Superior infectivity of the fiber chimeric oncolytic adenoviruses Ad5/35 and Ad5/3 over Ad5-delta-24-RGD in primary glioma cultures

Stepanenko, Aleksei A.; Сосновцева, А. О.; Valikhov, Marat P.; Chernysheva, Anastasia A.; Cherepanov, S. A.; Yusubalieva, Gaukhar M.; Ruszics, Zsolt; Lipatova, Anastasiya V.; Чехонин, В. П.

doi:10.1016/j.omto.2021.12.013

Cited by 18 publications

(10 citation statements)

References 70 publications

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“…L1 and E55 cells were transduced with Ad5 and Ad5/3K which engages DSG2 as a cell entry receptor [23]. Ad5/3K has previously been reported as demonstrating superior infectivity in glioma cells [43]. As previously demonstrated, Ad5 was able to transduce both cell lines efficiently.…”

Section: Discussionmentioning

confidence: 91%

Engineering Adenoviral Vectors With Improved GBM Selectivity

Bates¹,

Lovatt²,

Plein³

et al. 2023

Preprint

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Glioblastoma (GBM) is the most common and aggressive adult brain cancer with an average survival rate of around 15 months in patients receiving standard treatment. Oncolytic adenovirus expressing therapeutic transgenes represent a promising alternative treatment for GBM. Of the many human adenoviral serotypes described to date, adenovirus 5 (Ad5) has been most utilized clinically and experimentally. However, the use of Ad5 as an anti-cancer agent may be hampered by naturally high seroprevalence rates to Ad5 coupled with infection of healthy cells via native receptors. To explore whether alternative natural adenoviral tropisms are better suited to GBM therapeutics, we pseudotyped an Ad5 based platform with the fiber knob protein from alternative serotypes. We demonstrate that the adenoviral entry receptors coxsackie and adenovirus receptor (CAR) and CD46 are highly expressed by both GBM and healthy brain tissue, whereas Desmoglein 2 (DSG2) is expressed at low level in GBM. We demonstrate that adenoviral pseudotypes, engaging CAR, CD46 and DSG2, effectively transduce GBM cells. However, the presence of these receptors on non-transformed cells presents the possibility of off-target effects and therapeutic transgene expression in healthy cells. To enhance specificity of transgene expression to GBM, we assessed the potential for tumour specific promoters hTERT and survivin to drive reporter gene expression selectively in GBM cell lines. We demonstrate tightly GBM specific transgene expression using these constructs, indicating that the combination of pseudotyping and tumour specific promoters approaches may enable the development of efficacious therapies better suited to GBM.

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Section: Discussionmentioning

confidence: 91%

Engineering Adenoviral Vectors With Improved GBM Selectivity

Bates¹,

Lovatt²,

Plein³

et al. 2023

Preprint

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“…These data, coupled with a rapid development of the toxic signs, indicate that the hepatotoxicity of the oncolytic viruses is capsid-dependent rather than transcript-dependent. The improved safety of Ad5/35 is most likely associated with the Ad35 fiber that is shorter than the Ad5 fiber [ 32 , 33 ]. Previously, the Ad5/35 vectors, with the whole fiber derived from Ad35, demonstrated less toxicity, while the chimeric vectors containing only the Ad35 fiber knob were equally effective with parental Ad5 in killing KCs [ 10 , 11 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Ad5-RGD-Δ24-E1B-p2A-Fluc, Ad5/3-Δ24-E1B-p2A-Fluc, Ad5/35-Δ24-E1B-p2A-Fluc, Ad5-RGD-Δ24-E1B-p2A-EGFP, Ad5/3-Δ24-DBP-p2A-EGFP, Ad5/35-Δ24-DBP-p2A-EGFP, and Ad-5RGD-Δ24-pIIIA-EGFP (Fib-L5) were constructed, rescued, amplified, purified, stored, and titered, as detailed in [ 32 , 33 ]. The labeling of the adenoviral constructs was achieved by adding 10 μg Alexa Fluo 647 NHS Ester (Thermo Fisher Scientific, Waltham, MA, USA) to 8 × 10 11 viral particles (VP).…”

Section: Methodsmentioning

confidence: 99%

“…The AML12 murine hepatocytes (ATCC CRL-2254) were seeded onto 96-well white plates (2.5 × 10 4 cells/well) and infected in suspension with serial dilutions of Ads. At 24 h post-infection (hpi) the cells were analyzed, as previously described [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

“…The AML12 cells (2500 cells/well) were seeded onto 96-well plates and infected in suspension with serial dilutions of Ads. Five days post-infection, the cells were analyzed as previously described [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

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In Vivo Tracking for Oncolytic Adenovirus Interactions with Liver Cells

et al. 2022

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Hepatotoxicity remains an as yet unsolved problem for adenovirus (Ad) cancer therapy. The toxic effects originate both from rapid Kupffer cell (KCs) death (early phase) and hepatocyte transduction (late phase). Several host factors and capsid components are known to contribute to hepatotoxicity, however, the complex interplay between Ad and liver cells is not fully understood. Here, by using intravital microscopy, we aimed to follow the infection and immune response in mouse liver from the first minutes up to 72 h post intravenous injection of three Ads carrying delta-24 modification (Ad5-RGD, Ad5/3, and Ad5/35). At 15–30 min following the infusion of Ad5-RGD and Ad5/3 (but not Ad5/35), the virus-bound macrophages demonstrated signs of zeiosis: the formation of long-extended protrusions and dynamic membrane blebbing with the virus release into the blood in the membrane-associated vesicles. Although real-time imaging revealed interactions between the neutrophils and virus-bound KCs within minutes after treatment, and long-term contacts of CD8+ T cells with transduced hepatocytes at 24–72 h, depletion of neutrophils and CD8+ T cells affected neither rate nor dynamics of liver infection. Ad5-RGD failed to complete replicative cycle in hepatocytes, and transduced cells remained impermeable for propidium iodide, with a small fraction undergoing spontaneous apoptosis. In Ad5-RGD-immune mice, the virus neither killed KCs nor transduced hepatocytes, while in the setting of hepatic regeneration, Ad5-RGD enhanced liver transduction. The clinical and biochemical signs of hepatotoxicity correlated well with KC death, but not hepatocyte transduction. Real-time in vivo tracking for dynamic interactions between virus and host cells provides a better understanding of mechanisms underlying Ad-related hepatotoxicity.

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