The importance of imaging strategies for pre-clinical and clinical in vivo distribution of oncolytic viruses

Abstract

Oncolytic viruses (OVs) are an emergent and unique therapy for cancer patients. Similar to chemo- and radiation therapy, OV can lyse (kill) cancer cell directly. In general, the advantages of OVs over other treatments are primarily: a higher safety profile (as shown by less adverse effects), ability to replicate, transgene(s) delivery, and stimulation of a host's immune system against cancer. The latter has prompted successful use of OVs with other immunotherapeutic strategies in a synergistic manner. In spite of extended testing in pre-clinical and clinical setting, using biologically derived therapeutics like virus always raises potential concerns about safety (replication at non-intended locations) and bio-availability of the product. Recent advent in in vivo imaging techniques dramatically improves the convenience of use, quality of pictures, and amount of information acquired. Easy assessing of safety/localization of the biotherapeutics like OVs became a new potential weapon in the physician's arsenal to improve treatment outcome. Given that OVs are typically replicating, in vivo imaging can also track virus replication and persistence as well as precisely mapping tumor tissues presence. This review discusses the importance of imaging in vivo in evaluating OV efficacy, as well as currently available tools and techniques.

Keywords: NIS virus; clinical trial; mouse imaging; oncolytic virus; viral efficacy.

Figure 1

Decision paths for imaging tool technology. Notes: List of main imaging systems available for small animal research. Classification based on criteria that can help in the decision of the choice. Fluorescence and luminescence technologies are the most affordable and less invasive for animals, but less precise compared to MRI. Abbreviations: GFP, green fluorescent protein; RFP, red fluorescent protein; YFP, yellow fluorescent protein; MRI, magnetic resonance imaging; NIS, sodium iodide symporter; PET, positron emission tomography; SPECT, single-photon emission computed tomography; SSRT2, somatostatin receptor 2.

Figure 2

PET CT; bioluminescence and fluorescence illustration for use in cancer field. Notes: (A) HT29 tumors were established subcutaneously in nude mice. Then vaccinia virus was injected intratumorally at 1×10⁷ pfu as follow: vaccinia virus expressing NIS for SPECT image, vaccinia expressing firefly luciferase tag for bioluminescent image or vaccinia expressing eGFP tag for fluorescence. Four days after virus treatment, the mice were injected with ⁹⁹Tc radioisotope for small-animal SPECT/CT imaging, D-luciferin (Molecular Imaging Products, Ann Arbor, MI, USA) for bioluminescent. Images were taken using the in vivo imaging system IVIS 200 Series Imaging System (Xenogen, Hopkinton, MA, USA). Luminescent and fluorescent images data acquisition and analysis were performed using Living Image v2.5 software. (B) Ht29 tumors were established subcutaneously in nude mice. Fourteen days after tumor seeding, the mice were injected with vaccinia virus expressing firefly luciferase tag (3), vaccinia virus with no imaging reporter (2) or not injected (1). Mice were sacrificed, tumor harvested and cut in half for imaging analysis. (C) Transgenic mice (90 days old) were treated with vaccinia-expressing fluorescent marker intravenously. Four days later, the mice were sacrificed, tumor harvested and processed for image testing. Top: brightness and contrast; Bottom: fluorescence. Abbreviations: PET, positron emission tomography; CT, computed tomography; NIS, sodium iodide symporter, SPECT, single-photon emission computed tomography.