Table 2.
Preclinical studies on OV therapy mechanisms in lung cancer
| Oncolytic virus | Virus constructs | Applications and eventual combined (chemo)therapies | Carrier cell type | Results | Reference |
|---|---|---|---|---|---|
| Vaccinia virus | vvDD-IL2-RG, vvDD | Intratumoral | IL-2 linked with glycosylphosphatidylinositol anchor (IL2-RG) expression induces an increased immune response and almost total tumor clearing in the subcutaneous transplanted syngeneic LLC model. Increased CD4+/CD8+ and TNF-α in TME. | Liu et al.27 | |
| VV.mIFN-β | Systemic and intratumoral | Drastic 40% tumor reduction in both NSCLC syngeneic models using TC-1 and LKRM2 cells as subcutaneous transplant or orthotopic. Albeit virus replication was substantially low in LKRM2 compared with TC-1, both models showed high cytokine induction due to ectopic IFN-β expression. | Wang et al.28 | ||
| vvDD | Systemic, intravenously with anti-PD1 and -TIM3 treatment | Urethane-induced endogenous as well as syngeneic, subcutaneous transplanted NSCLC models were used. vvDD infection synergized with blockade of both PD-1 and TIM-3 through the efficient direct killing of lung cancer tumor cells and recruiting and activating T cells for indirect tumor killing, vvDD was shown to induce higher expression of both PD-1 and TIM-3 in refractory lung cancer. Therefore, the triple combination therapy is more effective for refractory lung cancer. | Yang et al.29 | ||
| vvDD-IL23, derived from VV-WR strain modified for expressing recombinant IL23 | Intratumoral | LLC (Lewis lung cancer) NSCLC cell line was used as a subcutaneous transplant in the syngeneic model. Intratumoral infection with IL-23-armed vaccinia virus can induce potent antitumor effects through increased tumor cell death. Oncolysis combined with expression of membrane-bound IL-23 induces elevated expression of chemokines and other antitumor factors that cause increased antitumor immunity. | Chen et al.30 | ||
| TG4010, a modified vaccinia strain Ankara (MVA), expressing human mucin1 (MUC1) and IL-2 | Systemic, intravenously with anti-PD1 treatment | Intravenous injection with CT26 (expressing human MUC1) colon cancer cells induced extensive tumor growth in the lung. TG4010 application combined with anti-PD1 caused a better antitumor immune response and tumor regression compared with a single TG4010 treatment. | Remy-Ziller et al.31 | ||
| Oncopox-trail, derived from VV-WR strain, expressing recombinant TRAIL | Both intravenous and intratumoral injections | Tumor regression of A549 xenotransplant and LLC syngeneic models. TRAIL-induced increase in apoptosis and necrosis. | Hu et al.32 | ||
| GLV-1h68, replication-competent recombinant vaccinia virus derived from the Lister strain | Intravenous injections and systemic cyclophosphamide (CPA) | Systemic application of GLV-1h68 and CPA have synergistic effects against human lung adenocarcinoma PC14PE6 cell line in subcutaneous xenograft models. | Hofmann et al.33 | ||
| WR A34R(IHD-J) TK-Luc+ recombinant virus derived from WR strain. This VV recombinant produces high levels of extracellular enveloped virus (EEV) | Intravenous | EEV is covered by host-cell-derived lipid bilayer with anti-complement proteins that protect against immune clearance. | WR A34R(IHD-J) TK-Luc+ injected in two syngeneic models. Subcutaneous transplanted lung cancer cell line CMT64 and lung metastases producing mammary tumor cell line JC. In both models, systemic infection with WR A34R(IHD-J) TK-Luc+ induced a significantly higher tumor clearance level as compared with the WR strain. | Kirn et al.34 | |
