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Oncolytic virotherapy represents an ideal therapeutic platform for cancer in which natural or engineered viruses selectively replicate in and destroy tumor cells, whereas sparing normal cells. Oncolytic virotherapy is considered a...
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Oncolytic virotherapy represents an ideal therapeutic platform for cancer in which natural or engineered viruses selectively replicate in and destroy tumor cells, whereas sparing normal cells. Oncolytic virotherapy is considered as a key contributor in modern immunotherapy. However, several challenges remain with regard to exploiting the potential of oncolytic viruses, such as the lack of biomarkers for precise treatment, the difficulty of systemic administration because of pre-existing neutralizing antibodies to popular oncolytic viral vectors in human serum and the lack of mature lyophilization technology for convenient transport and preservation of viral preparations. The M1 strain, which was isolated on Hainan Island of China in the 1960s, is a member of the alphavirus genus Togaviridae family. It was identified as a novel oncolytic virus in 2014. During the development of M1 virus, many challenges have been overcome: several biomarkers have been identified for precise treatment; systematic administration of M1 is suitable and feasible because of the extremely low percentage of pre-existing neutralizing antibodies in the general population, and a lyophilized powder that maintains high biological stability has been developed. This review provides an encyclopedia of studies supporting M1 as an oncolytic virus, including the biological characteristics, tumor selectivity and its mechanism, tumor killing mechanism, combination therapy, and nonclinical pharmacokinetics of M1 virus. The future development direction of oncolytic virus M1 is also discussed at the end of the review.
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Since the turn of the nineteenth century, when their existence was first recognized, viruses have attracted considerable interest as possible agents of tumor destruction. Early case reports emphasized regression of cancers during ...
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Since the turn of the nineteenth century, when their existence was first recognized, viruses have attracted considerable interest as possible agents of tumor destruction. Early case reports emphasized regression of cancers during naturally acquired virus infections, providing the basis for clinical trials where body fluids containing human or animal viruses were used to transmit infections to cancer patients. Most often the viruses were arrested by the host immune system and failed to impact tumor growth, but sometimes, in immunosuppressed patients, infection persisted and tumors regressed, although morbidity as a result of the infection of normal tissues was unacceptable. With the advent of rodent models and new methods for virus propagation, there were numerous attempts through the 1950s and 1960s to force the evolution of viruses with greater tumor specificity, but success was limited and many researchers abandoned the field. Technology employing reverse genetics later brought about a renewal of interest in virotherapy that allowed the generation of more potent, tumor-specific oncolytics. Here, examination of early oncolytic virotherapy before genetic engineering serves to highlight tremendous advances, yet also hints at ways to penetrate host immune defenses, a significant remaining challenge in modern virotherapy research.
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Recent years have seen tremendous advances in the development of exquisitely targeted replicating virotherapeutics that can safely destroy malignant cells. Despite this promise, clinical advancement of this powerful and unique app...
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Recent years have seen tremendous advances in the development of exquisitely targeted replicating virotherapeutics that can safely destroy malignant cells. Despite this promise, clinical advancement of this powerful and unique approach has been hindered by vulnerability to host defenses and inefficient systemic delivery. However, it now appears that delivery of oncolytic viruses within carrier cells may offer one solution to this critical problem. In this review, we compare the advantages and limitations of the numerous cell lineages that have been investigated as delivery platforms for viral therapeutics, and discuss examples showing how combined cell-virus biotherapeutics can be used to achieve synergistic gains in antitumor activity. Finally, we highlight avenues for future preclinical research that might be taken in order to refine cell-virus biotherapeutics in preparation for human trials.
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Creeping cautiously at 15 mph into the teeth of a driving snowstorm along a dark, deserted Canadian highway at 4 am, returning from the 5th International Meeting on Replicating Oncolytic Virus Therapeutics, provided an ideal oppor...
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Creeping cautiously at 15 mph into the teeth of a driving snowstorm along a dark, deserted Canadian highway at 4 am, returning from the 5th International Meeting on Replicating Oncolytic Virus Therapeutics, provided an ideal opportunity for some thoughtful reflection. To avoid contemplating the possibility of our imminent demise-perhaps by plunging off the mountain or being mowed down by a truck-we used the time to reflect on the content of the meeting and to formulate our ideas about the current state of the field.
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Creeping cautiously at 15 mph into the teeth of a driving snowstorm along a dark, deserted Canadian highway at 4 am, returning from the 5th International Meeting on Replicating Oncolytic Virus Therapeutics, provided an ideal oppor...
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Creeping cautiously at 15 mph into the teeth of a driving snowstorm along a dark, deserted Canadian highway at 4 am, returning from the 5th International Meeting on Replicating Oncolytic Virus Therapeutics, provided an ideal opportunity for some thoughtful reflection. To avoid contemplating the possibility of our imminent demise-perhaps by plunging off the mountain or being mowed down by a truck-we used the time to reflect on the content of the meeting and to formulate our ideas about the current state of the field.
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Virotherapy is a promising strategy for cancer treatment. Using the human telomerase reverse transcriptase promoter, we developed a novel tumor-selective replication oncolytic HSV-1. Here we showed that oHSV1-hTERT virus was cytop...
