First-in-man Study of Western Reserve Strain Oncolytic Vaccinia Virus: Safety, Systemic Spread, and Antitumor Activity

Abstract

Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 × 10(9) pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity.

Oncolytic Virus-Mediated Targeting of PGE 2 in the Tumor Alters the Immune Status and Sensitizes Established and Resistant Tumors to Immunotherapy

“…This virus bears the same thymidine kinase deletion as all three oncolytic vaccinia strains currently in the clinic (Kim et al, 2006; McCart et al, 2001; Worschech et al, 2009; Zeh et al, 2014) and expresses luciferase so that viral gene expression levels could be quantified over time in individual mice (as a surrogate for viral replication and persistence), and compared to subsequent response. It was noted that two distinct kinetic patterns of viral gene expression emerged in vivo (Figure 1C).…”

Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy

“…An oncolytic vaccinia virus armed with GM-CSF (Pexa-Vec) was associated with a 15% objective response rate in patients with advanced hepatocellular carcinoma in a randomized phase II clinical trial15. We have shown recently that a tumour-selective Western Reserve strain oncolytic vaccinia virus, vvDD (without any immunogenic transgene), was safe and exhibited some anti-tumour effects in patients with advanced solid tumours in phase I clinical trials1617. However, overall the therapeutic efficacy in patients has been limited, especially when the tumour is poorly immunogenic, and the TME highly immunosuppressive.…”

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…”

“…The live vaccinia Western Reserve (WR) strain was derived from serial passaging the New York City Board of Health (NYCBH) strain in the mouse brain, and has been shown to replicate to high titers in various mouse organs (Kaplan, 1989;Brandt and Jacob, 2001;Brandt et al, 2005). The oncolytic nature of the WR strain has been studied (Gnant et al, 1999;Thorne et al, 2007;Autio et al, 2014;Parviainen et al, 2015), and a modified version is in a clinical trial for various human cancers (Zeh et al, 2015). The modified vaccinia Ankara (MVA) strain was derived in the late 1950s by passaging the chorioallantois VACV Ankara (CVA) strain of vaccinia virus more than 570 times in chick embryo fibroblast cells, resulting in a host range-restricted virus that is replication-defective in most mammalian cells (McCurdy et al, 2004).…”