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Amalgamating oncolytic viruses to enhance their safety, consolidate their killing mechanisms, and accelerate their spread.

ABSTRACT: Oncolytic viruses are structurally and biologically diverse, spreading through tumors and killing them by various mechanisms and with different kinetics. Here, we created a hybrid vesicular stomatitis/measles virus (VSV/MV) that harnesses the safety of oncolytic MV, the speed of VSV, and the tumor killing mechanisms of both viruses. Oncolytic MV targets CD46 and kills by forcing infected cells to fuse with uninfected neighbors, but propagates slowly. VSV spreads rapidly, directly lysing tumor cells, but is neurotoxic and loses oncolytic potency when neuroattenuated by conventional approaches. The hybrid VSV/MV lacks neurotoxicity, replicates rapidly with VSV kinetics, and selectively targets CD46 on tumor cells. Its in vivo performance in a myeloma xenograft model was substantially superior to either MV or widely used recombinant oncolytic VSV-M51.

SUBMITTER: Ayala-Breton C

PROVIDER: S-EPMC3808140 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Amalgamating oncolytic viruses to enhance their safety, consolidate their killing mechanisms, and accelerate their spread.

Ayala-Breton Camilo C Suksanpaisan Lukkana L Mader Emily K EK Russell Stephen J SJ Peng Kah-Whye KW

Molecular therapy : the journal of the American Society of Gene Therapy 20130711 10

Oncolytic viruses are structurally and biologically diverse, spreading through tumors and killing them by various mechanisms and with different kinetics. Here, we created a hybrid vesicular stomatitis/measles virus (VSV/MV) that harnesses the safety of oncolytic MV, the speed of VSV, and the tumor killing mechanisms of both viruses. Oncolytic MV targets CD46 and kills by forcing infected cells to fuse with uninfected neighbors, but propagates slowly. VSV spreads rapidly, directly lysing tumor ce ...[more]

PMID: 23842448

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Project description:Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors that developed spontaneously and progressed as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8+ T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multitargeted receptor tyrosine kinase inhibitor. These effects were not mimicked by selective inhibition of VEGFR2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells and greater influx of activated CD8+ T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8+ T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by coadministration of sunitinib.Significance: These findings reveal multiple unrecognized features of the antitumor properties of oncolytic vaccinia viruses, all of which can be amplified by the multitargeted kinase inhibitor sunitinib. Cancer Res; 78(4); 922-37. ©2017 AACR.

Project description:BackgroundOncolytic viruses (OVs) have shown prospects in advanced and metastatic cancer, and many clinical trials have been carried out. To compare OV therapies comprehensively and provide a categorized profile and ranking of efficacy and safety, a network meta-analysis was conducted.MethodsA total of 5948 studies were screened and 13 randomized controlled trials with 1939 patients, of whom 1106 patients received OV therapies, comparing four OVs (NTX-010, pexastimogene devacirepvec (Pexa-Vec), talimogene laherparepvec (T-VEC), and pelareorep) were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: objective response rate (ORR) and grade ≥ 3 adverse events.ResultsCompared to systemic treatments alone, talimogene laherparepvec (T-VEC) (OR 7.00, 95% CI 1.90-26.00) and T-VEC plus systemic treatment (2.90, 0.80-11.00) showed better objective response rates (ORRs), whereas Pexa-Vec 1 * 109 pfu plus systemic treatment (0.91, 0.26-3.00) and pelareorep plus systemic treatment (1.10, 0.61-2.00) were found to be comparable. The grade ≥ 3 adverse event ranking of the treatments from worst to best was as follows: T-VEC (ranking probability 24%), Pexa-Vec 1 * 109 pfu plus systemic treatment (21%), Pexa-Vec 1 * 109 pfu (17%), T-VEC plus systemic treatment (13%), pelareorep plus systemic treatment (13%), systemic treatments (18%), Pexa-Vec 1 * 108 pfu (12%), and NTX-010 (20%).ConclusionsCompared with other oncolytic virus therapies for patients with advanced or metastatic cancer, T-VEC and T-VEC plus systemic treatment appear to provide the best ORR therapy in terms of monotherapy and combination respectively, but should be given with caution to grade ≥ 3 adverse events. Conversely, combining OVs with chemotherapy or target agents was demonstrated not to improve efficacy compared with chemotherapy or target agents alone. Combining OV therapies with immune-checkpoint inhibitors, instead of chemotherapy or target agents, tended to provide better ORRs without causing severe adverse events. This study will guide treatment choice and optimize future trial designs for investigations of advanced or metastatic cancer.

Dataset Information

Amalgamating oncolytic viruses to enhance their safety, consolidate their killing mechanisms, and accelerate their spread.

Publications

Amalgamating oncolytic viruses to enhance their safety, consolidate their killing mechanisms, and accelerate their spread.

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