Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans

TLDR: It is shown in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion.

Abstract: Oncolytic viruses, either natural or engineered, preferentially infect and lyse tumour cells. David Kirn and colleagues now report a phase I clinical trial in which they demonstrate systemic delivery of the engineered oncolytic virus JX-594 selectively to tumour tissue after a single injection. Tumour biopsies indicate that the virus replicates in cancer but not in adjacent normal tissue. JX-594 is engineered to replicate in a broad spectrum of cancer cells harbouring activation of the epidermal growth factor receptor/Ras pathway. Although the trial was not designed to demonstrate clinical efficacy, the results suggest that JX-594 may elicit a clinical response in some patients. The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity1. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.