
J. Ni ◽  
S. Zhou ◽  
J. Xu
Keyword(s):  
Advanced Nsclc ◽  
Survival Rates ◽  
Intratumoral Injection ◽  
Oncolytic Adenovirus ◽  
Time To Progression ◽  
Minor Response ◽  
Viral Particles ◽  
New Strategy ◽  
Nsclc Patients ◽  
First Time

17082 Background: Chemotherapy is main treatment for advanced NSCLC. But its efficacy is quite small with improvement of 1–2 months in median survival. New strategy against NSCLC is needed. Oncolytic adenovirus H101 is found to be effective against NSCLC. This trial is desigened to investigate efficacy and toxicity of intratumoral injection of H101 in combination with chemotherapy in the treatment of NSCLC. Methods: The NSCLC patients confirmed cytologically or pathologically were randomized to intratumoral injection of adenovirus H101 (1.5 × 1012 viral particles) plus NP chemotherapy (arm A) or NP chemotherapy (arm B). Objetive response was evaluated every two cycles and time to progression (TTP) and overall survival were followed up. Results: Out of 18 evaluable patients in Arm A, 4 patients showed partial response (PR),3 minor response(MR), 7 stable disease (SD) and 4 disease progression (PD), while in Arm B 16 evaluable patients showed 3 PR, 4 MR, 3 SD and 6 PD. At the first time of response evaluation, there was 1 PD in Arm A,but in Arm B there were 5 of PD. Failure rate in Arm B was significantly higher than in Arm B. Survival curves between the two arms were similar. Six month, 9 month and 1 year survival rates were slightly higher in Arm B and median TTP was also prolonged in Arm A. Except non-infectious fever, Arm A was similar in other toxicities to Arm B. there was only 2 patients developing mild pneumothorax. Conclusions: Intratumoral injection of H101 1.5 × 1012 viral particles in combination with NP chemotherapy was feasible, effective and safe in treatment of advanced NSCLC. No significant financial relationships to disclose.

scholarly journals Advanced Therapy Medicines Based on Oncolytic Viruses (Part I: Development and Authorisation of Products in China)

2021 ◽  
Vol 11 (3) ◽  
pp. 148-159
Author(s):  
E. V. Melnikova ◽  
O. A. Rachinskaya ◽  
V. A. Merkulov
Keyword(s):  
Combination Therapy ◽  
Oncolytic Viruses ◽  
Scientific Publications ◽  
Preclinical Trial ◽  
Clinical Trial Registries ◽  
Advanced Therapy ◽  
Selective Targeting ◽  
Innovative Products ◽  
The Russian Federation ◽  
Analyse Data

One of the promising areas in the development of innovative products for the treatment of cancer is the use of oncolytic (native or genetically modified) viruses (OLVs) for selective targeting of tumour cells and their destruction, especially as part of combination therapy. At present, there are three OLV-based products approved for medical use (two in China and one in the USА and EU). The aim of the study was to analyse data on specific aspects of OLV-based products’ development, preclinical and clinical research, and authorisation process in China. The authors analysed data freely available on the manufacturers’ websites, in public reports and documents of the Chinese regulatory authorities, in international clinical trial registries, and scientific publications. The products Gendicine® (SiBiono GeneTech Co., Ltd.) and Oncorine® (Shanghai Sunway Biotech Co., Ltd.) were originally developed and approved in China for clinical use as part of combination therapy. The analysis demonstrated long product development periods (Gendicine had been studied for 14 years before the start of the authorisation procedures), complex preclinical trial designs, and potential use of the products for several medical conditions with different tumour localisation. The identified specific aspects of OVL-based products’ development and authorisation in China could be taken into account in the regulatory practice of the Russian Federation.

scholarly journals Multiple Treatment Cycles of Neural Stem Cell Delivered Oncolytic Adenovirus for the Treatment of Glioblastoma

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6320
Author(s):  
Jennifer Batalla-Covello ◽  
Hoi Wa Ngai ◽  
Linda Flores ◽  
Marisa McDonald ◽  
Caitlyn Hyde ◽  
...  
Keyword(s):  
High Grade Glioma ◽  
Oncolytic Adenovirus ◽  
Human Trial ◽  
Multiple Treatment ◽  
Intracerebral Administration ◽  
Therapeutic Benefits ◽  
Viral Particles ◽  
Rapid Clearance ◽  
Immunocompetent Mice ◽  
Higher Doses

