The use of the NIS reporter gene for optimizing oncolytic virotherapy

Figures & data

Figure 1. Representative whole body nuclear imaging of mice infected with oncolytic virus expressing NIS following NIS-mediated uptake of radiotracer. The thyroid (T), stomach (S) and bladder (B) can be detected due to endogenous NIS expression and radiotracer excretion. Low-resolution SPECT/CT imaging clearly identifies intratumoral radiotracer uptake. High-resolution SPECT/CT imaging allows for spatial resolution of intratumoral infected centers.

Table 1. Available radiotracers and corresponding half-lives, decay mode and major γ emission energy for NIS-mediated imaging with SPECT of PET instrumentation.

Imaging modality	Radiotracer	Half-life	Decay mode	Major γ emission energy (MeV)
SPECT	^123I	13.2 h	EC	0.159
	^125I	59.4 d	EC	0.027
	^131I	8.0 d	β^−	0.364
	^99mTc	6.0 h	IT	0.140
	^188Re	17.0 h	β^−	0.155
PET	^124I	4.2 d	β^+	0.511
	^18F	109.8 m	β^+	0.511

Major γ emission energy is the mean energy with the greatest percentage of emission.

Created with data taken from [81].

d: day; h: hour; m: minute; β⁻: beta decay; β⁺: positron decay; EC: electron capture; IT: isomeric transition; SPECT: single-photon emission computed tomography; PET: positron emission tomography.

Figure 2. Schematic of NIS expression at the cellular level and corresponding NIS-mediated radiotracer uptake detected and quantified with nuclear imaging techniques. A. Tumor cell does not naturally express NIS and therefore does not concentrate radiotracers. B. Upon viral infection, the viral genome (green) will be replicated and viral genes, along with transgenes (blue), will be transcribed and translated into functional proteins. Expression of the NIS transgene (blue) leads to production of NIS protein that allows radiotracer uptake, corresponding with nuclear imaging detection. C. As viral replication continues, there is increased expression of viral genes and transgenes, leading to increased NIS protein for increased radiotracer uptake detected by nuclear imaging. D. As viral proteins continue to be produced, viral particles are assembled and exit the cell through budding or lysis. Cytopathic effects on cell cause loss of radiotracer uptake capabilities, corresponding to decrease in nuclear imaging detection.

Table 2. Table of oncolytic viruses expressing the NIS transgene to mediate radiotracer uptake for in vivo nuclear imaging monitoring of infection, separated by oncolytic virus and tumor type.**