| vvDD | Intravenous | Cytokine-induced killer (CIK) cells expressing NKG2D receptor. | CIKs loaded with vvDD were injected into syngeneic lung metastases producing mammary tumor (cell line JC) model causing almost complete clearance of primary tumor as well as lung metastases. | Thorne et al.35 | |
| VVΔTKΔN1L Recombinant virus with TK and N1L deletion in VVL15 strain |
Intratumoral | LLC NSCLC cell line was used as a subcutaneous transplant in the syngeneic model. Intratumoral infection with VVΔTKΔN1L marked tumor regression with increased intratumoral CD4+ and CD8+T cells and neutrophil accumulation. TME changed with increased systemic NK cells and augmented IL-α, IL1-β, and GCSF. | Ahmed et al.36 | ||
| Recombinant GLV-1h107, GLV-1h108 GLV-1h109 contains the GLAF-1 gene under the control of the VV SE, SEL, and SL promoters, respectively. All were inserted at the J2R locus in the parental virus GLV-1h68. | Intravenous | Intravenous injection of GLV-1h107, GLV-1h108, and GLV-1h109, in subcutaneous xenotransplanted A549 cell line tumor, caused tumor regression. GLAF-1 is a scAb against VEGF. Upon i.v. infection GLAF-1 is found inside the tumor and TME, causing a decrease in blood vessel formation occurs. | Frentzen et al.37 | ||
| EphA2-TEA-VV, a T cell engager armed oncolytic VV (TEA-VV) encoding secretory bispecific. T cell engagers (TEs) that bind both to human CD3 and a tumor cell surface antigen EphA2. Derived from original vvDD, WR strain. | Intravenous | After lung tumors were formed in systemic (i.v. injected A549 cell line) xenotransplanted NSCLC model, EphA2-TEA-VV was i.v. injected with or without unstimulated PBMCs. Strong tumor clearance and activation of T cells together with creased IFN-γ and IL-2 secretion. | Yu et al.38 | ||
| Myxoma virus | Oncolytic myxoma virus (MYXV) | Intraperitoneal and intratumoral application of MYXV, single or combined with a low dose of cisplatin | Intratumoral delivery of MYXV to the syngeneic immunocompetent murine SCLC model induces extensive tumor necrosis with marked host immune cell infiltration. Intratumoral injection of human SCLC PDX models in NSG mice background showed severe impairment of tumor growth | Kellish et al.39 | |
| Recombinant MYXV expressing IL-15 | Intravenous | Bone marrow-derived MSCs | i.v. injected B16-F10 melanoma cell line forming tumor foci in the lung of syngeneic C57BL6 mice, followed by i.v. injection with MYXV-IL-15 loaded MSCs. Formation of pulmonary melanoma foci was largely prevented, resulting in longer survival. Treated lungs showed high infiltration with NK and CD8+ T cells. | Jazowiecka-Rakus et al.40 | |
| Recombinant MYXV expressing TNF-α | Intravenous, combined with ICI anti- PD1/PD-L1 and CTLA-4 | Autologous peripheral blood mononuclear cells (PBMCs) | i.v. injected K7M2-Luc lung metastatic osteosarcoma cell line in syngeneic BALB/cJ mice, followed by i.v. injection with MYXV-TNF-loaded PBMCs. MYXV-loaded PBMCs caused efficient lung lesion regression and longer survival. Combined ICIs anti-PD1/PD-L1 and anti-CTLA-4 synergized well with MYXV-TNF. | Christie et al.41 | |
| Recombinant MYXV-expressing tumor necrosis factor family member TNFSF14 (LIGHT) | Retro-orbital intravenous, combined with ICI anti-PD1 | PBMCs | i.v. injected K7M2-Luc lung metastatic osteosarcoma cell line in syngeneic BALB/cJ mice, followed by systemic application of MYXV-LIGHT-loaded PBMCs. Treatment led to overall longer survival and tumor regression. Very efficient LIGHT expression and onset of innate and adaptive immune responses. | Christie et al.42 | |
| Reovirus | Reovirus type 3 Dearing strain (T3D) | Intravenous | H1299 human NSCLC cell line was used for the subcutaneous xenotransplanted lung cancer model. Reovirus i.v. injected caused tumor regression and induced a decrease in HIF-1α expression thereby lowering VEGFA levels in the tumor. | Hotani et al.43 | |