Tumor tropic neural stem cells (NSCs) can improve the anti-tumor efficacy of oncovirotherapy agents by protecting them from rapid clearance by the immune system and delivering them to multiple distant tumor sites. We recently completed a first-in-human trial assessing the safety of a single intracerebral dose of NSC-delivered CRAd-Survivin-pk7 (NSC.CRAd-S-pk7) combined with radiation and chemotherapy in newly diagnosed high-grade glioma patients. The maximum feasible dose was determined to be 150 million NSC.CRAd-Sp-k7 (1.875 × 1011 viral particles). Higher doses were not assessed due to volume limitations for intracerebral administration and the inability to further concentrate the study agent. It is possible that therapeutic efficacy could be maximized by administering even higher doses. Here, we report IND-enabling studies in which an improvement in treatment efficacy is achieved in immunocompetent mice by administering multiple treatment cycles intracerebrally. The results imply that pre-existing immunity does not preclude therapeutic benefits attainable by administering multiple rounds of an oncolytic adenovirus directly into the brain.

Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01

2019 ◽  
Vol 11 (476) ◽  
pp. eaat9321 ◽  
Author(s):  
Guillem Pascual-Pasto ◽  
Miriam Bazan-Peregrino ◽  
Nagore G. Olaciregui ◽  
Camilo A. Restrepo-Perdomo ◽  
Ana Mato-Berciano ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Phase 1 ◽  
Standard Of Care ◽  
Oncolytic Adenovirus ◽  
Systemic Complications ◽  
Oncolytic Adenoviruses ◽  
Short Time ◽  
The Brain ◽  
Local Side

Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressorRB1. VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. In mice, intravitreous administration of VCN-01 in retinoblastoma xenografts induced tumor necrosis, improved ocular survival compared with standard-of-care chemotherapy, and prevented micrometastatic dissemination into the brain. In juvenile immunocompetent rabbits, VCN-01 did not replicate in retinas, induced minor local side effects, and only leaked slightly and for a short time into the blood. Initial phase 1 data in patients showed the feasibility of the administration of intravitreous VCN-01 and resulted in antitumor activity in retinoblastoma vitreous seeds and evidence of viral replication markers in tumor cells. The treatment caused local vitreous inflammation but no systemic complications. Thus, oncolytic adenoviruses targeting RB1 might provide a tumor-selective and chemotherapy-independent treatment option for retinoblastoma.

scholarly journals High levels of Daxx due to low cellular levels of HSP25 in murine cancer cells result in inefficient adenovirus replication

2019 ◽  
Vol 51 (10) ◽  
pp. 1-20
Author(s):  
Zhezhu Han ◽  
Yeonsoo Joo ◽  
Jihyun Lee ◽  
Suwan Ko ◽  
Rong Xu ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cell Lines ◽  
Cancer Cell ◽  
Nuclear Translocation ◽  
Cancer Cell Lines ◽  
Oncolytic Adenovirus ◽  
Transcriptional Level ◽  
Death Domain ◽  
Oncolytic Adenoviruses ◽  
Mouse Cells

Abstract When the adenoviral protein E1B55K binds death domain-associated protein (Daxx), the proteasome-dependent degradation of Daxx is initiated, and adenoviral replication is effectively maintained. Here, we show that the cellular levels of Daxx differ between human and mouse cancer cell lines. Specifically, we observed higher cellular Daxx levels and the diminished replication of oncolytic adenovirus in mouse cancer cell lines, suggesting that cellular Daxx levels limit the replication of oncolytic adenoviruses that lack E1B55K in murine cells. Indeed, the replication of oncolytic adenoviruses that lack E1B55K was significantly increased following infection with oncolytic adenovirus expressing Daxx-specific shRNA. Cellular Daxx levels were decreased in mouse cells expressing heat shock protein 25 (HSP25; homolog of human HSP27) following heat shock or stable transfection with HSP25-bearing plasmids. Furthermore, Daxx expression in murine cell lines was primarily regulated at the transcriptional level via HSP25-mediated inhibition of the nuclear translocation of the signal transducer and activator of transcription 3 (stat3) protein, which typically upregulates Daxx transcription. Conversely, human HSP27 enhanced stat3 activity to increase Daxx transcription. Interestingly, human Daxx, but not mouse Daxx, was degraded as normal by ubiquitin-dependent lysosomal degradation; however, HSP27 downregulation induced the ubiquitin-independent proteasomal degradation of Daxx.

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