Oncolytic virotherapy evolved into the fourth generation as tumor immunotherapy

Wang, Xianwang; Shen, Yihua; Wan, Xingxia; Hu, Xiaoqing; Cai, Wen-Qi; Wu, Zijun; Xin, Qiang; Liu, Xiaoqing; Gui, Jingang; Xin, Hong-Yi; Xin, Hong-Wu

doi:10.1186/s12967-023-04360-8

Journal of Translational Medicine

Table 1 The preclinical studies of OVs

From: Oncolytic virotherapy evolved into the fourth generation as tumor immunotherapy

Virus name, type and strain	Virus short name	Viral gene modification	Non-viral gene addition	Cell culture, mouse, human	Tumor type	Virus administration route, dose, times	Combination therapy	Safety (Major AEs)	Efficacy, (Tumor size, Survival benefit)	Novelty, advantages	Comments, disadvantages	Refs
HSV-1	oHSV-1			6 to 8-week-old NOD. Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ (NSG) mice	Breast cancer, brain cancer, BCBMs	Intracranially infused with EGFR-CAR NK-92, oHSV-1, NK-92-EV	EGFR-CAR NK-92 cells		Suppression of tumor growth and significantly longer survival	Optimal efficacy in patients with EGFR + tumor		[36]
HSV-1	UV-HSV-1			NRG-3GS mice (15 weeks)	leukemia	3 × 10⁶ human PBMCs + 0.1 pfu/PBMC for 16 h	IL-15		Prolonged survival of T cell-depleted PBMCs mice	Herpesviridae members are potent stimulators of innate immune function	Future allogeneic mononuclear cell or NK infusion	[37]
HSV-1	oHSV-1			Female athymic nu/nu mice	GBM	IP, with PBS/ bortezomib (0.8 mg/kg) twice a week	Bortezomib		Necrosis in tumors	NK cell adjuvant therapy, virotherapy and proteasome blockade	Toxicities may be discovered	[155]
HSV	oHSV, MG18L			PARPi-sensitive or -resistant GSC. Female athymic mice	GBM	IP, olaparib (50 mg/kg) or vehicle; IT, MG18L or PBS	PARPi, Olaparib		Greatly extended survival	Applicable not only to GBM, but also to other tumor types	Treatment schedule not optimized	[33]
HSV	MG18L			7–8-week-old female SCID mice	GBM	Galunisertib (100 mg/kg), oral gavage daily from day 7 to 16. IT, MG18L (1 × 10⁶ pfu/3 µl) on day 9	TβR inhibitors SB431542, galunisertib		Cures in 60% of mice bearing orthotopic recurrent GBM	A novel synergistic interaction of oHSV therapy and TGF-β signaling blockade	Effect for initiating poorly invasiveGBM	[156]
HSV-1	oHSV			Mouse model of ATC	PDTC ATC	A single injection into the tumor using a Hamilton syringe	40 mg/kg of BRAFi (PLX4720) by oral gavage daily		Tumor reduced by 50% and inflammatory	Activated NK and T cells, and successfully incorporated anti-CTLA-4 or anti-PD-1		[157]
HSV	oHSV	γ1-34.5 deleted		6- 8-week-old C57BL/6 mice	MPNSTs	C134 (3.5 × 107 in 100 μL 10% glycerol in PBS) IT on day 4 and a week later	3 doses of RUX (INCB018424, AbexBio; 60 mg/kg) daily IP		Antitumor antigen and an antiviral responses	CD8 + T cell activation indispensable for the antitumor benefit	CTL response not been fully investigated	[31]
HSV	oHSV		Vstat120, anti-angiogenic	Female BALB/C mice or Bai1 wildtype or knockout C57/Bl/6 mice (littermates)	GBM	IT, HBSS/PBS, rHSVQ1, or RAMBO virus (1 × 10⁵ PFU/mouse)		Transient weight loss	Reduced macrophages/microglia, increased virus replication	Shielded from inflammatory macrophage antiviral response, without reducing safety	How Vstat12 blocks BAI1 unclear	[39]
