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Table 1 Selected oncolytic virus platforms in clinical development

From: Oncolytic viruses encoding bispecific T cell engagers: a blueprint for emerging immunovirotherapies

Virus platform Virology Safety Flexibility Production Selected candidates in clinical trials
Adenovirus [9,10,11] Non-enveloped icosahedral dsDNA virus (Adenoviridae) can cause common cold, > 50 serotypes targeting epithelia, entry via CD46/coxsackievirus adenovirus receptor/desmoglein-2, tumor-specific via genetic modification ↓ Derived from human pathogen, can cause respiratory illness and conjunctivitis
↓ Shedding observed
↓ Viral DNA enters nucleus; theoretical concern of insertion
↑ Oncoselective when engineered, requires deregulated cell division and growth pathways (defective Rb and upregulated RAS signaling)
↑ Low concern for mutations
↑ Generally well tolerated with mild side effects
↓ Intermediate transgene capacity
↑ Helper-dependent packaging vectors available
↓ Potential for retargeting limited by structural constraints
↑ Variety of serotypes
↑ Progeny produced at high titers
↑ Purification simple due to well-defined virion size and structure
H101/Oncorine with CTx in HCC (III) [NCT03780049]
DNX-2401 with ICI in GBM/GS (II) [NCT02798406]
OBP-301 in melanoma [NCT03190824]; with ICI and RTx in HNSCC (II) [NCT04685499]
ICOVIR-5 via carrier cells in pediatric solid tumors (I/II) [NCT01844661] [12]; with or without RTx in pediatric brain tumors (I/II) [NCT04758533]
Enadenotucirev in epithelial solid tumors (I/II) [NCT02028442] [13]
LOAd703 (enc. immune-stimulatory CD40L/4-1BBL) with CTx and ICI in pancreatic cancer (I/II) [NCT02705196]; with ICI in melanoma [NCT04123470]
ORCA-010 in prostate cancer (I/II) [NCT04097002]
CG7870 with CTx in prostate cancer (I/II) [NCT00103428]; in prostate cancer (I/II) [NCT00116155] [14]
CG0070 (enc. GM-CSF) in NMIBC (II/III) [NCT01438112]; (III) [NCT04452591]
ONCOS-102 (enc. GM-CSF) with CTx in mesothelioma (I/II) [NCT02879669]; with ICI in peritoneal cancer (I/II) [NCT02963831]
NG-641 (enc. FAP-TAc and CXCL9-CXCL10-IFNα) alone or with ICI and/or CTx in epithelial cancers (I) [NCT04053283]
Coxsackievirus [15,16,17] Non-enveloped icosahedral (+)ssRNA viruses (Picornaviridae) can cause common cold and hand-foot-and-mouth disease, > 20 serotypes, entry via ICAM-1/coxsackievirus adenovirus receptor ↓ Human pathogen
↑ Well-studied, causes mild disease
↓ Relatively high mutation rate
↓ Entry receptors widely expressed on healthy tissues
↑ Low toxicity reported (in immunocompetent adults)
↓ No genetic modification (bioselection from wild-type strains) ↑ GMP manufacturing established CVA21/V937 in melanoma (II) [NCT01227551]; with ICI in solid tumors (I/II) [NCT04521621]
Herpes simplex virus type I [18,19,20] Enveloped icosahedral dsDNA virus (Herpesviridae) can cause skin blisters and encephalitis, entry via heparin sulfate, nectin-1/PVRL1, and HVEM, tumor-specific via genetic modification ↓ Derived from human pathogen
↑ Modified for enhanced oncotropism and reduced neurovirulence
↑ Antiviral agent available
↓ Viral DNA enters nucleus, chromosomal integration rare but possible
↑ Good safety profile in clinical trials
↑ Multiple gene deletions and transgene insertions possible ↑ Large volume production Talimogene Laherparepvec/T-VEC/Imlygic (enc. GM-CSF) in melanoma (II) [NCT00289016]; (III) [NCT00769704] [21]; with ICI in melanoma (II) [NCT04068181], with RTx in sarcoma (II) [NCT04599062]
HF10 with ICI in melanoma (II) [NCT02272855]; (II) [NCT03153085]
