Table 1.

Preclinical studies of DNA viruses in glioma tumors.

Virus	Modifications	Cell Lines	In Vivo Models	Results
Herpes	dlsptk: TK deletion.	Human: U87 and T98G [22]	U87 i.c. and s.c. nude mice	Tumor cell infection and death. In vivo tumor reduction and increased surveillance.
	HSV-1716: γ134.5 loci partial deletion.	Human: U87, T98G, SB18, U373 and U251 [24]	-	Tumor cell infection and death.
	G207: γ134.5 loci deletion. ICP6 truncation.	Human: U87, U373, U138 and T98G [26]	U87 i.c. and s.c. nude mice, i.c. owl monkeys	Elimination of tumor cells, necrosis and no toxicity.
	rQNestin34.5: ICP6 deletion. γ134.5 expression under Nestin promoter.	Human: U251, U87dEGFR, T98G, Gli36d5, U138, and MGH238 [28]	U87dEGFR i.c. and s.c. nude mice	Increase of oncolytic activity at in vitro and in vivo models
	NG34: γ134.5 loci deletion. ICP6 deletion. GADD34 expression under Nestin promoter.	Human: U251, U87ΔEGFR and primary glioma cells Murine: GL261 [30]	U87ΔEGRF-RliFluc and G35 i.c. nude mice, BALB/c mice	Similar oncolytic activity as rQNestin34.5 with lower neurotoxicity.
	NG34scFvPD-1: γ134.5 loci deletion. ICP6 deletion. GADD34 expression under Nestin promoter. scFvPD-1 expression under CMV’s IE promoter.	Human: U87ΔEGFR and U251 Murine: GL261N4 and CT2A [31]	GL261N4 and CT2A i.c. C57Bl/6J mice, GL261N4 and U87ΔEGFR i.c. nude mice	Increased oncolytic activity in comparison to NG34 in immunocompetent mice. Development of specific immunity and memory.
	G47Δ: γ134.5 loci deletion. ICP6 truncation. α47 deletion. US11 expression under α47 promoter.	Human: U87 and U373 [34]	U87 s.c. in nude mice	Increased survival, higher number of cured mice than G207.
	C134: γ134.5 loci deletion. HCMV’s IRS1 protein expression.	Human: D54, U87 and U251 Murine: N2A [32]	U87 i.c. in SCID mice	Reduced tumor volume and increased surveillance.
		Human and murine: 12 established GBM [33]	N2A orthotopic in A/J and BALB/c mice	Improved replication and longer survival in vivo
	HSV-1 R-LM113: insertion of scFvHER2 in gD protein.	Murine: established GBM [35]	PDGFB/DsRed-induced gliomas in nude mice	No toxicity in nude mice and oncolytic effect in HER2 overexpressing and established tumors in vivo.
	RAMBO: γ134.5 loci deletion. ICP6 truncation. Vstat120 expression under IE4/5 HSV promoter.	Human: U343, U87, U87ΔEGFR, LN229, Gli36ΔEGFR-H2B-RFP, U251-T2, U87ΔEGFR-Luc [36]	U87ΔEGFR-Luc and Gli36ΔEGFR-H2B-RFP i.c. and U87ΔEGFR-Luc s.c. nude mice	Increased survival in vivo and inhibition of tumor vascularization.
	M002: γ134.5 loci deletion. IL-12 expression.	Murine: 4C8 [37]	4C8 i.c. gliomas in B6D2F1 mice	Increase mice survival, infiltration of CD4+, CD8+ and NK cells. Longer viral persistence in tumors
	HSV-IL4: γ134.5 loci deletion. IL-4 expression.	Human: U251 and D54 [21]	GL-261 i.c. in C57BL/6	Infiltration of macrophages, CD4+ and CD8+. Longer survival.
Adenovirus	ONIX-15: E1B-55kD deletion.	Human: 4 primary GBM [49]	S.c. xenograft in nude mice	Tumor regression.
	Delta-24-RGD: E1A partial deletion. RGD tripeptide incorporation.	Human: U251, U373, U87 and D54 [53]	D54 s.c. in nude mice	Cell death with low doses, single injection inhibits tumor growth, several injections resulted in 36% of animals with tumor regression.
	ICOVIR-5: E1A expression under E2F-1 promoter. E1A partial deletion. RGD tripeptide incorporation.	Human: U251 and U87 [54]	U87 i.c. xenograft in nude mice	Tumor cytotoxic effect in vitro high tumor selectivity and increase of survival in vivo.
Adenovirus	ICOVIR-17: E1A expression under a promoter including four palindromic E2F-1 sites and a Sp-1-binding site. E1A partial deletion. RGD tripeptide incorporation. PH20 expression under MLP promoter.	Human: U87, U138, LN308, Gli36, U373, LN229 and 6 primary GBM [60]	U87 and CSCs i.c. in nude mice	Better distribution in HA tumors. Longer mice survival.
	VCN-01: E1A expression under a promoter including four palindromic E2F-1 sites and a Sp-1-binding site. E1A partial deletion. RGD relocated in fiver shaft protein. PH20 expression under MLP promoter.	Human: U87, A172, T98G, U251, U373, SNB19 and 2 GBM CSC [61]	U87 and GBM CSC i.c. xenografts in nude mice	Control of tumor growth One single injection improves survival in aggressive infiltrative tumor.
