Zinnia P Parra-Guillen1,2, Tomoko Freshwater3, Youfang Cao4, Kapil Mayawala3, Sara Zalba Oteiza1,2, Maria J Garrido1,2, Dinesh de Alwis3, Iñaki F. Troconiz1,2
1 Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain. 2 IdiSNA, Navarra Institute for Health Research, Spain. 3 Quantitative Pharmacology and Pharmacometrics Immune/Oncology, Global Clinical Development, Merck & Co, Inc, Kenilworth, New Jersey, USA. 4 Quantitative Pharmacology and Pharmacometrics, PPDM, Merck & Co, Inc, Kenilworth, New Jersey, USA.
Objectives: Oncolytic viral therapy represents a promising class of immunotherapy which relies on the ability of the oncolytic virus to selectively replicate in cancer cells leading to direct and/or immune dependent tumor lysis (1). Although intratumoral (i.t.) administration route is most frequently used, intravenous (i.v.) administration could expand viral treatment to less accessible tumors if different biological barriers can be overcome to achieve sufficient viral exposure. The aim of this work was to develop a mechanistic framework to quantitatively understand viral kinetics, dynamics, distribution to tumor lesions and tumor response of a novel oncolytic virus currently under development, V937, following i.t. and i.v. administration in human xenograft tumor models in immunodeficient mice.
Methods: To build the mathematical model, a sequential and integrative approach using in vitro and in vivo data from literature and in-house preclinical studies was followed. First, in vitro viral replication data were used to characterize viral dynamics (2). Then, sera and tumor viral RNA measurements from xenografts bearing one tumor lesion and receiving a single dose i.v. V937 administration (104 or 107 TCDI50) were used to characterize viral kinetics and distribution to tumor using a minimal physiological model and taking into account previously developed viral dynamic model in step 1. In addition, tumor volume measurements from immunodeficient mice bearing one or two lesions and receiving placebo or a single dose i.v. or i.t. V937 administration (10-107 TCID50) were integrated to characterized drug effect. Data were analyzed using NONMEM 7.4. Simulations and a global sensitivity analysis were performed.
Results: Estimates of viral infection and replication calculated from in vitro experiments were successfully used to describe the tumor response in vivo under various experimental conditions. The final model characterized following biological processes: (i) systemic viral clearance (t1/2=4.3 min), (ii) distribution between sera and tumor vasculature, (iii) viral infection of tumor cells (b=0.489 x10–8 1/TCID50/h), (iv) production and release of newly formed virions by infected tumor cells (a=208 copies/cell) and (v) and viral induced tumor cell death (d=0.17 1/day). Despite the predicted high viral clearance, high viral replication was observed resulting in tumor shrinkage with both routes of administration. Only increments in viral replication, viral infectivity or tumor retention were able to modify the course of tumor response (i.e. from non-responders to responders). Simulations allow us to identify the parameter space where probability of observing tumor response are higher.
Conclusions: The described framework represents the first quantitative characterization of viral distribution, replication, and oncolytic effect of a novel oncolytic virus following i.t. and i.v. administrations in the absence of an immune response. This model allows for a better understanding of the role that the different processes play in the final outcome. Moreover, the model may be expanded to integrate the role of the immune system to support the clinical development of oncolytic viruses.
References:
[1] Kaufman et al. Nat Rev Drug Discov 2015.
[2] Titze et al. Eur J Pharm Sci 2017
Reference: PAGE 29 (2021) Abstr 9621 [www.page-meeting.org/?abstract=9621]
Poster: Drug/Disease Modelling - Oncology