Adenovirus Receptor Expression in Cancer and Its Multifaceted Role in Oncolytic Adenovirus Therapy

Hensen, Lobke C.; Hoeben, Rob C.; Bots, Selas T. F.

doi:10.3390/ijms21186828

Cited by 30 publications

(25 citation statements)

References 113 publications

(172 reference statements)

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“…Moreover, the novel AdV-D24-ICOSL-CD40L has been produced to purposefully infect cancer cells through the DSG-2 receptor. Indeed, in order to target tumor cells, the expression of the adenovirus receptor on the tumor cell surface is crucial [ 78 , 79 ]. Hence, it has been reported that different adenovirus serotypes bind various receptors on the cell of which the expression can vary between tumor types.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, it has been reported that different adenovirus serotypes bind various receptors on the cell of which the expression can vary between tumor types. Moreover, adenovirus 5 infects the cells through the CAR receptor, while adenovirus 3 binds to the DSG-2 and CD46 instead [ 79 ]. Accordingly, in our experiments, the expression level of the primary entry receptors has been assessed in both tested melanoma cell lines: MUG Mel-1 and MUG Mel-2.…”

Section: Discussionmentioning

confidence: 99%

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Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model

et al. 2021

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Malignant melanoma, an aggressive form of skin cancer, has a low five-year survival rate in patients with advanced disease. Immunotherapy represents a promising approach to improve survival rates among patients at advanced stage. Herein, the aim of the study was to design and produce, by using engineering tools, a novel oncolytic adenovirus AdV-D24- inducible co-stimulator ligand (ICOSL)-CD40L expressing potent co-stimulatory molecules enhancing clinical efficacy through the modulation of anti-cancer immune responses. Firstly, we demonstrated the vector’s identity and genetic stability by restriction enzyme assay and sequencing, then, by performing in vitro and in vivo pre-clinical studies we explored the anti-cancer efficacy of the virus alone or in combination with anti PD-1 inhibitor in human melanoma cell lines, i.e., MUG Mel-1 and MUG Mel-2, and in immunocompetent C57BL/6 melanoma B16V mouse model. We showed that both monotherapy and combination approaches exhibit enhanced anti-cancer ability and immunogenic cell death in in vitro settings. Furthermore, AdV-D24-ICOSL-CD40L combined with anti PD-1 revealed a fall in tumor volume and 100% survival in in vivo context, thus suggesting enhanced efficacy and survival via complementary anti-cancer properties of those agents in melanoma therapy. Collectively, the novel oncolytic vector AdV-D24-ICOSL-CD40L alone or in combination with anticancer drugs, such as check point inhibitors, may open novel therapeutic perspectives for the treatment of melanoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model

et al. 2021

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“…Syrian hamster models have been developed as an animal model for oncolytic species C HAdV vectors; however, AdV receptor studies are otherwise based on cell culture models. From a structural biological point of view, among the primary AdV receptors, only CAR and CD46 have solved structures in complex with their adenoviral ligands according to the entries in Protein Data Bank (PDB) database (Kilcher and Mercer, 2014;Brito and Pinney, 2017;Lasswitz et al, 2018;Hensen et al, 2020;Li et al, 2020;Stasiak and Stehle, 2020).…”

Section: Background Adenoviral Receptorsmentioning

confidence: 99%

ML-AdVInfect: A Machine-Learning Based Adenoviral Infection Predictor

Karabulut

Karpuzcu

Türk

et al. 2021

Front. Mol. Biosci.

