Oncolytic and Immunotherapeutic Vaccinia Induces Antibody-Mediated Complement-Dependent Cancer Cell Lysis in Humans

Abstract

Oncolytic viruses cause direct cytolysis and cancer-specific immunity in preclinical models. The goal of this study was to demonstrate induction of functional anticancer immunity that can lyse target cancer cells in humans. Pexa-Vec (pexastimogene devacirepvec; JX-594) is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony-stimulating factor (GM-CSF). Pexa-Vec demonstrated replication, GM-CSF expression, and tumor responses in previous phase 1 trials. We now evaluated whether Pexa-Vec induced functional anticancer immunity both in the rabbit VX2 tumor model and in patients with diverse solid tumor types in phase 1. Antibody-mediated complement-dependent cancer cell cytotoxicity (CDC) was induced by intravenous Pexa-Vec in rabbits; transfer of serum from Pexa-Vec-treated animals to tumor-bearing animals resulted in tumor necrosis and improved survival. In patients with diverse tumor types treated on a phase 1 trial, CDC developed within 4 to 8 weeks in most patients; normal cells were resistant to the cytotoxic effects. T lymphocyte activation in patients was evidenced by antibody class switching. We determined that patients with the longest survival duration had the highest CDC activity, and identified candidate target tumor cell antigens. Thus, we demonstrated that Pexa-Vec induced polyclonal antibody-mediated CDC against multiple tumor antigens both in rabbits and in patients with diverse solid tumor types.

Treatment of Liver Cancer

“…Pexa-Vec utilizes the unique characteristics of vaccinia, which allows the virus to survive in the bloodstream in the presence of neutralizing antibodies, leading to its ability to be administered both intravenously and intratumorally (Kim et al 2006). Pexa-Vec has shown proof-of-concept mechanisms in clinical trials for cancer patients, including HCC patients Park et al 2008;Hwang et al 2011;Kim et al 2013). Notably, Liu et al (2008) showed that HCC tumor tissue could serve as a source of acute HBV replication and posttreatment HBV release, and that Pexa-Vec can suppress underlying HBV replication in HCC patients.…”

Immune Checkpoint Blockade, Immunogenic Chemotherapy or IFN-α Blockade Boost the Local and Abscopal Effects of Oncolytic Virotherapy

“…In the majority of cases, the most effective OV treatments combine potent viral oncolysis with induction of a specific immune response against tumor antigens, as shown in several clinical and preclinical studies (9)(10)(11)(12). The mechanisms how OV therapies elicit antitumor immune responses are not clearly understood yet, but likely involve the capture of released tumor antigens by bystander antigen-presenting cells (APC) following tumor cell lysis (13).…”

Pexa-Vec double agent engineered vaccinia: oncolytic and active immunotherapeutic

“…Inflammation within tumors was detected following intratumoral Pexa-Vec administration in patients with melanoma [17,26]. Furthermore, functional anti-cancer immunity in the context of Pexa-Vec treatment was demonstrated by measuring induction of antibody-mediated complement-dependent cytotoxicity (CDC) utilizing a panel of tumor cell lines of different histologies [24,48 ]. Furthermore, T cell responses to b-galactosidase peptides were detected in HCC patients treated with Pexa-Vec, as shown by Enzyme-Linked ImmunoSpot (ELISPOT) analysis; this provides proof-of-concept that T cell responses can be induced to transgenes encoded by oncolytic vaccinia viruses [24].…”