| Reovirus T3D | Intravenous | Adipose-derived MSCs | TC1 NSCLC cell line was used for the subcutaneous syngeneic lung cancer model. MSCs loaded with reovirus were i.v. injected causing tumor regression and growth arrest, followed by an increase of IFN-γ secretion. | Seyed-Khorrami et al.44 | |
| Measles virus | Attenuated measles virus (MV) HU-191 strain | Intratumoral | Intratumoral injection with MV Hu-191 in a syngeneic model with subcutaneously transplanted A549 and LLC tumor cell lines caused clear tumor cell death and regression with increased T cell infiltration of TME. | Zhao et al.45 | |
| Attenuated Schwartz vaccinal strain of measles virus expressing recombinant GFP (MV-eGFP) | Intratumoral | MV-eGFP infection of subcutaneous xenotransplanted human NSCLC cell lines ADK3, ADK117, ADK153, and A549 caused high levels of tumor cell death and tumor regression. MV oncolysis is associated with in vivo activation of caspase-3. | Boisgerault et al.46 | ||
| Influenza virus | Low pathogenic oncolytic influenza virus IAV | Intranasal injections | IAV infection of somatic NSCLC in Raf-BxB mice leads to reversal of immunosuppressed tumor-associated lung macrophage function to an M1-like pro-inflammatory active phenotype. | Masemann et al.47 | |
| Herpes simplex virus | AP27i145 HSV-1, recombinant HSV-1 expressing complement miRNA145 sequences in 3′ UTR of ICP27 | In vitro only | The combination of radiotherapy and AP27i145 infection was significantly more potent in killing NSCLC cell lines (A549, H1975, H460, and H838) than each therapy alone. | Li et al.48 | |
| R-LM249, recombinant HSV-1 retargeted to exclusively infect HER2 expressing cells | Intravenously | Fetal membrane (FM)-derived MSCs | Single i.v. injection with R-LM249-loaded FM-MSCs efficiently prevented metastatic tumor formation in the lungs of subcutaneous xenotransplanted human ovarian cancer cell line SK-OV-3. | Leoni et al.49 | |
| Cf33-GFP | Chimeric poxvirus generated through homologous recombination among nine strains/species of poxviruses, expressing GFP | Intratumoral injections | Tumor regression in both xenotransplant and syngeneic NSCLC models. Infiltration of tumors by CD8+ T cells. | Chaurasiya et al.50 | |
| Coxsackievirus | Coxsackievirus B3 (CVB3) strain | Intratumoral, injections | CVB3 was injected in a subcutaneous xenotransplant NSCLC (A549 or EBC-1 cells) model. Tumor regression and clearance with NK and granulocyte inside tumor and TME. Tumor cells express calreticulin and secreted ATP as well as HMGB1. | Miyamoto et al.51 | |
| CVB3 strain | Intratumoral injections, with wild-type or UV-inactivated CVB3 | Single-dose CVB3 injection in subcutaneous xenotransplanted, KRASmut human NSCLC cell line (A549, H2030, and H23) tumors. A specific increase in tumor cell death and regression occurred, suggesting that CVB3 is a potent OV for preferential KRAS-mutant lung adenocarcinoma. | Deng et al.52 | ||
| microRNA-modified CVB3 (miR-CVB3) strain containing multiple miR-145/miR-143 sequences | Intraperitoneal | Infection of miR-CVB3 in both NSCLC, KRASmut (cell lines A549, H2030, and H23) and SCLC, Trp53mut/RBmut (cell lines H524 and H526) causes significant tumor regression in both lung tumor types, expanding CVB3 tropism to SCLC, independent from KRAS status. | Liu et al.53 | ||
| Bovine herpes virus | Bovine herpes virus 1 (BoHV-1) strain | Intratumoral with trichostatin A treatment | Infection of BoHV-1 in subcutaneous xenotransplanted A549 cell line tumor caused tumor regression. HDAC levels are repressed, and BoHV-1 shows synergy with HDAC inhibitor trichostatin A. | Qiu et al.54 | |
