Rodents Versus Pig Model for Assessing the Performance of Serotype Chimeric Ad5/3 Oncolytic Adenoviruses

Koodie, Lisa; Robertson, Matthew; Chandrashekar, Malavika; Ruth, G. R.; Dunning, Michele; Bianco, Richard W.; Davydova, Julia

doi:10.3390/cancers11020198

Cited by 17 publications

(21 citation statements)

References 55 publications

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“…Second, the highly efficient binding of coagulation FX of human origin to HAdv-C5 was also shown for mouse coagulation FX [8]. Sixth and last, leukocytopenia and thrombocytopenia observed after intravenous administration of HAdv to mice [] are also observed in rabbits [150], nonhuman primates [59], and humans [148] but not in pigs [151]. Fourth, the cytosolic inactivation of HAdv-Ab complexes by TRIM21 appears to function in both mouse and human systems [141,142].…”

Section: Complexity Of Designing Hadv Vectors With Reduced Innate Immmentioning

confidence: 92%

“…Fifth, high-dose intravenous delivery to mice [143] and nonhuman primates [59] of HAdv triggers an acute release of IL-6 and TNF-a, a response stereotypically observed in patients with severe natural HAdv infection [144][145][146] and during clinical gene therapy trials with systemic delivery of high doses of HAdv-based vectors [60,147,148]. Sixth and last, leukocytopenia and thrombocytopenia observed after intravenous administration of HAdv to mice [] are also observed in rabbits [150], nonhuman primates [59], and humans [148] but not in pigs [151]. The vast majority of humans are exposed to various HAdv serotypes through natural infections [152].…”

Section: Relevance Of Mice and Other Animals As Models Of Human Immunmentioning

confidence: 99%

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Innate immunity to adenovirus: lessons from mice

2019

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Adenovirus is a highly evolutionary successful pathogen, as it is widely prevalent across the animal kingdom, infecting hosts ranging from lizards and frogs to dolphins, birds, and humans. Although natural adenovirus infections in humans rarely cause severe pathology, intravenous injection of high doses of adenovirus-based vectors triggers rapid activation of the innate immune system, leading to cytokine storm syndrome, disseminated intravascular coagulation, thrombocytopenia, and hepatotoxicity, which individually or in combination may cause morbidity and mortality. Much of the information on exactly how adenovirus activates the innate immune system has been gathered from mouse experimental systems. Intravenous administration of adenovirus to mice revealed mechanistic insights into cellular and molecular components of the innate immunity that detect adenovirus particles, activate pro-inflammatory signaling pathways and cytokine production, sequester adenovirus particles from the bloodstream, and eliminate adenovirus-infected cells. Collectively, this information greatly improved our understanding of mechanisms of activation of innate immunity to adenovirus and may pave the way for designing safer adenovirus-based vectors for therapy of genetic and acquired human diseases.Human adenovirus (HAdv) is remarkably efficient at infecting and replicating in human cells. These properties made HAdv-based vectors an attractive platform for developing novel therapeutics to combat genetic diseases and cancer. Unfortunately, early studies revealed that HAdv is a potent activator of the innate and adaptive arms of the immune system, and administration to animals or patients of high doses of HAdv-based vectors, especially via an intravascular route, leads to severe immunopathology, manifested by cytokine storm syndrome, disseminated intravascular coagulation, thrombocytopenia, and hepatotoxicity, which may lead to morbidity and even mortality. To harness the full potential of HAdv as a gene delivery or oncolytic virus platform, a complete understanding of the molecular and cellular components of innate Abbreviations is a founder, shareholder, and chief scientific officer of AdCure Bio, LLC, which develops Ad-based therapies for clinical use.

