Therapeutic Applications for Oncolytic Self-Replicating RNA Viruses

Therapeutic Applications for Oncolytic Self-Replicating RNA Viruses: Comparison

Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Kenneth Lundstrom.

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.

recombinant viral particles
RNA replicons
DNA replicons
oncolytic viruses
cancer vaccines
cancer immunotherapy

1. Introduction

Cancer still remains the leading cause of worldwide mortality, with 10 million deaths annually ^[1]. Despite progress in diagnostics and therapy, the incidence and mortality numbers remain high due to pollution, unhealthy eating habits, lifestyle choices, and an aging population ^[2]. Although progress in conventional chemotherapy and radiotherapy approaches have been made, the efficient and safe delivery of cancer drugs has been a major obstacle. In this context, both non-viral and viral delivery vectors have been engineered for cancer therapy in parallel to conventional approaches ^[3].

Different applications of viral vectors have been used for the development of cancer vaccines and therapy, focusing on the overexpression of tumor-associated antigens (TAAs), anticancer genes, and immunostimulatory genes [4,5]^[4][5]. One relatively novel approach comprises the use of oncolytic viruses, which specifically kill tumor cells without causing damage to normal tissue due their targeted replication in tumor cells ^[6]. Oncolytic viruses exist as naturally occurring ^[7] and engineered ^[8] versions. Different types of viruses such as adenoviruses ^[9], alphaviruses ^[8], Herpes simplex viruses ^[10], rhabdoviruses ^[11], Newcastle disease virus ^[12], and vaccinia viruses ^[13] have demonstrated oncolytic properties.

2. Characterization of Oncolytic Self-Replicating RNA Viruses

Studies on the origin of cancer have indicated that a subpopulation of cells known as cancer stem cells (CSCs) or cancer-initiating cells (CICs) are responsible for tumorigenesis [16]^[14]. As CICs have been shown to be resistant to conventional anticancer therapies, the potential of oncolytic viruses to destroy CICs have made them attractive for alternative therapeutic applications. Oncolytic viruses of different origin [7,8,9,10,11,12,13,14,15]^{[7][8][9][10][11][12][13][15][16]} comprise wild-type viruses, which are unable to infect normal cells but are cytotoxic to cancer cells ^[17]. Moreover, the deletion of viral genes critical for replication in normal cells but dispensable in cancer cells has generated attenuated oncolytic strains. Serial passaging in cell cultures has also resulted in attenuated viruses. The mechanisms have been postulated to involve RAS pathway activation or take place by genetic modifications ^[18]. For these reasons, oncolytic viruses present efficient tumor killing, while only minimal toxicity is caused in normal cells. Self-replicating RNA viruses possess a special feature in the ability of self-replicating of their RNA genome in infected host cells, resulting in approximately 200,000-fold RNA amplification ^[19]. The single-stranded RNA (ssRNA) genome is of positive polarity for alphaviruses ^[19] and flaviviruses ^[20]. In contrast, measles viruses ^[21] and rhabdoviruses ^[22] possess a negative-stranded genome. This difference is significant, as, in the former case, viral RNA can directly be translated in the cytoplasm of infected cells, whereas, in the latter case, positive-stranded copies need to be generated prior to translation. Among alphaviruses, the naturally oncolytic M1 alphavirus has been used in several cancer therapeutic applications [23,24]^[23][24]. Moreover, attenuated Sindbis virus (SIN) strains such as SIN AR339 ^[25] and vectors based on the Semliki Forest virus (SFV) strain SFV-A7(74) ^[26] have demonstrated oncolytic properties. Additionally, Aura virus (AURAV) has shown oncotropism for certain tumor cell lines ^[27]. In the context of flaviviruses, the Zika virus (ZIKV) has demonstrated oncolytic activity against glioblastoma stem cells (GSCs) [14,28]^[15][28]. The negative-stranded measles viruses (MV) have also demonstrated oncolytic activity in several preclinical studies [15]^[16]. In the case of rhabdoviruses, the vesicular stomatitis virus (VSV) has been utilized for cancer therapy due to its oncolytic activity [11,29]^[11][29]. Moreover, the oncolytic Maraba virus has been used for the treatment of sarcoma ^[30]. The delivery of self-replicating RNA viruses is illustrated in Figure 1.

Figure 1. Schematic illustration of the delivery of self-replicating RNA viruses. Viral particles, naked RNA replicons, lipid nanoparticle (LNP)-encapsulated RNA, or DNA replicons can be used.

3. Preclinical Studies Using Oncolytic Self-Replicating RNA Viruses

Due to the large number of preclinical studies conducted with oncolytic self-replicating RNA viruses, selected examples for studies using alphaviruses, flaviviruses, measles viruses, and rhabdoviruses are summarized in Table 1.

Table 1.

Examples of preclinical studies using 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; rMV^EGFP-L_DMV, 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; ZIKV^BR, Brazilian ZIKV strain; ZVp, inactivated ZIKV prototype.

4. Clinical Trials Using Oncolytic Self-Replicating RNA Viruses

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

	Oncolytic Virus

	Phase

	Findings

	Ref

Ovarian

GBM

Colorectal

Pancreatic

CTCL

Ovarian

Mesothelioma

MPNST

Head & Neck

Myeloma

Prostate

Breast

MV-CEA

VEE-CEA

MV-EZ

MV-NIS

MV.NIS

VEE-PSMA

VEE-HER2

I/II

No toxicity, SD in patients, 2-fold extended OS

Study in progress

Antigen-specific responses, extended survival

T cell responses, tumor toxicity, extended OS

Good safety, complete tumor regression

SD in patients, significantly extended OS

Study in progress

Complete remission in one patient

Safe, but disappointingly weak immune response

SD in 1 patient, PR in 2 patients

[77]

[78.79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

Ovarian	MV-CEA	I/II	No toxicity, SD in patients, 2-fold extended OS	^[76]
GBM	MV-CEA	I	Study in progress	^[77]^[78]
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.

5. Conclusions

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.

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