| Newcastle disease virus | Wild-type NDV strain (NDV/Altai/pigeon/770/201) | Intratumoral | NDV infection of A549 human lung tumor cells in subcutaneous xenotransplant model. Increased necrotic effect on tumor cells but not on non-tumor cells and PBMCs. | Yurchenko et al.55 | |
| Wild-type FMW strain (NDV/FMW) | Intratumoral | FMW infection in subcutaneous xenotransplanted tumor cell lines A549 and H460 induced tumor regression and tumor cell death mainly via autophagy. | Ye et al.56 | ||
| Wild-type FMW strain (NDV/FMW) | NDV-FMW triggers caspase-dependent apoptosis in lung cancer spheroids and promotes autophagic degradation in lung cancer spheroids by inhibiting the AKT/mTOR pathway. NDV-FMW injected in subcutaneous xenotransplanted H460 spheroid cell clusters induced tumor regression. | Hu et al.57 | |||
| Attenuated NDV-HUJ strain derived from the original NDV B1 strain | Intravenous | NDV-HUJ was injected in a syngeneic model with metastasizing lung adenocarcinoma cell line 3LL-D122 as a subcutaneous and orthotopic lung transplant. Virus-selective oncolysis is dependent on apoptosis and is associated with higher levels of viral transcription, translation, and progeny virus formation. | Yaacov et al.58 | ||
| Recombined NDV strain (NDV-D90) | Intratumoral | NDV-D90 maintains tumor-selective replication properties and induces tumor cell apoptosis. A549 human lung tumor cells in subcutaneous xenotransplant model showing impairment of tumor growth. | Chai et al.59 | ||
| Adenovirus | H101, generated by both deleting E1B and E3 in adenovirus type 5 (Ad5) | Intratumoral | Human lung adenocarcinoma cell line XWLC-05 subcutaneous xenotransplant model. High levels of cytotoxicity, efficient cell lysis, and G2/M arrest cause significant tumor regression. | Lei et al.60 | |
| Ad-apoptin, recombinant Ad5-expressing apoptin | Intratumoral | Ad-apoptin injected in subcutaneous xenotransplant lung tumor (A549 cells) model showing impairment of tumor growth, and increased apoptosis. Ad-apoptin targets AMPK and inhibits glycolysis, migration, and invasion of lung cancer cells through the AMPK/mTOR signaling pathway. | Song et al.61 | ||
| Ad.hTERT-E1A-TK, recombinant Ad5 expressing HSV-TK and hTERT driving | Intratumoral | Ad.hTERT-E1A-TK infection combined with administration of prodrug gancyclovir (GCV) resulted in more potent cytotoxicity on A549 cells and synergistically suppressed human lung cancer A549 tumor growth in the subcutaneous xenotransplant model. | Zhang et al.62 | ||
| Complete E1B-deleted conditionally replicating Ad (CRAd) Adhz60 | Intratumoral and intrape, with temozolomide (TMZ) | H441 human lung tumor cell line in subcutaneous xenotransplant model. Adhz60 acted synergistically with TMZ in suppressing tumor growth. | Gomez-Gutierrez et al.63 | ||
| OBP-301 (telomelysin) is an attenuated Ad5 with a hTERT promoter driving both E1A and E1B to regulate viral replication. OBP-301 sensitizes human cancer cells to ionizing radiation by inhibiting DNA repair | Intratumoral, with gemcitabine | OBP-301 and gemcitabine have synergistic effects causing increased regression of tumor lesions in subcutaneous xenografts of human lung cancer cell lines H460, H322, and H358. | Liu et al.64 | ||
| Ad5/3-Δ24aCTLA4 Expressing Ig2 type anti-CTLA4 mAb in E1A-deleted Ad5/3 chimeric virus |
Intratumor | Ad5/3-Δ24aCTLA4, injected in a subcutaneous xenotransplant lung tumor (A549 cells) model. Severe tumor regression and inhibition of Tregs and increased CD8+/Treg ratios; increased T cell activity. | Dias et al.65 | ||
