A Mechanistic Proof-of-concept Clinical Trial With JX-594, a Targeted Multi-mechanistic Oncolytic Poxvirus, in Patients With Metastatic Melanoma

Abstract

JX-594 is a targeted and granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In order to study the mechanisms-of-action (MOA) of JX-594 in humans, a mechanistic proof-of-concept clinical trial was performed at a low dose equivalent to ≤10% of the maximum-tolerated dose (MTD) in other clinical trials. Ten patients with previously treated stage IV melanoma were enrolled. Tumors were injected weekly for up to nine total treatments. Blood samples and tumor biopsies were analyzed for evidence of transgene activity, virus replication, and immune stimulation. The β-galactosidase (β-gal) transgene was expressed in all patients as evidenced by antibody induction. Six patients had significant induction of GM-CSF-responsive white blood cell (WBC) subsets such as neutrophils (25-300% increase). JX-594 replication and subsequent shedding into blood was detectable in five patients after cycles 1-9. Tumor biopsies demonstrated JX-594 replication, perivascular lymphocytic infiltration, and diffuse tumor necrosis. Mild flu-like symptoms were the most common adverse events. In sum, JX-594 replication, oncolysis, and expression of both transgenes were demonstrated; replication was still evident after multiple cycles. These findings have implications for further clinical development of JX-594 and other transgene-armed oncolytic viruses.

Eradication of Liver-Implanted Tumors by Semliki Forest Virus Expressing IL-12 Requires Efficient Long-Term Immune Responses

“…As an example, we recently showed that a combination of SFV-IL-12 and a CD137 agonistic Ab can enhance antitumor immune responses against s.c. colon tumors in mice (33). In contrast, oncolytic viruses able to kill tumor cells in an immunogenic way showed very promising results in recent clinical trials (41,42). Based on both approaches, we believe that the combination of an SFV vector able to induce tumor cell death with a potent immunostimulatory cytokine, such as IL-12, and additional cytokines/factors able to enhance effector or memory immune responses or to inhibit suppressor responses could have a significant impact on cancer therapy.…”

A Vaccinia Virus Armed with Interleukin-10 Is a Promising Therapeutic Agent for Treatment of Murine Pancreatic Cancer

“…Extremely promising clinical trial data have recently emerged in which GM-CSF-armed vaccinia virus induced objective responses in patients with liver, colon, kidney, and lung cancer and melanoma (3,4). Vaccinia virus has several inherent features that make it particularly suitable for use as an oncolytic agent, including fast and efficient replication with rapid cell-to-cell spread, natural tropism for tumors, a well-documented safety record, and an ability to replicate in many different cell types, a feature not shared by adenoviruses.…”

Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor actions in a mouse model

“…The strategy improves cancer therapy through the dual action of the therapeutic gene and the oncolytic virus itself. The oncolytic poxvirus JX-594, which delivers granulocyte macrophage-colony stimulating factor (GM-CSF), exhibited outstanding antitumor results in a clinical trial via viral oncolysis and tumor-specific anti-cancer immunity [28] . JX-594 could selectively infect, replicate and express its transgene in cancer tissues but did not affect normal tissue; JX-594 was delivered into human metastatic solid tumors via intravenous infusion [29] .…”