Self-replicating RNA viruses have become attractive delivery vehicles for therapeutic applications. They are easy to handle, can be rapidly produced in large quantities, and can be delivered as recombinant viral particles, naked or nanoparticle-encapsulated RNA, or plasmid DNA-based vectors. The self-replication of RNA in infected host cells provides the means for generating much higher transgene expression levels and the possibility to apply substantially reduced amounts of RNA to achieve similar expression levels or immune responses compared to conventional synthetic mRNA. Alphaviruses and flaviviruses, possessing a single-stranded RNA genome of positive polarity, as well as measles viruses and rhabdoviruses with a negative-stranded RNA genome. Particularly, oncolytic self-replicating RNA viruses have demonstrated tumor growth inhibition, tumor eradication and cure in animal tumor models. Stable disease and prolonged overall survival have been reported from clinical trials with oncolytic self-replicating RNA viruses.
Cancer |
Oncolytic Virus |
Gene(s) |
Findings |
Ref. |
---|---|---|---|---|
Alphaviruses |
||||
GBM |
SFV VA7 |
EGFP, Rluc |
Tumor eradication, long-term survival in mice |
[31] |
Lung A459 |
SFV-VA7 |
EGFP |
Prolonged survival in mice |
[26] |
Prostate LNCaP |
SFV-VA7 |
EGFP |
Tumor cell killing, tumor eradication in mice |
[32] |
GBM |
SFV-AM6-124T |
miR124 |
Targeting GL261 gliomas, enhanced by anti-PD1 |
[33] |
GBM |
SFV4miRT |
miR124,125,134 |
Prolonged survival in mice |
[34] |
Cervical |
SIN AR339 |
SIN AR339 |
Tumor cell killing, tumor regression in mice |
[25] |
Ovarian |
SIN AR339 |
SIN AR339 |
Tumor cell killing, tumor regression in mice |
[25] |
Liver |
M1 |
GFP |
Targeting of liver tumors in mice |
[35] |
Glioma |
M1 |
M1 |
Killing of malignant glioma cells in mice, rats |
[36] |
Bladder MIBC |
M1 |
GFP |
Tumor growth inhibition in mice |
[37] |
Bladder |
M1 |
M1 |
Oncolytic activity in mouse bladder tumor model |
[38] |
Breast TNBC |
M1 |
M1 + Dox |
Reduced tumor growth in mice |
[39] |
Pancreatic |
M1 |
M1 + IRE |
Superior tumor inhibition, prolonged survival |
[40] |
Liver |
M1 |
M-LPO |
Inhibition of Hep3B cancer cell growth in vitro |
[41] |
Colorectal |
M1 |
M-LPO |
Inhibition of LoVo cancer cell growth in vitro |
[41] |
Flaviviruses |
||||
GBM |
ZIKV |
m-ZIKV |
Prolonged survival in mice |
[28] |
MB, ependymoma |
ZIKV |
ZIKV |
Infection and killing of GSCs |
[42] |
GBM |
ZIKV |
ZIKV + anti-PD1 |
Synergistic effect on survival in mice |
[43] |
Embryonal CNS |
ZIKV |
ZIKVBR |
Eradication of brain tumors, no effect on normal cells |
[44] |
Spontaneous CNS |
ZIKV |
ZIKVBR |
Tumor eradication, prolonged survival in dogs |
[45] |
Prostate |
ZIKV |
ZVp |
Metabolomics to identify PC-3 cancer cell markers |
[46] |
Measles viruses |
||||
Medulloblastoma |
MV |
GFP |
Complete tumor regression in mice |
[47] |
Medulloblastoma |
MV |
GFP |
Significantly prolonged survival in mice |
[48] |
Glioma |
MV |
CEA, NIS |
Cytopathic effects in GSC cell lines |
[49] |
Breast |
MV |
SLAMblind |
Anti-tumor activity in mice |
[50] |
Breast |
MV |
MV |
Infection, killing of MCF-7 and CAL-51 cancer cells |
[51] |
Breast |
MV |
MV-Edm |
Re-sensitization of Dox and ironicizing radiation |
[52] |
Lung |
MV |
MV Hu-191 |
Suppression of tumor growth in mice |
[53] |
Lung. colorectal |
MV |
MV-Schwarz |
Repression of tumor growth in mice |
[54] |
Lung |
MV |
CEA |
Tumor growth inhibition in mice |
[55] |
Melanoma |
MV |
MV L-16 |
Killing of tumor cells, tumor inhibition in mice |
[56] |
Pancreatic |
MV |
SLAMBlind |
Inhibition of tumor growth in mice |
[57] |
Pancreatic |
MV |
MV-SCD + Gem |
Reduced tumor mass in pancreatic cell lines |
[58] |
Pancreatic |
MV |
MV-miR-148 |
Delayed tumor growth, prolonged survival in mice |
[59] |
Prostate |
MV |
CEA |
Delayed tumor growth, prolonged survival in mice |
[60] |
Prostate |
MV |
sc-Fv-PSMA |
Killing of prostate cancer cells |
[61] |
Prostate |
MV |
MV + MuV |
Superior anti-tumor activity, survival in mice |
[62] |
Rhabdoviruses |
||||
Glioma, breast |
VSV |
VSVrp30a |
Targeting and eradication of tumors in mice |
[63] |
Olfactory bulb |
VSV |
VSVrp30a |
Tumor targeting, no damage to normal cells in mice |