| Capsid-modified, Ad5-derived virus | Intravenous | Mesenchymal stem cells (MSCs) | MSCs loaded with modified Ad5 homed primarily to lungs in orthotopic xenotransplanted NSCLC cell line model. Significantly increased tumor regression. Very efficient systemic delivery of Ad5 in various organs besides the liver. | Hakkarainen et al.66 | |
| Ad-IAI.3b, derived from Ad5 | Intravenous | A549 cells were first infected with Ad-IAI.3b and then irradiated | Irradiated and with Ad-IAI.3b-loaded A549 tumor cells into orthotopic xenotransplanted lung squamous cell carcinoma cell line (KLN205) model. Accumulation of Ad-IAI.3b in the lung with strong tumor regression. Increased tumor-infiltrating lymphocytes (TILs) with high Th1-related cytokine expression. | Saito et al.67 | |
| Ad-uPAR-MMP-9, expressing antisense RNAs against uPAR and MMP-9 | Intratumoral and intravenous | Ad-uPAR-MMP-9 was injected into a subcutaneous xenotransplant lung tumor (H1299). Severe tumor regression and impaired angiogenesis. Ad-uPAR-MMP-9 was i.v. injected into a subcutaneous xenotransplant metastasizing lung tumor (A549). A strong decrease in angiogenesis but also metastasizing capacity is shown by the low number and size of lung metastases. | Rao et al.68 | ||
| AdE3-SCCA1 derived from Ad E3. Here the squamous cell carcinoma (SCC) specific promoter SCCA1 drives E1A expression | Intratumoral | A549 cells infected with AdE3-SCCA1 | A549 tumor cells loaded with AdE3-SCCA1 were injected into a syngeneic subcutaneous SCC (SCC7 cells) model. Mice were preimmunized against AdE3 and only the loaded A549 cells induced complete tumor regression. Co-loading A549 with AdE3-SCCA1 and Ad-mGM-CSF augmented the anti-tumor effect. | Hamada et al.69 | |
| ICO15K-FBiTE, expressing FBiTE, a bispecific T cell engager against FAP. Fibroblast activation protein-α (FAP) is highly overexpressed in cancer-associated fibroblasts (CAFs) |
Intravenous combined with preactivated T cells from human PBMCs | ICO15K-FBiTE, injected in subcutaneous xenotransplant lung tumor (A549 cells) model. Clearance of tumor lesion and activation and proliferation of T cells; resulting in CAF targeting. Increased tumor T cell retention and accumulation in tumor and TME. | Sostoa et al.70 Freedman et al.71 |
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| Recombinant adenovirus KGHV500, expressing anti-p21Ras scFv | Intravenous | CIK cells | CIKs loaded with KGHV500 were intravenously injected into an A549 tumor xenotransplant model leading to significantly increased tumor regression. Note that A549 has high expression of KRASV12 and KGHV500 and anti-p21Ras scFv were observed in tumor tissue but were nearly undetectable in normal tissues. | Lin et al.72 | |
| Recombinant adenovirus ZD55 harboring tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), manganese-containing superoxide dismutase (MnSOD), and TRAIL-isoleucine-aspartate-threonine-glutamate (IETD)-MnSOD |
Intravenous | CIK cells | CIKs loaded with ZD55 were intravenously injected into an A549 tumor xenotransplant model inducing a significantly higher level of tumor cell death and lower tumor volumes as compared with the non-transgene expressing control ZD55. Tumor tropism of ZD55-loaded CIKs was very high. | Jiang et al.73 | |
| ICOVIR-15 with E2F responsive palindromes in E1A promoter, as CRAd derived from AdΔ24-RGD; replication-incompetent Ad-iC9, expressing inducible caspase-9 | Intravenous | Bone marrow-derived MSCs loaded with combined ICOVIR-15 and Ad-iC9 | MSC loaded with ICOVIR-15/Ad-iC9 were systemically applied in a subcutaneous A549 tumor xenotransplant model After 48–72 h, MSCS could be detected in local tumor tissue resulting in consistent tumor clearance and longer survival of treated mice. | Hoyos et al.74 | |
