PURPOSE: Although oncolytic viral vectors show promise for the treatment of various cancers, ineffective initial distribution and propagation throughout the tumor mass often limit the therapeutic response. A mathematical model is developed to describe the spread of herpes simplex virus from the initial injection site. EXPERIMENTAL DESIGN: The tumor is modeled as a sphere of radius R. The model incorporates reversible binding, interstitial diffusion, viral degradation, and internalization and physiologic parameters. Three species are considered as follows: free interstitial virus, virus bound to cell surfaces, and internalized virus. RESULTS: This analysis reveals that both rapid binding and internalization as well as hindered diffusion contain the virus to the initial injection volume, with negligible spread to the surrounding tissue. Unfortunately, increasing the dose to saturate receptors and promote diffusion throughout the tumor is not a viable option: the concentration necessary would likely compromise safety. However, targeted modifications to the virus that decrease the binding affinity have the potential to increase the number of infected cells by 1.5-fold or more. An increase in the effective diffusion coefficient can result in similar gains. CONCLUSIONS: This analysis suggests criteria by which the potential response of a tumor to oncolytic herpes simplex virus therapy can be assessed. Furthermore, it reveals the potential of modifications to the vector delivery method, physicochemical properties of the virus, and tumor extracellular matrix composition to enhance efficacy.
PURPOSE: Although oncolytic viral vectors show promise for the treatment of various cancers, ineffective initial distribution and propagation throughout the tumor mass often limit the therapeutic response. A mathematical model is developed to describe the spread of herpes simplex virus from the initial injection site. EXPERIMENTAL DESIGN: The tumor is modeled as a sphere of radius R. The model incorporates reversible binding, interstitial diffusion, viral degradation, and internalization and physiologic parameters. Three species are considered as follows: free interstitial virus, virus bound to cell surfaces, and internalized virus. RESULTS: This analysis reveals that both rapid binding and internalization as well as hindered diffusion contain the virus to the initial injection volume, with negligible spread to the surrounding tissue. Unfortunately, increasing the dose to saturate receptors and promote diffusion throughout the tumor is not a viable option: the concentration necessary would likely compromise safety. However, targeted modifications to the virus that decrease the binding affinity have the potential to increase the number of infected cells by 1.5-fold or more. An increase in the effective diffusion coefficient can result in similar gains. CONCLUSIONS: This analysis suggests criteria by which the potential response of a tumor to oncolytic herpes simplex virus therapy can be assessed. Furthermore, it reveals the potential of modifications to the vector delivery method, physicochemical properties of the virus, and tumor extracellular matrix composition to enhance efficacy.
Authors: A Pluen; Y Boucher; S Ramanujan; T D McKee; T Gohongi; E di Tomaso; E B Brown; Y Izumi; R B Campbell; D A Berk; R K Jain Journal: Proc Natl Acad Sci U S A Date: 2001-03-27 Impact factor: 11.205
Authors: J Nemunaitis; F Khuri; I Ganly; J Arseneau; M Posner; E Vokes; J Kuhn; T McCarty; S Landers; A Blackburn; L Romel; B Randlev; S Kaye; D Kirn Journal: J Clin Oncol Date: 2001-01-15 Impact factor: 44.544
Authors: Ann H Rux; Huan Lou; John D Lambris; Harvey M Friedman; Roselyn J Eisenberg; Gary H Cohen Journal: Virology Date: 2002-03-15 Impact factor: 3.616
Authors: Zinnia P Parra-Guillén; Gloria González-Aseguinolaza; Pedro Berraondo; Iñaki F Trocóniz Journal: Pharm Res Date: 2010-04-13 Impact factor: 4.200
Authors: Mi-Yeon Jung; Chetan P Offord; Matthew K Ennis; Iris Kemler; Claudia Neuhauser; David Dingli Journal: Cancer Res Date: 2018-08-16 Impact factor: 12.701
Authors: James M Markert; James J Cody; Jacqueline N Parker; Jennifer M Coleman; Kathleen H Price; Earl R Kern; Debra C Quenelle; Alfred D Lakeman; Trenton R Schoeb; Cheryl A Palmer; Samuel C Cartner; G Yancey Gillespie; Richard J Whitley Journal: J Virol Date: 2012-02-29 Impact factor: 5.103