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Mechanistic modeling of a novel oncolytic virus, V937, to describe viral kinetic and dynamic processes following intratumoral and intravenous administration
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  • Zinnia P Parra Guillen,
  • Tomoko Freshwater,
  • Youfang Cao,
  • Kapil Mayawala,
  • Sara Zalba Oteiza,
  • Maria Garrido,
  • Dinesh de Alwis,
  • Iñaki Trocóniz
Zinnia P Parra Guillen
University of Navarra
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Tomoko Freshwater
Merck & Co Inc
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Youfang Cao
Merck & Co Inc
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Kapil Mayawala
Merck & Co Inc
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Sara Zalba Oteiza
University of Navarra
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Maria Garrido
University of Navarra
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Dinesh de Alwis
Merck & Co Inc
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Iñaki Trocóniz
University of Navarra

Corresponding Author:[email protected]

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Abstract

V937 is an investigational novel oncolytic, non-genetically modified Kuykendall strain of Coxsackievirus A21 which is in clinical development for the treatment of advanced solid tumor malignancies. V937 infects and lyses tumor cells expressing the intercellular adhesion molecule I (ICAM-I) receptor. We integrated in vitro and in vivo data from six different preclinical studies to build a mechanistic model that allowed a quantitative analysis of the biological processes of V937 viral kinetics and dynamics, viral distribution to tumor, and anti-tumor response to V937 in human xenograft models in immunodeficient mice following intratumoral and intravenous administration. Estimates of viral infection and replication which were calculated from in vitro experiments were successfully used to describe the tumor response in vivo under various experimental conditions. Despite the predicted high clearance rate of V937 in systemic circulation (t1/2=4.3 min), high viral replication was observed in immunodeficient mice which resulted in tumor shrinkage with both intratumoral and intravenous administration. The described framework represents a step towards the quantitative characterization of viral distribution, replication, and oncolytic effect of a novel oncolytic virus following intratumoral and intravenous administrations in the absence of an immune response. This model may further be expanded to integrate the role of the immune system on viral and tumor dynamics to support the clinical development of oncolytic viruses.