| Single ICOVIR-15 | Intravenous with allogeneic PBMCs | Human menstrual blood-derived MSCs loaded with ICOVİR-15 | MSCs loaded with ICOVIR-15, combined with allogeneic PBMCs, systemically infected in a subcutaneous A549 cell xenotransplant model. Efficient clearance of tumor mass and antitumor efficacy partially mediated by monocytes and NK cells. | Moreno et al.75 | |
| ICOVIR-5, strain analog to ICOVIR-15 | Intraperitoneal | Murine bone marrow-derived MSCs | MSCs loaded with ICOVIR-5 (Celyvir therapy), i.p. infected in syngeneic murine lung adenocarcinoma (CMT64 cells) model. Significant tumor clearance occurred, loaded MSCs homing into the CMT64 tumor followed by an invasion of the tumor bed by a high number of CD8+ and CD4+ cells. | Rincón et al.76 | |
| ICOVIR-5, strain analog to ICOVIR-15 | Intravenous | Murine bone marrow-derived MSCs, either syngeneic or allogeneic | MSCs loaded with ICOVIR-5 (Celyvir therapy), systemically infected in syngeneic murine lung adenocarcinoma (CMT64 cells) model. Tumor clearance after Celyvir treatment. Both syngeneic and allogeneic Celyvir induce systemic activation of the immune system, similar antitumor effect, and a higher intratumoral infiltration of leukocytes, as shown by high infiltration of CD45+ cells in the tumor core. | Morales-Molina et al.77 | |
| ICOVIR15-cBiTE, expressing an epidermal growth factor receptor (EGFR)-targeting bispecific T cell engager (cBiTE) | Intraperitoneal with allogeneic PBMCs | Human menstrual blood-derived MSCs | MSCs loaded with ICOVIR15-cBiTE, systemically infected in subcutaneous (A549) xenotransplanted human adenocarcinoma model. Enhanced tumor clearance compared with unarmed IVOVIR-15. | Barlabé et al.78 | |
| Vesicular stomatitis virus | Recombinant oncolytic vesicular stomatitis virus (VSV) pseudo-typed with LCMV-GP expressing tumor-associated antigens, termed VSV-GP-TAA | Intravenous with KISIMA-TAA as a self-adjuvant cancer vaccine in combination with anti-Pd1 antibody | Priming vaccination with KISIMA-TAA followed by VSV-GP-TAA resulted in strong tumor regression and even increased with anti-PD1, in the syngeneic NSCLC model using TC-1 cell line as subcutaneous transplant. | Das et al.79 | |
| Attenuated, recombinant Av3 strain, expressing GFP | Intravenous | Murine CT26 colon carcinoma and L1210 leukemia cell lines. Human A549 lung adenocarcinoma cell line | Tumor cell lines loaded with Av3 were injected in orthotopic transplanted (CT26 lung tumor cell line) syngeneic models. Both murine tumor cell lines delivered high doses of VSV, even when recipient tumor-bearing mice were pre-immunized against VSV. The xenogeneic human A549 cell line showed similar carrier efficiency. Lung tumor carrier cells end up preferentially in the lung while leukemic carrier cells disperse systemically. Cell-mediated delivery of VSV can be achieved using allogeneic or xenogeneic carrier tumor cell lines, proving that carrier cells can evade immune responses against OVs. | Power et al.22 | |
| Voyager-V1 (VV1) VSV strain expressing IFN-β and sodium iodide symporter (NIS) |
Intravenous, combined with anti- CTLA4 and PD1 Abs | VV1, combined with anti-CTLA4 and anti-PD-1, were intravenously injected in syngeneic CMT64 adenocarcinoma cell line models and induced durable tumor regression, high level of TILs and efficient CD8 TL response against CMT64 neo epitopes. | Ram et al.80 | ||
| VSV-IFN-β, recombinant VSV expressing interferon-β | Intravenous | Blood outgrowth endothelial cells (BOECs) | Syngeneic lung metastatic LM2 mammary tumor model was intravenously injected with VSV-IFN-β loaded BOECs causing a major regression of lung metastases. Similar i.v. application in an A549 xenotransplantation model led to severely increased antitumor activity and survival. | Patel et al.81 |