HSV	oHSV-TRAIL		TRAIL	Athymic mice (6 weeks of age); TMZ-resistant primary and recurrent GSC	GBM	IT, 3–6 μl, 2.0 × 10⁶ pfu, twice on days 14 and 26			Prolong survival through robust apoptosis	Potent therapeutic efficacy		[158]
HSV	MSC-oHSV		MSCs	a BRAF mutant line from BrafV600E/wtCdkn2A^−/−Pten^−/− mice	Melanoma	ICA, intracarotid injection	PD-L1 blockade		Significantly prolongs the survival	Target melanoma brain metastasis		[72]
HSV-1	oHSV-1- SU4-124	ICP4 under survivin promoter	Rat FGF2 5’UTR in front of ICP4 ORF	Female C57BL6 mice	Glioma U87	IT, 100 mm3 tumor, 3galΔ3, or CMV-ICP4 HSV-1 or SU4-124 HSV-1			a significantly enhanced antitumor effect	Triple-regulated ICP4 gene expressed from an amplicon to supplement a replication-defective HSV-1		[38]
HSV	oHSV- G47Δ	G47Δ-mCherry, G47Δ-Us11-fluc	G47Δ	MN3 cells, 7–8-week-old female SCID mice	Meningiomas	IT, 2 G47Δ injections (2 × 10⁶ pfu/3 µL)			Significantly prolonged survival	Efficacy against several patient-derived meningioma lines of different grade	To study MN3 as CSC	[159]
HSV	oHSVG47Δ(G47Δ-mIL12)	G47Δ	IL-12	Female C57Bl/6 mice (8–9 weeks)	GBM	IT, G47Δ-mIL12 in 2 μl	Anti-CTLA-4, anti-PD-1		89% long-term survivors; the cure rate 4/6 and 5/7	Synergistic effect and inducing immunological memory	Lack of representative murine models	[32]
Ad	oAd- CARsc-pSia		Bispecific adapter CARsc-pSia	C57BL/6 and NMRI-nu/nu mice	SCLC	IV pretreated with CARsc-pSia (15 μg/250 μL/mouse) or PBS	hTERT-AdLuc (1 × 10⁹ pfu/mouse)	None	Tumor regression,prolonged survival, but not in T-cell-deficient mice	Effective retargeting elicits an effective tumor-directed T-cell response		[41]
Ad	ICOVIR-15 K	BiTA under major late promoter	ICOVIR-15 K-cBiTAto EGFR	8-week-old female SCID/beige mice	Lung cancer A549, Colon cancer HCT116	A549 tumors, IV 2 × 10⁹ VP; HCT116 tumors, IV 1 × 10¹⁰ VP			Enhances antitumor efficacy in vivo	OV-BiTA can overcome key limitations	Oncolytic properties reduced twofold	[43]
Ad	EnAd		BiTA to EpCAM	HEK293A, DLD, SKOV3, MCF7, A431, A549, NHDF and PC3, CHO	Multiple cancers	Cells incubated in 50% exudate in 500 ng/ml BiTA or 100 vp/cell EnAd			A marked cancer cell depletion	A new treatment of disseminated cancer		[101]
Ad	NSC.CRAd-S-pk7		NSC. Survivin promotor, a poly-L-lysine (pk7)		Ovarian cancer mice model	3 weeks of 1 × 10⁶ cells [5 × 10⁸ pfu]/day	Cisplatin	Not significantly worsen toxicity by daily score	More substantial decreases in omental tumor burden	Increased efficacy with no added toxicity	Its replication is conditional upon overexpression of survivin	[84]
Ad	DNX-2401 (Delta-24-RGD; tasadenoturev)	a 24 bp deletion in E1A	RGD-motif into the fiber H-loop	DIPG and pHGG cell lines	pHGG/DIPG mice model	Delta-24-RGD (10⁸ pfu/animal) intracranially 1 or 3 times in 3–4 μl 3 days later		No adverse effect	Increased survival by an average of 40 days (P = 0.024, Log-rank test)	Therapeutic option for pHGG and DIPG		[42]
Ad	oAd-MSCs			BALB/c mice	Renal adenocarcinoma, melanoma	2 × 10⁶ DiR-labeled oAd-MSCs per mouse, IP injected			Tumors decrease by 50% and inflammatory	TAMS and NK infiltrated, and TIL changed		[40]