	Delta-24-RGDOX: E1A partial deletion. RGD tripeptide incorporation. OX40L expression.	Human: U87 Murine: GL261 [62]	GL261 i.c. in C57BL/6 mice	Proliferation of tumor specific T cells. Sinergy with anti PD-L1.
	Delta-24-GREAT: E1A partial deletion. RGD tripeptide incorporation. GITRL expression.	Human: U87 and U251 Murine: GL261 [63]	GL261 i.c. in C57BL/6 mice	Extended survival and development of antiviral and antitumor specific response and memory.
	Ad-RTS-IL-12: No replicative. Expression of IL-12 under RTS® system with veledimex as a co-treatment.	Murine: GL261 [64]	GL261 i.c. in C57BL/6 mice	Tumor infiltration with CD8, extended survival and immune memory development.
Vaccinia	rVV-p53: p53 expression.	Rat: C6 [69]	C6 s.c. in nude mice	Moderate cell apoptosis. Tumor growth control.
	rVV-mIL12/mIL2: IL12 expression. IL2 expression.	Rat: C6 [71]	C6 s.c. in nude mice	Cytokine toxicity at high dose Antitumor NK dependent effect.
	rVV-p53 and rVV-mL12: p53 expression. IL12 expression.	Rat: C6 [74]	C6 s.c. in nude mice	Better tumor growth control. Higher NK and macrophage infiltration.
	vvDD: TK deletion. VGF deletion.	Human: A172, U87MG and U118 Rat: RG2, F98 and C6 [73]	U87, U118 and C6 s.c. and RG2, F98 i.c. in nude mice	Control of tumor growth. Sinergy with rapamycin or cyclophosphamide.
			Rhesus macaques [75]	No adverse effects.
	vvDD-IL15Rα: TK deletion. VGF deletion. IL15Rα expression.	Murine: GL261 [75]	GL261 i.c. in C57BL/6J	Increase of NK and CD8+ in tumor. Prolonged survival.
	TG6002: TK deletion. ribonucleotide reductase genes deletion. FCU1 expression.	Human: U87 and patient derived GBM [76]	U87 i.c. and s.c. in nude mice	Prolonged survival in s.c. and i.c. Synergic effect with 5FC in i.c. model.
Myxoma	MYXV WT	Human: U87, U251, U373, U343, A172 and U118 Rat: RG2 and 9L [79]	U87 and U251 i.c. in nude mice	Regression and longer survival in both models.
		Human: U87, U251, and U118 [80]	U87 orthotopic in CB-17 SCID mice	Inhibition of MHC-I tumor expression and promotes NK mediated death.
		Human: U118 and 3 patient samples Murine: GL261 Rat: T9 [81]	-	SOC co-treatment increases results of MYXV.
	MYXV WT: administered in ADSCs	Human: U87 and U251 [82]	U87 orthotopic in nude mice	Increase the tumor infection rate
	MYXV-M011L-KO: M11L deletion	Human: Brain tumor initiating cells (BTIC) [80]	mBITCs i.c. in C57Bl/6J mice	Prolonged survival. TMZ increases oncolysis
Parvovirus		Human: U87 Rat: RG-2 [89]	U87 i-deficient rats and RG-2 i-competent	Complete remission of the tumors
	H-1PV WT	Human: U373, U138 and 5 CSCs [87] Human: U87 Rat: RG-2 [89]	RGD orthotopic ratsU87 i-deficient rats and RG-2 i-competent	Cathepsin B activation induces cell death in H-1PVComplete remission of the tumors
		Human: U87, U373, U118, MO59J and A172 Murine: GL261 [90] Human: U373, U138 and 5 CSCs [87]	U87 and U373 s.c. U87 orthotopic CB17-SCID miceRGD orthotopic rats	Selective infection, no toxicity, reduce tumor volume in vivo Cathepsin B activation induces cell death in H-1PV
	MVMp WT	Human: U373, U87, SW1088, SK-N-SH Rat: C6 [91] Human: U87, U373, U118, MO59J and A172 Murine: GL261 [90]	-U87 and U373 s.c. U87 orthotopic CB17-SCID mice	MVM p strain cytotoxic only in U373 and C6 (MVM) selective infection, no toxicity, reduce tumor volume in vivo
		Human: U87 and MO59J [92] Human: U373, U87, SW1088, SK-N-SH Rat: C6 [91]	-	Selective infection MVM p strain cytotoxic only in U373 and C6 (MVM)
		Murine: Fibroblast L929 and A9. Astrocytoma MT539MG [93], Human: U87 and MO59J [92]	-	Safe for microglia (MVMp) selective GBM infection (MVM)
		Murine: Fibroblast L929 and A9. Astrocytoma MT539MG [93],	-	Safe for microglia (MVMp)

i.c.: intracranial, s.c.: subcutaneous, i-deficient: immunodeficient, i-competent: immunocompetent; VGF: vaccinia growth factor; HCMV: human cytomegalovirus; TMZ: temozolomide; EGFR: epidermal growth factor receptor; MVM: murine minute virus.