G207 in brain tumors (I/II) [NCT00028158]; with RTx in pediatric gliomas (II) [NCT04482933]
RP1 with ICI in solid tumors (II) [NCT03767348]; with ICI in SCC (II) [NCT04050436]
Maraba virus [22,23,24] Enveloped bullet-shaped (−)ssRNA virus (Rhabdoviridae), originally isolated from Brazilian sand flies, apathogenic in humans, entry via LDLR, enhanced tumor specificity via genetic modification ↑ Apathogenic in humans
↑ Well tolerated even at high doses
↑ Transgene insertion, e.g., of tumor antigens, possible via reverse genetics ↑ Rapid progeny production at high titers
↑ Efficient filtration and purification due to small size and defined shape
MG1-MAGEA3 (enc. MAGE-A3) following prime with non-replicating adenovirus (enc. MAGE-A3) in solid tumors (I/II) [NCT02285816]; with ICI in NSCLC (I/II) [NCT02879760]
Measles virus [25,26,27,28,29] Enveloped pleomorphic (−)ssRNA virus (Paramyxoviridae), causes measles and can cause encephalitis, fusogenic, live attenuated vaccine strains, entry preferentially via CD46, also via nectin-4/PVLR4 and CD150 ↑ Safety of vaccine strains well established
↑ Generally well-tolerated, different administration routes tested
↑ Natural oncotropism
↑ Very low mutation rate, no conversion to wild-type observed
↑ Replication strictly cytosolic
↑ Reverse genetics system established for convenient cloning, transgene capacity > 5 kb
↓ Structural requirements for transgene, including “rule of six” (complete genome must be divisible by six)
↑ Pre- and post-entry re
-/de-targeting
↑ Envelope exchange
↓ Lower titers compared to other viruses
↓ Generation of defective interfering particles
↓ Purification challenging (pleomorphic virions, sensitive to pH and shear stress)
MV-NIS (enc. human sodium/iodide symporter) with or without CTx in multiple myeloma (I/II) [NCT00450814] [30]; in ovarian/fallopian/peritoneal cancer (II) [NCT02364713]
Parvovirus [31,32,33,34] Non-enveloped small icosahedral rodent ssDNA virus (Parvoviridae), apathogenic in humans, clathrin-mediated entry via unknown receptor ↑ Apathogenic in humans ↓ Transgene capacity limited to small RNAs ↑ High-titer production
↑ Stability
H-1PV in glioblastoma (I/II) [NCT01301430] [35, 36] and in pancreatic cancer (I/II) [NCT02653313] [37]
Poliovirus [17, 38] Non-enveloped icosahedral (+)ssRNA virus (Picornaviridae), can cause gastroenteritis, flu-like symptoms, and poliomyelitis, entry via CD155, live attenuated vaccine strain, enhanced oncoselectivity and reduced neurovirulence of genetically modified variants or polio-rhinovirus chimera ↓ Derived from human pathogen
↑ Abrogated neurovirulence of chimeric polio-rhinovirus
↓ Relatively high mutation rate
↓ Dose-limiting toxicities observed
↑ Well tolerated at deescalated dose
↑ Sublethal infection of APCs induces sustained immune response
↓ Small genome size restricts transgene capacity ↑ Production of polio vaccine well established PVSRIPO in glioblastoma (II) [NCT02986178], following [39]; with ICI in glioblastoma (II) [NCT04479241]; with ICI in melanoma (II) [NCT04577807]
Reovirus [40, 41] Non-enveloped icosahedral virus with segmented dsRNA genome (Reoviridae), can cause gastrointestinal and respiratory symptoms, entry via JAM-A ↓ Virus shedding observed
↓ Relatively high mutation rate
↓ Viral replication despite presence of neutralizing antibodies
↑ Well tolerated in clinical trials
↓ Genetic modification not trivial, limited transgene size
↑ Novel approaches increase engineering potential
↑ Large volume production to high titers Reolysin in sarcoma lung metastases (II) [NCT00503295]; with CTx in HNSCC (III) [NCT01166542]
