Table 2.

Preclinical and clinical studies on in vivo monitoring and imaging of measles virus (MV) infection, replication, and expression

Study/year	Imaging technique	Tumor type	Data sources	Genes/protein	Route	Protein targeting drug	Main results
Deyle et al./2015 [55]	SPECT/CT	Malignant peripheral nerve sheath	Athymic nude mice	hNIS	IT	125I	MV localization and distribution could be monitored by imaging of I-125 uptake
Dingli et al./2004 [56]	Gamma camera	Myeloma	Mice	hNIS	IV	123I	In vivo replication of MV-NIS peaked 9 days after virus injection
Galanis et l./2015 [58]	SPECT/CT	Ovarian cancer	Human	hNIS	IP	123I	No dose-limiting toxicity was observed in 16 patients treated at the 108–109 TCID50 dose level; all observed toxicities were grade 1 and 2
Hasegawa et al./2006 [75]	Gamma camera and bioluminescence	Ovarian cancer	Mice	hNIS; blood CEA	IT, IV	Tc-99 m sodium pertechnetate; luciferase (Fluc) and bhCG	Viral gene expression was monitored by measuring blood CEA levels, and the location of virus-infected cells was monitored by gamma camera imaging; The gamma camera scans were significantly less sensitive than the plasma CEA marker for monitoring virus infection
Hutzen et al./2012 [65]	Bioluminescent (Cherenkov) imaging	Medulloblastoma	Mice	hNIS	IT	D-Luciferin	The MV-NIS mouse indicated an increased bioluminescent signal originating from the tumor that 131I had accumulated
Msaouel et al./2009 [64]	Gamma camera	Prostate	Nude mice	hNIS	IT, IV	123I	In vivo replication of MV-NIS depends on the administration route. Strong positive tumor 123I uptake is seen 4 days after IT administration of MV-NIS, and 14 days after IV administration of MV-NIS. Persistent transgene expression can be detected for as long as 36 days after IV administration of the virus
Myers et al./2007 [19]	–	Myeloma	SCID mice, squirrel monkey	hNIS	IV	123I	No adverse effect was observed
Opyrchal et al./2012 [67]	Gamma camera	Glioblastoma	BALB/c nude mice	hNIS	IT	123I; Tc-99 m sodium pertechnetate	Tumor uptake of radioisotope in MV-NIS-treated mice was increased; peak at day 3 and persistence at 20 days after viral administration. Expression of NIS protein in infected cells results in the effective concentration of radioactive iodine that allows for in vivo monitoring of localization of MV-NIS infection by measuring uptake of I-123 and Tc-99 m
Penheiter et al./2012 [62]	SPECT/CT	Pancreatic	Nude mice	hNIS	IT, IV	123I	Pinhole micro-SPECT/CT imaging using the NIS reporter allows for precise localization and quantitation of oncolytic MV-NIS infection. This method can replace autoradiography and Immunohistochemistry analysis
Penheiter et al./2012 [77]	SPECT/CT	Pancreatic	Nude mice	hNIS	IT	Tc-99 m sodium pertechnetate	IT viral delivery can be monitored using image-guided injection techniques
Penheiter et al./2010 [59]	SPECT/CT	Pancreatic	Nude mice	hNIS	IT	123I	Delivery of 131I radiotherapy to NIS-expressing tumors can be optimized using micro-SPECT/CT imaging guidance. In vivo viral replication was variable among mice (peak between 2 days and 6 days following viral administration, and undetectable at 9 days after viral injection)
Reddi et al./2012 [73]	SPECT/CT	Anaplastic thyroid	Nude mice	hNIS	IT	Tc-99 m sodium pertechnetate	NIS expression peaked at day 3 and was persistence up to day 22 following viral administration
Russell et al./2014 [60]	SPECT/CT	Myeloma and plasmacytoma	Human	hNIS	IV	123I	In all the two patients, tumor imaging was clearly documented. The size of the lesions was variable in hNIS mediated radioiodine SPECT-CT for the same lesions shown in the imaging in comparison with the normal FDG PET-CT. In vivo viral replication depends on patient and plasmacytoma. Radioiodine uptake returned to the background at day 28 following MV-NIS administration
Carlson et al./2009 [61]	Gamma camera, SPECT/CT	Pancreatic	Nude mice	hNIS	IT	123I	Mice infected with MV-NIS concentrated radioiodine, that allows for serial quantitative imaging with 123I micro-SPECT/CT. The peak iodide uptake was 2 days after MV-NIS administration
Dispenzieri et al./2017 [57]	SPECT/CT	Multiple myeloma	Human	hNIS	IV	123I	8 out of the 31 patients had some degree of 123I uptake on their SPECT/CT scans
Miest et al./2013 [72]	SPECT/CT	Mantle cell lymphoma	SCID mice	hNIS	IT, IV	Tc-99 m sodium pertechnetate	NIS gene results in concentrating iodide within infected cells, allowing non-invasive imaging. High-resolution imaging visualized the spread of infections in primary and metastatic tumors for over 2 weeks after treatment, documenting homogeneous virus seeding and spread restricted to perfused tissue
Jung et al./2018 [78]	SPECT/CT	Pancreatic	Nude mice	hNIS	IT	Tc-99 m	In vivo radioisotope uptake was significantly correlated with viral N and NIS gene expression
Kemler et al./2019 [63]	Intravital imaging	Fibrosarcoma	Athymic nude mice	Blue fluorescent protein containing the nuclear localization sequence	–	–	Intravital imaging system using the dorsal skin fold chamber allows for serial, non-invasive imaging of tumor cells and replication of a fusogenic and a hypofusogenic MV. There were distinctly different replication kinetics and phenotypes of these two viruses
Li et al./2012 [66]	SPECT/CT	Squamous cell carcinoma	Athymic nude mice	hNIS	IT	125I	In vivo viral replication peak occurred 3 days after viral administration

SPECT/CT Single-photon emission computed tomography/computed tomography, hNIS Human sodium iodide symporter, IT Intra-tumoral, IV Intravenous, IP Intraperitoneal, MV Measles virus, PET Positron emission tomography