Imaging of Intratumoral Inflammation during Oncolytic Virotherapy of Tumors by 19F-Magnetic Resonance Imaging (MRI)

Stephanie Weibel,Thomas Kampf,Peter Michael Jakob,Carolin Seubert,Thomas Christian Basse-Luesebrink,Michael Hess,Johanna Langbein-Laugwitz,Ivaylo Gentschev,Elisabeth Hofmann,Aladar A Szalay,Yuxiang Ye,Volker Jörg Friedrich Sturm

doi:10.1371/journal.pone.0056317

Abstract

BackgroundOncolytic virotherapy of tumors is an up-coming, promising therapeutic modality of cancer therapy. Unfortunately, non-invasive techniques to evaluate the inflammatory host response to treatment are rare. Here, we evaluate 19F magnetic resonance imaging (MRI) which enables the non-invasive visualization of inflammatory processes in pathological conditions by the use of perfluorocarbon nanoemulsions (PFC) for monitoring of oncolytic virotherapy.Methodology/Principal FindingsThe Vaccinia virus strain GLV-1h68 was used as an oncolytic agent for the treatment of different tumor models. Systemic application of PFC emulsions followed by 1H/19F MRI of mock-infected and GLV-1h68-infected tumor-bearing mice revealed a significant accumulation of the 19F signal in the tumor rim of virus-treated mice. Histological examination of tumors confirmed a similar spatial distribution of the 19F signal hot spots and CD68+-macrophages. Thereby, the CD68+-macrophages encapsulate the GFP-positive viral infection foci. In multiple tumor models, we specifically visualized early inflammatory cell recruitment in Vaccinia virus colonized tumors. Furthermore, we documented that the 19F signal correlated with the extent of viral spreading within tumors.Conclusions/SignificanceThese results suggest 19F MRI as a non-invasive methodology to document the tumor-associated host immune response as well as the extent of intratumoral viral replication. Thus, 19F MRI represents a new platform to non-invasively investigate the role of the host immune response for therapeutic outcome of oncolytic virotherapy and individual patient response.

Highlights

Oncolytic virotherapy of tumors is based on the lytic destruction of solid tumors mediated by infection of the malignant tissue by tumor-specific viruses [1,2,3,4]
To test the applicability of 19F magnetic resonance imaging (MRI) to monitor virus-induced inflammation during oncolytic virotherapy, we used 1936-MEL melanoma-bearing mice and administered Vaccinia virus (VACV) (GLV-1h68) i.v. followed by i.v. injection of emulsified perfluorocarbon nanoemulsions (PFC) at day 4 and day 6 pi and MR imaging at 8 dpi (Fig. 1A)
We have shown that the VACV-induced infiltration of myeloid cells into different tumor models is reliably detectable by 19F MRI

Summary

Introduction

Oncolytic virotherapy of tumors is based on the lytic destruction of solid tumors mediated by infection of the malignant tissue by tumor-specific viruses [1,2,3,4]. In addition to the oncolytic tissue destruction massive inflammation within the tumor microenvironment occurs, which is primarily directed against the virus [8,9,10]. A longitudinal, non-invasive quantification of the intratumoral inflammation during oncolytic virotherapy may provide substantial benefits to therapeutic monitoring, tumor diagnostics and indirect virus imaging as well as to the optimization of new therapeutic virus strains. Oncolytic virotherapy of tumors is an up-coming, promising therapeutic modality of cancer therapy. We evaluate 19F magnetic resonance imaging (MRI) which enables the non-invasive visualization of inflammatory processes in pathological conditions by the use of perfluorocarbon nanoemulsions (PFC) for monitoring of oncolytic virotherapy

Methods

Results

Conclusion