Virus	Recombinant	Tumor type	Route	In vivo imaging modality		In vivo replication tracking	Ref.
				Radiotracer	Instrument
Preclinical
ADENOVIRUS
	Ad-CMV-hNIS9, Ad-CMV-hNIS (rep-)	glioma	IT	^99mTcO4^−	gamma camera scintigraphy		[49]
	Ad-CMV-rNIS (AdNIS)(rep-)	mammary, cervical	IT	^123I	gamma camera scintigraphy		[62]
	Ad-CMV-hNIS (rep-)	prostate	IT [28], intra- prostatic [57]	^123I	]		[28,57]
		pancreatic	IT, IV	^124I	PET		[25]
		hepatocellular carcinoma	Intra-portal	^123I, ^131I	gamma camera scintigraphy		[68]
	Ad5-yCD/mutTK(SR39)rep-hNIS (rep+)	prostate	IT	^99mTcO4^−	gamma camera scintigraphy	peak d5, undetectable by d7	[46]
	Ad-MUC1-hNIS (rep-)	breast	IT	^123I	gamma camera scintigraphy		[33]
		pancreatic	IT, IV	^123I	gamma camera scintigraphy		[34]
		ovarian	IT	^123I	gamma camera scintigraphy		[35]
	Ad-MUC1-NIS (3ʹ minimal MUC1 promoter) (rep-)	pancreatic cancer	IT	^123I	gamma camera scintigraphy		[31]
	AdIP1-NIS (rep+)	colon	IT	^99mTcO4^−	SPECT/CT	positive d1, peak d2, undetectable by d5	[48]
	AdAM6-NIS (CR)	colon	IT	^99mTcO4^−	SPECT/CT	positive d1, peak d3, undetectable by d5	[48]
	Ad5-CEA-NIS (rep-)	medullary thyroid	IT	^123I	gamma camera scintigraphy		[43]
	AdSERE (rep-)	breast	IT	^99mTcO4^−	SPECT/CT		[14]
	AdIP2 (CR)	colorectal	IT, IV	^99mTcO4^−	SPECT/CT	positive d1, peak d2, undetectable by d3	[40]
	AdPLEN (rep-)	hepatocellular carcinoma	IT	^131I	gamma camera scintigraphy		[58]
	Ad5AMUCH_RSV-NIS (CR)	breast	IT	^123I	gamma camera scintigraphy		[59]
	Ad5/3-∆24-hNIS (CR)	prostate	IT	^123I	gamma camera scintigraphy		[38]
	Ad Ad5PB_RSV-NIS (CR)	prostate	IT	^99mTcO4^−	SPECT/CT	positive d1, persistence at 1mo	[44]
	AdAM7 (rep+)	peritoneal (ovarian)	IP	^99mTcO4^−	SPECT/CT	positive d1, peak d2, undetectable by d8	[82]
	Ad5-AFP-NIS (rep-)	hepatocellular carcinoma	IT	^123I, ^188Re	gamma camera scintigraphy		[83]
	Ad-SUR-NIS (rep-)	prostate	IT	^99mTcO4^−	gamma camera scintigraphy		[84]
	Ad5/3-hTERT-hNIS (CR)	prostate	IT	^123I	gamma camera scintigraphy, SPECT/CT		[70]
	Ad5/3PB-ADP-hNIS, Ad5/3PB-hNIS, Ad5PB-RSV-hNIS (CR)	prostate	IT	^99mTcO4^−	SPECT/CT	virus dependent; positive d1, persistence at d14	[85]
	Ad5/3-ADP-hNIS, Ad5/3-hNIS, Ad5-ADP-hNIS, Ad5-hNIS (rep+)	lung adenocarcinoma	IT	^99mTcO4^−	SPECT/CT	virus dependent; positive d1, peak or plateau d4	[86]
	Ad5-E1/AFP-E3/NIS (CR)	hepatocellular carcinoma	IT	^123I	gamma camera scintigraphy	peak d3	[87]
HERPES SIMPLEX VIRUS
	HSV-NIS	prostate	IT, IV	^99mTcO4^−	SPECT/CT	administration route dependent; positive d3, peak d8, undetectable by d15	[88]
MEASLES VIRUS
	MV-NIS	myeloma	IV	^123I [24,47,89] ^124I [24]	]		[24,47,89]
		ovarian	IT, IV	^99mTcO4^−	gamma camera scintigraphy		[26]
		hepatocellular carcinoma	IV	^123I	gamma camera scintigraphy	peak between d7 and d10	[45]
		pancreatic	IT, IV	^123I [7,41,51,64], ^99mTcO4^− [90]	gamma camera scintigraphy (planar SPECT) [7,41,64], SPECT/CT [7,41,51,64,90]	peak d2, undetectable by d8 [7] variable among mice, peak between d2 and d6, undetectable by d9 [41]	[7,41,51,64,90]
		prostate	IT, IV	1^23I	gamma camera scintigraphy	administration route dependent; peak d4 (IT), d14 (IV), persistence at d36 (IV)	[39]
		medullo-blastoma	IT	^131I	bioluminescent (Cherenkov) imaging		[91]
		glioblastoma	IT	^123I, ^99mTcO4^−	gamma camera scintigraphy	peak d3, persistence at d20	[92]
		squamous cell carcinoma	IT	^125I	SPECT/CT	peak d3	[93]
		anaplastic thyroid	IT	^99mTcO4-	SPECT/CT	peak d3, persistence at d22	[94]
		osteosarcoma	IT, IV	^99mTcO4^−, Na [18F]BF4	SPECT/CT, PET/CT		[95]
		malignant peripheral nerve sheath	IT	^125I	SPECT/CT		[96]
	MV-IFNβ-NIS	mesothelioma	IT	^125I	SPECT/CT		[56]
VESICULAR STOMATITIS VIRUS
	VSV-∆51-NIS	myeloma	IT, IV	^123I	gamma camera scintigraphy		[37]
	VSV-IFNβ-NIS	myeloma	IV	^99mTcO4^−	SPECT/CT	]	[50, 63]
VACCINIA VIRUS
	GLV-1h153	pancreatic	IT,IV	^124I [15,53,69], ^99mTcO4^− [53,69]	PET [15,53,69], PET/CT [53,69], gamma camera scintigraphy [53,69]	]	[15, 53, 69]
		anaplastic thyroid	IT	^99mTcO4-	gamma camera scintigraphy		[97]
		malignant pleural mesothelioma	IP	^131I	SPECT/CT		[79]
		breast	IT, resection wound	^124I	PET		[36,66]
		gastric	IT	^124I, ^99mTcO4-	PET, gamma camera scintigraphy		[98]
		colorectal peritoneal carcinomatosis	IP	^131I	SPECT/CT		[99]
	VV-NIS-C and VV-NIS-W	endometrial	IV	^125I	SPECT/CT	tumor model and virus strain dependent; persistence at d21	[72]
CLINICAL
ADENOVIRUS
	Ad5-yCD/utTK(SR39) rep-hNIS	prostate	intra-prostatic	^99mTcO4^−	SPECT/CT	patient dependent; peak d1–d2, undetectable by d4–d8	[76]
	Ad5/3-∆24-hNIS	metastatic cervical carcinoma	IT	^123I, ^99mTcO4^−	SPECT/CT	no detection	[74]
Measles Virus
	MV-NIS	myeloma	IV	^123I	SPECT/CT	patient and plasmacytoma dependent; undetectable by d28	[55]
		ovarian cancer	IP	^123I	SPECT/CT	patient dependent	[77]