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Adenoviruses (AdVs) constitute a diverse family with many pathogenic types that infect a broad range of hosts. Understanding the pathogenesis of adenoviral infections is not only clinically relevant but also important to elucidate the potential use of AdVs as vectors in therapeutic applications. For an adenoviral infection to occur, attachment of the viral ligand to a cellular receptor on the host organism is a prerequisite and, in this sense, it is a criterion to decide whether an adenoviral infection can potentially happen. The interaction between any virus and its corresponding host organism is a specific kind of protein-protein interaction (PPI) and several experimental techniques, including high-throughput methods are being used in exploring such interactions. As a result, there has been accumulating data on virus-host interactions including a significant portion reported at publicly available bioinformatics resources. There is not, however, a computational model to integrate and interpret the existing data to draw out concise decisions, such as whether an infection happens or not. In this study, accepting the cellular entry of AdV as a decisive parameter for infectivity, we have developed a machine learning, more precisely support vector machine (SVM), based methodology to predict whether adenoviral infection can take place in a given host. For this purpose, we used the sequence data of the known receptors of AdVs, we identified sets of adenoviral ligands and their respective host species, and eventually, we have constructed a comprehensive adenovirus–host interaction dataset. Then, we committed interaction predictions through publicly available virus-host PPI tools and constructed an AdV infection predictor model using SVM with RBF kernel, with the overall sensitivity, specificity, and AUC of 0.88 ± 0.011, 0.83 ± 0.064, and 0.86 ± 0.030, respectively. ML-AdVInfect is the first of its kind as an effective predictor to screen the infection capacity along with anticipating any cross-species shifts. We anticipate our approach led to ML-AdVInfect can be adapted in making predictions for other viral infections.

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“…Wild type Ad5 transduces host cells by attaching via the fiber knob domain to coxsackievirus and adenovirus receptor (CAR) and internalizing by endocytosis through the interaction of the conserved RGD sequences of its penton base proteins with αVβ3/αVβ5 integrins. However, expression of CAR is frequently barely detectable in primary tumor cells reducing Ad5 infection 9 – 13 . Ad5 tropism modification by inserting the RGD-4C peptide in the HI loop of the fiber knob domain enhanced CAR-independent transduction of a wide range of tumor cells of different tissue origin, including glioma 1 , 14 , 15 .…”

Section: Introductionmentioning

confidence: 99%

A new insight into aggregation of oncolytic adenovirus Ad5-delta-24-RGD during CsCl gradient ultracentrifugation

Stepanenko

Сосновцева

Valikhov

et al. 2021

Sci Rep

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Two-cycle cesium chloride (2 × CsCl) gradient ultracentrifugation is a conventional approach for purifying recombinant adenoviruses (rAds) for research purposes (gene therapy, vaccines, and oncolytic vectors). However, rAds containing the RGD-4C peptide in the HI loop of the fiber knob domain tend to aggregate during 2 × CsCl gradient ultracentrifugation resulting in a low infectious titer yield or even purification failure. An iodixanol-based purification method preventing aggregation of the RGD4C-modified rAds has been proposed. However, the reason explaining aggregation of the RGD4C-modified rAds during 2 × CsCl but not iodixanol gradient ultracentrifugation has not been revealed. In the present study, we showed that rAds with the RGD-4C peptide in the HI loop but not at the C-terminus of the fiber knob domain were prone to aggregate during 2 × CsCl but not iodixanol gradient ultracentrifugation. The cysteine residues with free thiol groups after the RGD motif within the inserted RGD-4C peptide were responsible for formation of the interparticle disulfide bonds under atmospheric oxygen and aggregation of Ad5-delta-24-RGD4C-based rAds during 2 × CsCl gradient ultracentrifugation, which could be prevented using iodixanol gradient ultracentrifugation, most likely due to antioxidant properties of iodixanol. A cysteine-to-glycine substitution of the cysteine residues with free thiol groups (RGD-2C2G) prevented aggregation during 2 × CsCl gradient purification but in coxsackie and adenovirus receptor (CAR)-low/negative cancer cell lines of human and rodent origin, this reduced cytolytic efficacy to the levels observed for a fiber non-modified control vector. However, both Ad5-delta-24-RGD4C and Ad5-delta-24-RGD2C2G were equally effective in the murine immunocompetent CT-2A glioma model due to a primary role of antitumor immune responses in the therapeutic efficacy of oncolytic virotherapy.

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Adenovirus Receptor Expression in Cancer and Its Multifaceted Role in Oncolytic Adenovirus Therapy

Cited by 30 publications

References 113 publications

Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model

Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model

ML-AdVInfect: A Machine-Learning Based Adenoviral Infection Predictor

A new insight into aggregation of oncolytic adenovirus Ad5-delta-24-RGD during CsCl gradient ultracentrifugation

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