Pelareorep with ICI in breast cancer (II) [NCT04445844]
Wild-type Reovirus with CTx in pancreatic cancer (II) [NCT01280058]
Vaccinia virus [42,43,44,45,46,47] Enveloped large brick-shaped dsDNA virus (Poxviridae), origin unclear, variants found in buffalos, cattle, and rabbits, complex structure and genome, used for vaccination against smallpox, can cause rashes and fever and rare potentially lethal complications including gangrene and neurological symptoms, multiple gene deletions enhance oncoselectivity ↓ Virus shedding observed
↓ Complications associated with vaccine
↑ Low number of high-grade adverse events reported
↑ Large genome with great potential for engineering (multiple gene deletions and insertions)
↓ Genome complexity requires careful consideration
↑ High titer production
↓ Complex purification process
Pexastimogene Devacirepvec/PexaVec/JX-594 (enc. GM-CSF) in melanoma (I/II) [NCT00429312]; with TTx in HCC (III) [NCT02562755] (terminated after interim futility analysis without safety concerns)
GL-ONC1 (enc. several reporter genes) in peritoneal carcinomatosis (I/II) [NCT01443260]; with CTx in ovarian cancer (I/II) [NCT02759588]
T601 (enc. a prodrug conversion enzyme) with CTx in solid tumors (I/II) [NCT04226066]
TBio-6517 (enc. Flt3L, anti-CTLA4, and IL-12) with ICI in solid tumors (I/II) [NCT04301011]
BT-001 (enc. anti-CTLA4 and GM-CSF) with ICI in solid tumors (I/II) [NCT04725331]
  1. A selection of the clinically most advanced oncolytic virus platforms (see [6,7,8] for recent reviews) is described in the Table with a focus on their safety profile, possibilities for engineering, and scalability of production. Clinical studies found on clinicaltrials.gov (as of March 13, 2021) are listed for candidates that are at least in phase I/II and include the first registered phase I/II or higher study and the most recent or most advanced trial for each therapeutic. In addition, the phase III study leading to approval of T-VEC and the first phase I study assessing a BiTE-encoding OV are highlighted. Direct comparison of different platforms is extremely challenging; mechanisms of action are highly complex and efficacy strongly depends on tumor diseases or experimental models. For more detailed information on specific viruses, the interested reader is referred to indicated reviews. Further relevant considerations for OV therapy include the route of administration and pre-existing and induced anti-viral immunity (reviewed in [7])
  2. ds, double-stranded; (−), negative-sense; (+), positive-sense; ss, single-stranded; ICD, immunogenic cell death; CTx, chemotherapy; RTx, radiotherapy; ICI, immune checkpoint inhibition; ITx, other immunotherapy; TTx, targeted therapy (small molecule; enzyme inhibitor); I/II/III, clinical trial phase; HCC, hepatocellular carcinoma; GBM, glioblastoma multiforme; GS, gliosarcoma; HNSCC, head and neck squamous cell carcinoma; enc., encoding; GM-CSF, granulocyte macrophage colony-stimulating factor; NMIBC, non-muscle invasive bladder cancer; ICAM, intercellular adhesion molecule; GMP, good manufacturing practice; PVRL, poliovirus-receptor-like; HVEM, herpes virus entry mediator; LDLR, low density lipoprotein receptor; SCC, squamous cell carcinoma; MAGE, melanoma antigen; NSCLC, non-small cell lung cancer; NIS, human sodium/iodide symporter; H-1PV, H-1 protoparvovirus; APCs, antigen-presenting cells; JAM-A, junctional adhesion molecule A; CTLA4, cytotoxic T lymphocyte-associated protein 4; Flt3L, Flt3 ligand; IL12, interleukin-12