Virus structure, tumor target, administration route and nuclear imaging radiotracer and instrument used are noted. The use of NIS-mediated imaging to track kinetics of infection is noted when applicable.

Ad: adenovirus; CR: conditionally replicative; d: day; HSV: herpes simplex virus; IP: intraperitoneal; IT: intratumoral; IV: intravenous; MV: measles virus; rep−: replication deficient; rep+: replication competent; VSV: vesicular stomatitis virus; VV: vaccinia virus; CMV: cytomegalovirus.

Table 3. Resolution and sensitivity of imaging instruments used to detect oncolytic virus replication via NIS mediated radiotracer uptake.

Instrument	Minimum resolution (mm)	Sensitivity at minimum resolution (%)	Reference
Clinical
SPECT	~10	0.03	[60,100]
PET	~5	3	[60,100]
Preclinical (1st generation)
SPECT	~1.2	0.3	[100]
PET	~1.5	4	[100]
Preclinical (2nd generation)
SPECT
U-SPECT II	0.25	0.39	[61]
X-SPECT	0.75	0.06	[101]
nanoSPECT	0.6	0.07	[101]
PET
inveon	1.15	11.1	[102,103]
Focus 120	1.5	7	[104]

Spatial resolution (overall spatial resolution for the entire camera system) refers to the ability to detect discrete sources of radioactivity and is measured as the smallest diameter of radioactive sources (capillaries) separated by the same distance that remain distinguishable.[61] Sensitivity is defined as the percentage of emitted events that are able to be detected and recorded at the given resolution.[42].

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