Mechanistic Modeling of a Novel Oncolytic Virus, V937, to Describe Viral Kinetic and Dynamic Processes Following Intratumoral and Intravenous Administration.

Zinnia P Parra-Guillen,Youfang Cao,Dinesh De Alwis,Tomoko Freshwater,Iñaki F Troconiz,Maria J Garrido,Kapil Mayawala,Sara Zalba

doi:10.3389/fphar.2021.705443

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 elicited by 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.

Highlights

Over the past 4 decades, the oncology treatment landscape has dramatically changed with the development of advanced and targeted immunotherapies, which complement or even replace classical chemotherapy and radiotherapy strategies (Madden, 2018)
In vitro V937 replication data, in vivo V937 levels in sera and tumors, and tumor sizes in control and V937-treated mice in multiple human melanoma xenograft studies were integrated in the analysis to build the mechanistic model
Descriptions of the available data are as follows: In Vitro Viral Replication Data of V937 replication in two human melanoma cells lines SKMel-28 (NCI-DTP Cat# SK-MEL-28, RRID:CVCL_0526) and ME4405 (RRID:CVCL_C680) and a rhabdomyosarcoma cell line transfected with ICAM-1, RD-ICAM-1, were extracted from Au et al, 2005

Summary

Introduction

Over the past 4 decades, the oncology treatment landscape has dramatically changed with the development of advanced and targeted immunotherapies, which complement or even replace classical chemotherapy and radiotherapy strategies (Madden, 2018). Oncolytic virus therapy represents one such novel class of immunotherapy. Advantages of this approach rely on the ability of oncolytic viruses to selectively replicate in cancer cells without harming normal tissues. This process leads to a direct lysis of the tumor mass, as well as the generation of a de novo anti-tumor immune response or boosting of an existing one (Kaufman et al, 2015). The intravenous (i.v.) administration would potentially expand oncolytic viral treatment to less accessible tumors as well as obviate the need for interventional radiology, among other benefits. Systemic administration needs to overcome viral neutralization, liver and spleen sequestration, and vessel extravasation to exceed the a priori unknown “viremic threshold” above which tumor destruction can be achieved (Russell et al, 2012)

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