Engineering Rapalog-Inducible Genetic Switches Based on Split-T7 Polymerase to Regulate Oncolytic Virus-Driven Production of Tumour-Localized IL-12 for Anti-Cancer Immunotherapy

被引：6

作者：

Martin, Nikolas T. ^{[1
,2
]}

Crupi, Mathieu J. F. ^{[1
,2
]}

Taha, Zaid ^{[1
,2
]}

Poutou, Joanna ^{[1
,2
]}

Whelan, Jack T. ^{[1
,2
]}

Vallati, Sydney ^{[1
,2
]}

Petryk, Julia ^{[1
]}

Marius, Ricardo ^{[1
]}

Austin, Bradley ^{[1
]}

Azad, Taha ^{[1
,2
]}

Boulanger, Mason ^{[1
]}

Burgess, Tamara ^{[1
]}

Sanders, Ilson ^{[1
]}

Victoor, Camille ^{[1
]}

Dickinson, Bryan C. ^{[3
]}

Diallo, Jean-Simon ^{[1
,2
]}

Ilkow, Carolina S. ^{[1
,2
]}

Bell, John C. ^{[1
,2
]}

机构：

[1] Ottawa Hosp, Ctr Innovat Canc Res, Res Inst, Ottawa, ON K1H 8L6, Canada

[2] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON K1H 8M5, Canada

[3] Univ Chicago, Dept Chem, Chicago, IL 60637 USA

来源：

PHARMACEUTICALS | 2023年 / 16卷 / 05期

基金：

加拿大自然科学与工程研究理事会; 加拿大健康研究院; 美国国家卫生研究院;

关键词：

Split-T7 RNA polymerase; interleukin-12; chlorotoxin; oncolytic vaccinia virus; VACCINIA VIRUS; RNA-POLYMERASE; EXPRESSION; CANCER; CHLOROTOXIN; THERAPY; SYSTEMS; VECTOR; TEMSIROLIMUS; COMBINATION;

D O I：

10.3390/ph16050709

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The approval of different cytokines as anti-neoplastic agents has been challenged by dose-limiting toxicities. Although reducing dose levels affords improved tolerability, efficacy is precluded at these suboptimal doses. Strategies combining cytokines with oncolytic viruses have proven to elicit potent survival benefits in vivo, despite promoting rapid clearance of the oncolytic virus itself. Herein, we developed an inducible expression system based on a Split-T7 RNA polymerase for oncolytic poxviruses to regulate the spatial and temporal expression of a beneficial transgene. This expression system utilizes approved anti-neoplastic rapamycin analogues for transgene induction. This treatment regimen thus offers a triple anti-tumour effect through the oncolytic virus, the induced transgene, and the pharmacologic inducer itself. More specifically, we designed our therapeutic transgene by fusing a tumour-targeting chlorotoxin (CLTX) peptide to interleukin-12 (IL-12), and demonstrated that the constructs were functional and cancer-selective. We next encoded this construct into the oncolytic vaccinia virus strain Copenhagen (VV-iIL-12mCLTX), and were able to demonstrate significantly improved survival in multiple syngeneic murine tumour models through both localized and systemic virus administration, in combination with rapalogs. In summary, our findings demonstrate that rapalog-inducible genetic switches based on Split-T7 polymerase allow for regulation of the oncolytic virus-driven production of tumour-localized IL-12 for improved anti-cancer immunotherapy.

引用

页数：23