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Section: Complexity Of Designing Hadv Vectors With Reduced Innate Immmentioning

confidence: 92%

Section: Relevance Of Mice and Other Animals As Models Of Human Immunmentioning

confidence: 99%

Innate immunity to adenovirus: lessons from mice

2019

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“…Viral copy number was quantitated by SYBR Green RT-PCR with adenoviral E4 primers and compensated with β-actin. 23 , 33 …”

Section: Methodsmentioning

confidence: 99%

Cancer imaging and therapy utilizing a novel NIS-expressing adenovirus: The role of adenovirus death protein deletion

Robertson

Eidenschink

Iguchi

et al. 2021

Molecular Therapy - Oncolytics

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Encoding the sodium iodide symporter (NIS) by an adenovirus (Ad) is a promising strategy to facilitate non-invasive imaging and radiotherapy of pancreatic cancer. However, insufficient levels of NIS expression in tumor cells have limited its clinical translation. To optimize Ad-based radiotherapy and imaging, we investigated the effect of Ad death protein (ADP) deletion on NIS expression. We cloned two sets of oncolytic NIS-expressing Ads that differed only in the presence or absence of ADP. We found that ADP expression negatively affected NIS membrane localization and inhibited radiotracer uptake. ADP deletion significantly improved NIS-based imaging in pancreatic cancer models including patient-derived xenografts, where effective imaging was possible for up to 6 weeks after a single virus injection. This study demonstrates that improved oncolysis may hinder the therapeutic effect of oncolytic viruses designed to express NIS. In vivo studies in combination with 131 I showed potential for effective radiotherapy. This also highlights the need for further investigation into optimal timing of 131 I administration and suggests that repeated doses of 131 I should be considered to improve efficacy in clinical trials. We conclude that ADP deletion is essential for effective NIS-based theranostics in cancer.

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“…However, since murine models are not permissive to human Ad5 replication due to species-specificity, preclinical assessment of Ad5 vectors has been limited. Thus far, Syrian hamster and porcine species have emerged as replication-competent animal models for investigating oncolytic adenoviruses [67] [68] [69]. Nonetheless, a suitable breast cancer cell line overexpressing CXCR4 or CXCR7 must also be developed to utilize these in vivo models.…”

Section: Discussionmentioning

confidence: 99%

CXCL12 Retargeting of an Oncolytic Adenovirus Vector to the Chemokine CXCR4 and CXCR7 Receptors in Breast Cancer

O’Bryan¹,

Mathis²

2021

JCT

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Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant progress has been made in developing targeted therapies for breast cancer, advanced breast cancer continues to have high mortality, with poor 5-year survival rates. Thus, current therapies are insufficient in treating advanced stages of breast cancer; new treatments are sorely needed to address the complexity of advanced-stage breast cancer. Oncolytic virotherapy has been explored as a therapeutic approach capable of systemic administration, targeting cancer cells, and sparing normal tissue. In particular, oncolytic adenoviruses have been exploited as viral vectors due to their ease of manipulation, production, and demonstrated clinical safety profile. In this study, we engineered an oncolytic adenovirus to target the chemokine receptors CXCR4 and CXCR7. The overexpression of CXCR4 and CXCR7 is implicated in the initiation, survival, progress, and metastasis of breast cancer. Both receptors bind to the ligand, CXCL12 (SDF-1), which has been identified to play a crucial role in the metastasis of breast cancer cells. This study incorporated a T4 fibritin protein fused to CXCL12 into the tail domain of an adenovirus fiber to retarget the vector to the CXCR4 and CXCR7 chemokine receptors. We showed that the modified virus targets and infects CXCR4-and CXCR7overexpressing breast cancer cells more efficiently than a wild-type control vector. In addition, the substitution of the wild-type fiber and knob with the modified chimeric fiber did not interfere with oncolytic capability. Overall, the results of this study demonstrate the feasibility of retargeting adenovirus vectors to chemokine receptor-positive tumors.

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Rodents Versus Pig Model for Assessing the Performance of Serotype Chimeric Ad5/3 Oncolytic Adenoviruses

Cited by 17 publications

References 55 publications

Innate immunity to adenovirus: lessons from mice

Innate immunity to adenovirus: lessons from mice

Cancer imaging and therapy utilizing a novel NIS-expressing adenovirus: The role of adenovirus death protein deletion

CXCL12 Retargeting of an Oncolytic Adenovirus Vector to the Chemokine CXCR4 and CXCR7 Receptors in Breast Cancer

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