Table 3.

Clinical applications of systemic OV therapy for lung cancer

Oncolytic virus	Virus construct	Combination therapy	Phase of development	Method and results	Clinical trials identifier and references
Adenovirus	Ad-HSVtk	Stereotactic body radiotherapy and pembrolizumab	II window of opportunity,	Metastatic non-small cell lung cancer (NSCLC). In situ, intratumoral, OV therapy consists of adenovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSVtk) plus valacyclovir therapy. Initial 28.5% complete or partial response. The study is ongoing.	NCT03004183
	Ad-HSVtk	Stereotactic body radiotherapy and nivolumab	II window of opportunity terminated	Intratumoral injection with Ad-HSVtk in metastatic squamous and non-squamous NSCLC. No results, the study is terminated.	NCT02831933
	Adapted Ad-HSVtk (CAN-2409)	Pembrolizumab	II	Intratumoral injection of CAN-2409 in patients with stage III/IV, refractory NSCLC. The study is ongoing.	NCT04495153
	ColoAd1, chimeric adenovirus strain (enadenotucirev)		I	i.v. infusion with enadenotucirev to assess delivery in patients with NSCLC. A study completed: enadenotucirev was delivered in most tumor samples following i.v. infusion, with almost no activity in normal tissue. Virus delivery coincided with high local CD8+ cell infiltration in 80% of tested tumor samples, suggesting a potential enadenotucirev-driven immune response. Enadenotucirev delivery was well tolerated, with no serious adverse events.	NCT02053220 Garcia-Carbonero et al.95
	Ad-MAGEA3, adenovirus vaccine expressing MAGE-A3	Pembrolizumab	I/II	IO-resistant stage IV NSCLC. Study is ongoing.	NCT02879760
	MEM-288, adenovirus expressing recombinant CD40L and human IFN-β		I	Intratumoral injection in stage III/IV NSCLC patients. Initial determination of MTD and recommended phase II dose for the planned combination of MEM-288 with an immune checkpoint inhibitor. The study is ongoing.	NCT05076760
	Combination of oncolytic Onc.Ad5Δ24 and helper -dependent HDΔ28E4 PD-L1, expressing PD-L1 antibody	Onc.Ad5Δ24 and HDΔ28E4 PD-L1 (CAd-VECPDL1) in combination with HER2-specific CAR T cell therapy	I	Patients with HER2-positive (including NSCLC) solid tumors. Intratumoral injection with CAdVEC followed by HER2-CAR T cell application. Determining MTD and influence of tumor microenvironment changes on CAR T therapy efficacy. The study is ongoing.	NCT03740256 Tanoue et al.96
	Recombinant adenovirus expressing human IFN-λ, Onc.Ad.L-IFN	Onc.Ad.L-IFN (YSCH-01) single use	I	Intratumoral injection with YSCH-01 in solid tumors (including NSCLC) determining MTD and safety. Study ongoing.	NCT05180851
	ICOVIR-5 (CELYVIR)	MSCs loaded with ICOVIR-5	II	Trial to determine the toxicity and clinical outcome of infusion of autologous MSCs infected with the oncolytic adenovirus ICOVIR5 (CELYVIR) systemically applied in children with refractory or recurrent metastatic solid tumors. Results not posted. Ended prematurely.	EudraCT no. 2008-000364-16
	CELYVIR	MSCs loaded with ICOVIR-5	I/II	Evaluation of the safety and clinical response of weekly (n = 6) infusions of CELYVIR in children and adults with metastatic and refractory solid tumors. Well-tolerated treatment, with only mild toxicity, with the potential to achieve clinical responses in patients with advanced tumors. The study is completed.	NCT01844661 Ruano et al.97
	CELYVIR	MSCs loaded with ICOVIR-5	I/II	Studies the feasibility of the combination of AloCELYVIR with chemotherapy and radiotherapy for the treatment of children and adolescents with relapsed or refractory extracranial solid tumors. The study is ongoing, and results are not posted.	EudraCT no. 2019-001154-26
Measles virus	MV-NIS	Atezolizumab	I	Intratumoral injection with measles virus, expressing sodium iodide symporter (MV-NIS) for recurrent and metastatic NSCLC. Study is ongoing.	NCT02919449
Maraba virus	MG1 strain expressing tumor-associated antigen MAGE-A3 (MG1-MAGEA3)	MG1-MAGEA3 with vaccine Ad-MAGEA3	I/II	Initial vaccination with Ad-MAGEA3 is followed by intravenous injections with MG1-MAGEA3 in refractory NSCLC after complete platinum-based chemotherapy and PD-1 or PD-L1 antibody-targeted therapy. Study is ongoing.	NCT02879760
Coxsackie virus	Coxsackie A21 strain (CVA21)	CVA21 with pembrolizumab	I	Intravenous injection in refractory NSCLC patients. Study is ongoing.	NCT02043665
Vaccinia virus	Recombinant vaccinia virus VV-GL-ONC1, derived from Lister strain. Expressing luciferase and β-galactosidase	GLV-1h68 or GL-ONC1 alone	I	Intra-pleural administration in NSCLC patients with malignant pleural effusion. The study is ongoing.	NCT01766739
	GL-ONC1	GL-ONC1 alone	I	Systemic application for NSCLC patients. Dose safety profile and viral delivery were monitored. Study is ongoing.	NCT00794131
