A novel vaccinia virus with dual oncolytic and anti-angiogenic therapeutic effects against triple-negative breast cancer

Abstract

Purpose Vascular endothelial growth factor (VEGF) expression is higher in triple-negative breast cancers (TNBC) compared to other subtypes and is reported to predict incidence of distant metastases and shorter overall survival. We investigated the therapeutic impact of a vaccinia virus (VACV) GLV-1h164 (derived from its parent virus GLV-1h100), encoding a single-chain antibody (scAb) against VEGF (GLAF-2) in an orthotopic TNBC murine model. Methods GLV-1h164 was tested against multiple TNBC cell lines. Viral infectivity, cytotoxicity, and replication were determined. Mammary fat pad tumors were generated in athymic nude mice using MDA-MB-231 cells. Xenografts were treated with GLV-1h164, GLV-1h100, or PBS and followed for tumor growth. Results Viral infectivity was time- and concentration-dependent. GLV-1h164 killed TNBC cell lines in a dose-dependent fashion with greater than 90% cytotoxicity within 4 days at a multiplicity of infection of 5.0. In vitro, cytotoxicity of GLV-1h164 was identical to GLV-1h100. GLV-1h164 replicated efficiently in all cell lines with an over 400-fold increase in copy numbers from the initial viral dose within 4 days. In vivo, mean tumor volumes after 2 weeks of treatment were 73, 191, and 422mm3 (GLV-1h164, GLV-1h100, and PBS, respectively) (p<0.05). Both in vivo Doppler ultrasonography and immuno-staining showed decreased neo-angiogenesis in GLV-1h164-treated tumors compared to both GLV-1h100 and PBS controls (p<0.05). Conclusion This is the first study to demonstrate efficient combination of oncolytic and anti-angiogenic activity of a novel vaccinia virus on TNBC xenografts. Our results suggest that GLV-1h164 is a promising therapeutic agent that warrants testing for patients with TNBC.

Colonization of xenograft tumors by oncolytic vaccinia virus (VACV) results in enhanced tumor killing due to the involvement of myeloid cells

“…In the tumor, NO was shown to be both friend and foe [5, 14]. It is believed that by producing variable levels of NO, iNOS can orchestrate various functions in different microenvironments [15].…”

“…Until now, preclinical and clinical studies have demonstrated that various VACVs have a broad spectrum of anticancer activity and good safety [2]. Tumor-targeting mechanisms of VACV include virus-mediated direct oncolysis, antivascular effects and induction of antitumor immune responses [3–5]. The latter mechanism of action might be essential in the elimination of tumor cells which are able to escape virus infection [6].…”

Single peptides and combination modalities for triple negative breast cancer

“…The cancer cells infected by these viruses are induced for self-destruction by apoptosis or killed by autophagy and necrosis. After infection, viruses typically inactivate the cellular regulatory mechanisms and take control of the cancer cell oncolytic function has been shown to be able to kill the TNBC cell lines in a dose-dependent fashion (Gholami et al, 2014). GLV-1h153…”

“…is another vaccinia oncolytic virus which has been shown to be effective in TNBC and mTNBC (Gholami et al, 2014).…”

Replicating poxviruses for human cancer therapy

“…SQPV was isolated from a grey squirrel (Sciurus carolinensis) in Maryland in 1953 and initially placed into the genus Leporipoxvirus by Kilham et al (1953); it was later thought to be a member of the genus Parapoxvirus (Housawi et al, 1998), but a sub- (Chen et al, 2001;Zhang et al, 2007;Kochneva et al, 2012;Chan and McFadden, 2014) Breast tumor model, Ovarian tumor model, etc (Hung et al, 2007;Zhang et al, 2007;Hiley et al, 2010;Gholami et al, 2014) Various solid tumors, Breast cancer (Gentschev et al, 2014;Mell et al, 2014) GLV-1h68*, GLV-1h99, GLV-1h108, VV-mIL2, VVhEA, VV-hup53, etc Wyeth Attenuated, transgenes inserted (Mastrangelo et al, 1999;Liu et al, 2014) Melanoma model, Bladder cancer model, etc (Mastrangelo et al, 1999;Gomella et al, 2001) Melanoma cancer, Liver cancer, etc (Mastrangelo et al, 1999;Park et al, 2008;Heo et al, 2013) JX-594* WR Attenuated, transgenes inserted (Gnant et al, 1999;McCart et al, 2001;Thorne et al, 2007;Parviainen et al, 2015) Colon cancer model. etc (Gnant et al, 1999;McCart et al, 2001;Autio et al, 2014) Various tumors (Zeh et al, 2015) JX-795, JX-963*, vvDD*, VV-TRAIL, etc MVA Severely attenuated, transgenes inserted (Sutter and Moss, 1992;Kochneva et al, 2012) Various cancer model (Drexler et al, 1999;Carroll et al, 1997) Various tumors (Larocca and Schlom, 2011;Amato et al, 2012;Gómez et al, 2013) MVA-5T4*, MVAhup53…”