Intravesical treatment of advanced urothelial bladder cancers with oncolytic HSV-1 co-regulated by differentially expressed microRNAs

Abstract

Urothelial bladder cancer is the most common malignancy of the urinary tract. Although most cases are initially diagnosed as non-muscle-invasive, more than 80% of patients will develop recurrent or metastatic tumors. No effective therapy exists currently for late-stage metastatic tumors. By intravesical application, local administration of oncolytic Herpes Simplex virus (oHSV-1) can provide a promising new therapy for this disease. However, its inherent neurotoxicity has been a perceived limitation for such application. In this study, we present a novel microRNA-regulatory approach to reduce HSV-1-induced neurotoxicity by suppressing viral replication in neurons while maintaining oncolytic selectivity toward urothelial tumors. Specifically, we designed a recombinant virus that utilizes differentially expressed endogenous microR143 (non-cancerous, ubiquitous) and microR124 (neural-specific) to regulate expression of ICP-4, a gene essential for HSV-1 replication. We found that expression of ICP-4 must be controlled by a combination of both miR143 and miR124 to achieve the most effective attenuation in HSV-1-induced toxicity while retaining maximal oncolytic capacity. These results suggest that interaction between miR143 and miR124 may be required to successfully regulate HSV-1 replication. Our resent study is the first proof-in-principle that miRNA combination can be exploited to fine-tune the replication of HSV-1 to treat human cancers.

Oncolytic HSV Vectors and Anti-Tumor Immunity

“…The use of differential miRNA expression to limit oHSV replication to tumor cells was first described in a prostate cancer model using an amplicon vector with recognition sequences for miR-143 and miR-145 engineered into the 3'UTR of the ICP4 gene; both miRNAs are expressed in normal tissues but are significantly down-regulated in prostate cancer cells (Lee et al, 2009). The promise of this strategy was confirmed in models of other tumors, including liver tumors where miR-222 expression is highly reduced compared to hepatocytes (Fu et al, 2012), non-small-cell lung cancer (miR-145) (Li et al, 2013), and urothelial bladder cancer (miR-143 + miR-124) (Zhang et al, 2016).…”

Oncolytic Viruses for the Treatment of Bladder Cancer: Advances, Challenges, and Prospects

“…Third-generation OVs are “armed viruses” that have been cloned with immune stimulatory or toxic genes such as granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-2 to accelerate resistant antitumor immunity and increase tumor destruction [ 32 , 33 ]. A wide diversity of viruses have been investigated for their potential to act as oncolytic agents for BC, including adenoviruses, herpes simplex virus (HSV), Coxsackievirus, alphavirus, vaccinia virus, Newcastle disease virus (NDV), and vesicular stomatitis virus (VSV), et al [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. Table 1 listed the OVs in preclinical studies.…”

“…Adenovirus is the most explored and studied OVs in BC. As a double-stranded DNA virus, it has an icosahedral capsid and infects the cell through Coxsackie and adenovirus receptors [ 65 ]. To increase antitumor effectiveness and cancer cell selectivity, many genetically modified adenoviruses have been created.…”

“…They found that the miR143/124-regulated HSV-1 could restrict viral replication in neurons and normal bladder cells while killing BC cells with high potency. Thus, it is possible to maintain the full viral genome for the greatest oncolytic potency while maintaining the highest level of safety by translationally regulating the expression of essential viral genes [ 65 ].…”

Trial Watch: Oncolytic viro-immunotherapy of hematologic and solid tumors

“…70,71 Oncotropism can be natural or, more frequently, genetically acquired/restricted. Genetic engineering procedures implemented so far to OVs consisted of 1) modifying the OV attachment protein to redirect or strengthen its binding to a tumor-associated receptor, [72][73][74][75][76][77][78][79][80][81] 2) inserting cis-regulatory elements in the OV genome to guarantee a transcriptional and/or post-transcriptional control of its expression/replication in target rather than off-target tissues, 61,[82][83][84][85][86][87][88][89][90][91][92][93][94][95][96] and/or 3) abolishing the activity of virulence factors in charge of hacking proliferation, survival and/or antiviral machineries of the host cell. 41,92,[96][97][98][99][100][101][102][103][104][105] The latter strategy has been extensively applied in the development of most OVs currently evaluated into the clinic.…”