	TG4010 (Mva-Muc1-Il2), a modified vaccinia strain Ankara (Mva), expressing human mucin1 (MUC1) and IL-2	TG4010 alone or after combined vinorelbine/cisplatin	II	i.v. infusion with TG4010 in stage IIIB or IV NSCLC patients. A total of 65 patients were treated: 35.1% of TG4010 (combined) showed PR and 14.1% of TG4010 (alone) had CR. The OS for TG4010 (combined) was 12.7 months and for TG4010 (alone) 14.9 months. The combination of TG4010 with chemotherapy was well-tolerated and gave promising results.	Ramlau et al.98
	TG4010	TG4010 in combination with first-line chemotherapy	IIB/III	Intravenous infusion with TG4010 in stage IV NSCLC patients. A total of 222 patients were treated: median PFS in TG4010 patients was 5.9 months and in the placebo group 5.1 months. No adverse treatment effects were noted. Overall TG4010 combined with chemotherapy improves PFS vs. single chemotherapy treatment. The study is completed.	NCT01383148 Quoix et al.99
	BT-001, modified vaccinia strain expressing anti- CTLA4 and human GM-CSF	BT-001 and pembroluzimab	I/II	Intratumoral injection BT-001 in patients with metastatic and advanced NSCLC. The study is ongoing.	NCT04725331
	JX-594, modified vaccinia virus expressing human GM-CSF		I	Intravenous infusion of JX-594 in advanced NSCLC patients. The study is ongoing. MTD was determined but virus delivery efficacy was moderate. Good safety/toxicity profile.	NCT00625456 Breitbach et al.100
Vesicular stomatitis virus	Voyager-V1 (VV1) VSV strain expressing IFN-β and NIS	VV1 and pembroluzimab	II	Intravenous injection with VV1 in refractory NSCLC or pulmonary neuroendocrine cancer (NEC, including SCLC) patients after initial treatment with pembroluzimab.	NCT03647163
Reovirus	reolysin: human reovirus type 3- Dearing strain	reolysin combined with docetaxel and pemetrexed	II	Systemic intravenous injection of reolysin in patients with recurrent or metastatic NSCLC; 166 patients were enrolled (14 to the safety run-in). The study is completed: reolysin did not improve the progress-free survival (PFS vs. single agent chemotherapy (median PFS 3.0 months, 95% confidence interval [CI], 2.6–4.1) vs. 2.8 months (95% CI, 2.5–4.0), hazard ratio (HR) 0.90 (95% CI, 0.65–1.25), p = 0.53). Neither KRAS nor EGFR mutation was associated with improved PFS, but STK11 mutations did appear to have an association with improved PFS (HR 0.29 [0.12–0.67); as did PIK3CA mutation (HR 0.45 [0.22–0.93]). The combination was tolerable, although associated with increased rates of neutropenic fever.	NCT01708993 Bradbury et al.101
	reolysin	reolysin combined with paclitaxel and carboplatin	II	Systemic intravenous injection of reolysin in patients with recurrent or metastatic NSCLC. Out of 37 patients enrolled, 20 patients had detected K-Ras mutations, 3 patients had EGFR mutations, 10 patients had EGFR amplifications alone, and 4 patients had BRAF V600E mutations. The study is completed: median PFS was 4 months (95% CI, 2.9–6.1), median OS was 13.1 months (95% CI, 9.2–21.6), and 1-year OS rate was 57% (95% CI, 39%–72%).	NCT00861627 Gong et al.102 Villalona-Carrero et al.103
	reolysin	reolysin combined with paclitaxel and carboplatin	II	Systemic intravenous injection of reolysin in patients with recurrent or metastatic SCC. Out of 25 patients who received more than 1 cycle of therapy, the best overall response was PR in 12 patients (48%) and SD in 10 patients (40%) for a CBR of 88%. Of 21 patients with >6 months follow-up 7 had PFS ≥6 months (33.3%).	NCT00998192 Gong et al.102
Senecavirus	Seneca Valley virus (NTX-010)	NTX-010 after 4 cycles of platinum-based chemotherapy	II	Systemic i.v. injection with NTX-010 in patients with extensive stage SCLC after completion of first-line chemotherapy. A total of 50 patients were treated. Study completed: median PFS was 1.7 months for both the NTX-010 group and the placebo group; therefore, OV as a single agent could not generate obvious clinical responses in patients with advanced SCLC.	NCT01017601 Schenk et al.104
Non-specified	RT-01	RT-01 combined with durvalumab	I	Intravenous injection of RT-01 followed by durvalumab treatment of patients with extensive-stage SCLC. Determining efficacy MTD and safety. Study is ongoing.	NCT05205421
Herpes simplex virus	T3011, a genetically modified oncolytic herpes simplex virus (HSV-1) strain	T3011 and pembroluzimab	I/IIA	Intratumoral injection of T3011 followed by pembrolizumab. Total 64 patients with advanced solid tumors, including NSCLC. Safety and MTD measurements. The study is ongoing.	NCT04370587
	R130 genetically modified HSV-1 strain		I	Intratumoral or intraperitoneal injection in patients with advanced, refractory solid tumors (including NSCLC). Initial MTD and safety/toxicity evaluation. Study is ongoing.	NCT05886075 NCT05860374