VV	EphA2-TEA-VV		EphA2-TEA	SCID Beige mice; A549 cells	NSCLC	IP injection, 1 × 10⁸ pfu	PBMCs	None	Significant tumor growth decrease	The EphA2-TEA-VVs activated human PBMCs		[47]
VV	VVDD	hSNF5		CB17 SCID mice	AT/RT	50 μl VVDD-hSNF5 or VVDD GFP			Significant tumor regression	Cell cycle arrest and proliferation inhibit		[160]
MV	MV-H		DARPins	6- to 12-week-old female Hsd: Athymic Nude-Foxn1^nu mice	ovarian carcinoma	IP four times, 2 × 10⁶ TCID₅₀/injection			The tumor burden reduced by 76% (MV-Ec4-Pro₉-G3) to 95% (MV-Ec4)	harbor an intrinsic and robust specificity for heterogeneous tumor cells	DARPin/HER2 interaction inhibitsvirus spread	[48]
MV	MV-BiTA		MV-eGFP-mCD3xCEA	C57BL/6 J mice	Primary human colorectal cancer	intra-/peritumoral injection, 10⁶ pfu in 100 mL	BiTA to CEA		Increased T-cell infiltration and activation	Tumor-restricted continuous BiTA expression and in situ vaccination effects	OVs comparison lacking	[100]
Arenavirus	LCMV			MOPC-tumur-bearing C57BL/6 mice	Colon cancer, melanoma, hepatocellular carcinoma	2 × 10⁴ PFU peritumourally or 2 × 10⁶ PFU IV	CD8⁺ T cells; PD-1 blockade		Increased local and splenic virus propagation for more than 30 days	Effective tumor treatment	Not known in humans	[161]
Rhabdovirus	MG1		eGFP tagged Maraba	S180; 6 week old female Balb/C mice	Sarcoma	IT, 3 doses MG1 (1 × 10⁸ pfu/mouse) at days 8, 10 and 13			Eradication of 80% of tumors and protection from re-challenge	MG1 based oncolytic immunotherapy		[162]
NDV	NDV-ICOSL		NDV-ICOSL	Mice	B16-F10 melanoma	On days 7, 10, 13 and 16, IT, 100 μl of 2 × 10⁷ pfu	Anti-CTLA-4		Enhanced T cells infiltration and anti-tumor effect	A strong rationale for clinical evaluation	Mechanism not known. Subset patients	[108]
Canine virus serotype 2	ICOCAV17	E1ΔD21	human PH20 hyaluronidase (PH20)	Dogs	Spontaneous tumors	dCelyvir administered over 45 min through a peripheral or central venous line at 0.5 × 10⁶ cells/kg	i.v. with metilprednisone 1 mg/kg, metamizol 30, difenhidramine 0.5	27% (4) show clinical AE	74% response rate, 14.8% complete responses	OV-MSC represents an effective cancer therapy	Hyaluronidase for EMC	[44]
Coxsackievirus	CVA21			Peripheral blood mononuclear cells	AML MM	The PBMC exposed to CVA21 for 24 h			CVA21 stimulated potent anti-tumor immunity	AML cells resistant oncolysis, immune- killing of MM/AML observed		[163]
Myxoma virus	MYXV		IL-15 complex with a subunit of its receptor and tdTR	6–8-week-old C57BL/6 female mice	Melanoma	Injected (day 9) with a single dose of MSCs (5 × 10⁵/100 mL PBS)			Marked regression of lesions and could increase survival	MSCs ferrying MYXV to pulmonary melanoma foci triggering immune effects		[83]
Bovine pestivirus	BVDV			NOD-SCID mice	MM	IT twice a week for 2 weeks	bortezomib		significantly reduced tumor burden	BVDV has direct oncolytic effect in myeloma		[164]
Zika virus	ZIKV-Dakar	a 10-nt deletion in the 3’ UTR		C57BL6/J mice, 4 × 10⁴ GL261 or CT2A glioma cells	GBM	IT, mouse-adapted ZIKV (10⁵ FFU)	Anti-PD-1, IP on days 8, 10, 12, and 14, 10 mg/kg		Combination therapy improved long-term survival to 80%		Optimization of the timing of ZIKV administration	[27]

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