[63] |
Glioblastoma |
VSV |
VSV-p1-GFP |
Killing of tumor cells, not normal cells |
[64] |
Breast 4T1 |
VSV |
VSV(M51R)-LacZ |
Lesions in breast cancer cells in mice |
[65] |
Colon CT-26 |
VSV |
VSV(M51R) |
Prolonged survival in mice |
[66] |
Lung LLC-1 |
VSV |
VSV-LCMV GP |
Tumor-to-tumor spread, killing of tumor cells |
[67] |
Melanoma |
VSV |
VSV-LCMV GP |
Tumor regression, prolonged survival in mice |
[68] |
Ovarian |
VSV |
VSV-LCMV GP |
Superior tumor regression with ruxolitinib |
[69] |
Melanoma |
VSV |
VSV-XN2-ΔG |
Tumor regression in mice |
[70] |
Ovarian |
VSV |
VSVMP-p DNA |
Tumor weight decrease, prolonged survival in mice |
[71] |
Ovarian |
VSV |
VSVMP-p DNA |
87–98% tumor regression, prolonged survival |
[72] |
Prostate |
VSV |
VSV(M51R) |
Superior oncolysis after curcumin treatment |
[73] |
Melanoma |
Maraba MG1 |
hDCT + Ad-hDCT |
Immune response after prime Ad-hCDT |
[74] |
Sarcoma |
Maraba MG1 |
MG1 |
Protection against tumor challenges, cure in mice |
[30] |
Breast |
MV, RABV |
rMVEGFP-LDMV |
Blue light induced tumor regression |
[75] |
Ad-hCT, adenovirus hDCT; anti-PD1, anti-programmed death 1; CEA, carcinoembryonic antigen; CNS, central nervous system; Dox, doxorubicin; EGFP, enhanced green fluorescent protein; GBM, glioblastoma multiforme; Gem, gemcitabine; GSCs, glioblastoma stem cells; hDCT, human dopachrome tautomerase; IRE, irreversible electroporation; LCMV GP, lymphocytic choriomeningitis virus glycoprotein; M1, M1 alphavirus; miRNA, microRNA; MB, medulloblastoma; M-LPO, liposome encapsulated M1; MuV, mumps virus; MV, measles virus; MV L-16, MV Leningrad-16 strain: m-ZIKV, mouse adapted ZIKV; NIS, sodium iodide symporter; PSMA, prostate-specific membrane antigen; RABV, rabies virus; rMVEGFP-LDMV, MV with EGFP and controllable Magnet; Rluc, Renilla luciferase; sc-Fv, single-chain antibody; SFV, Semliki Forest virus; SIN, Sindbis virus; SLAMBlind, disenabled signaling lymphocyte activation molecule; TNBC, triple-negative breast cancer; VSV, vesicular stomatitis virus; VSV(M51R), VSV with mutation in matrix protein; VSVMP-p, liposome encapsulated VSV DNA vector with matrix protein ZIKV, Zika virus; ZIKVBR, Brazilian ZIKV strain; ZVp, inactivated ZIKV prototype.
A number of clinical trials have also been conducted with oncolytic self-replicating RNA viruses, of which selected examples are listed in Table 2.
Table 2. Examples of clinical studies using oncolytic self-replicating RNA viruses.
Cancer |
Oncolytic Virus |
Phase |
Findings |
Ref |
---|---|---|---|---|
Ovarian |
MV-CEA |
I/II |
No toxicity, SD in patients, 2-fold extended OS |
[76] |
GBM |
MV-CEA |
I |
Study in progress |
|
Colorectal |
VEE-CEA |
I |
Antigen-specific responses, extended survival |
[79] |
Pancreatic |
VEE-CEA |
I |
T cell responses, tumor toxicity, extended OS |
[80] |
CTCL |
MV-EZ |
I |
Good safety, complete tumor regression |
[81] |
Ovarian |
MV-NIS |
I |
SD in patients, significantly extended OS |
[82] |
Mesothelioma |
MV-NIS |
I |
Study in progress |
[83] |
MPNST |
MV-NIS |
I |
Study in progress |
[84] |
Head & Neck |
MV-NIS |
I |
Study in progress |
[85] |
Myeloma |
MV.NIS |
I |
Complete remission in one patient |
[86] |
Prostate |
VEE-PSMA |
I |
Safe, but disappointingly weak immune response |
[87] |
Breast |
VEE-HER2 |
I |
SD in 1 patient, PR in 2 patients |
[88] |
CEA, carcinoembryonic antigen; CTCL, cutaneous T-cell lymphoma; GBM, glioblastoma multiforme; HER2, human epidermal growth factor receptor 2; MPNSST, malignant peripheral nerve sheath tumor; MV, measles virus; MV-EZ, MV Edmonston-Zagreb strain; NIS, sodium iodide symporter; OS, overall survival; PR, partial response; PSMA, prostate-specific membrane antigen; SD, stable disease; VEE, Venezuelan equine encephalitis virus.
Oncolytic self-replicating RNA viruses have been evaluated for the treatment and prevention of various cancers in animal models and clinical trials showing efficient targeting and specific killing of tumor cells. Tumor growth inhibition, tumor regression and cure have been achieved in preclinical studies and stable disease and prolonged survival in clinical trials.
This entry is adapted from the peer-reviewed paper 10.3390/ijms232415622