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Virotherapy is a promising strategy for cancer treatment. Using the human telomerase reverse transcriptase promoter, we developed a novel tumor-selective replication oncolytic HSV-1. Here we showed that oHSV1-hTERT virus was cytopathic in telomerase-positive cancer cell lines but not in telomerase-negative cell lines. In intra-venous injection in mice, oHSV1-hTERT was safer than its parental oHSV1-17+. In human blood cell transduction assays, both viruses transduced few blood cells and the transduction rate for oHSV1-hTERT was even less than that for its parental virus. In vivo, oHSV1-hTERT inhibited growth of tumors and prolong survival in telomerase-positive xenograft tumor models. Therefore, we concluded that this virus may be a safe and effective therapeutic agent for cancer treatment, warranting clinical trials in humans.
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Abstract Purpose No standard of care therapy exists for patients with metastatic uveal melanoma who are not HLA-A2:01 positive. The phase 1b, open-label CLEVER study (NCT03408587) evaluated V937 in combination with ipilimumab in p...
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Abstract Purpose No standard of care therapy exists for patients with metastatic uveal melanoma who are not HLA-A2:01 positive. The phase 1b, open-label CLEVER study (NCT03408587) evaluated V937 in combination with ipilimumab in patients with uveal melanoma.Methods Adults with advanced uveal melanoma and liver metastases received up to 8 cycles of intravenous V937 (1?×?109 TCID50 per infusion; infusions on days 1, 3, 5, and 8 [cycle 1], then every 3?weeks [Q3W] thereafter [cycles 2–8]) and 4 cycles of intravenous ipilimumab 3?mg/kg Q3W (beginning at cycle 1?day 8). The primary endpoint was safety. Secondary endpoints included objective response rate and progression-free survival (PFS) per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).Results Eleven patients were enrolled (median age, 65.0?years) and received a median of 6 injections of V937 and 3.5 infusions of ipilimumab. The best overall response was stable disease in 3 patients and progressive disease in 8 patients. All patients exhibited progression per irRECIST, with a 9% irPFS rate at week 26. Ten patients had treatment-related AEs, the most frequent of which were diarrhea (55%), fatigue (45%), and myalgia (36%). Two grade 3 AEs (diarrhea, n?=?2) were considered related to ipilimumab; neither was related to V937.Conclusion Although the combination of V937 with ipilimumab had a manageable safety profile, meaningful clinical benefit was not observed in patients with uveal melanoma and liver metastases.Trial registration ClinicalTrials.gov, NCT03408587 (January 24, 2018).
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Oncolytic virotherapy has currently emerged as a promising approach upon which scientists have been able to induce tumor-specific cell death in a broad spectrum of malignancies. Paramyxoviruses represent intrinsic oncolytic capabi...
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Oncolytic virotherapy has currently emerged as a promising approach upon which scientists have been able to induce tumor-specific cell death in a broad spectrum of malignancies. Paramyxoviruses represent intrinsic oncolytic capability, which makes them excellent candidates to be widely used in oncolytic virotherapy. The mechanisms through which these viruses destroy the cancerous cells involve triggering the autophagic machinery and apoptosis in target cells. Interestingly, oncolytic paramyxoviruses have been found to induce autophagy and lead to tumor cells death rather than their survival. Indeed, the induction of autophagy has been revealed to enhance the immunogenicity of tumor cells via the release of damage-associated molecular patterns (DAMPs) and the activation of autophagy-related immunogenic cell death (ICD). Subsequent cross-presentation of tumor-associated antigens (TAA) through the MHC-I complex to CD8+ T cells results in the productive priming of the tumor-specific immune response. In this review, we first briefly discuss autophagy and explain the process of viral xenophagy. Finally, we focus on the interactions between virus and autophagy proteins, elaborating on the global preclinical studies on oncolytic paramyxoviruses.
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ABSTRACT Interferons (INFs) elicit antiviral responses in tumor cells upon binding to cell surface receptors. Oncolytic virotherapy (OV) is an effective antitumor therapeutic approach which in combination with standard radiotherap...
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ABSTRACT Interferons (INFs) elicit antiviral responses in tumor cells upon binding to cell surface receptors. Oncolytic virotherapy (OV) is an effective antitumor therapeutic approach which in combination with standard radiotherapy or chemotherapy regimens potentiates treatment responses in cancer patients. However, oncolytic viruses are susceptible to the IFN‐induced antiviral state in the tumor microenvironment. A number of studies have, therefore, investigated the effects of combined therapy of IFN signaling pharmacological inhibitors with oncolytic viruses, which result in improved virus replication and oncolysis. This review summarizes the current knowledge of the mechanisms of interferon‐mediated tumor resistance to oncolytic virotherapy and provides new insights regarding the effectiveness of combinatorial treatment strategies to attenuate INF‐induced OV resistance for greater clinical significance in the treatment of cancer patients. J. Cell. Biochem. 118: 1994–1999, 2017. ? 2017 Wiley Periodicals, Inc.
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