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

Abstract

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 immunity. 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.

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

“…Tumour volume was calculated as ¼ (length  width 2 )/2. For survival studies, mice were culled when tumours had reached 1,600 mm 3 . For in vivo imaging, an IVIS (Perkin Elmer, Waltham, MA) was used as described previously 44 .…”

“…2). While promising early-and late-phase clinical trials employing OVs to treat cancers continue to generate great enthusiasm, heterogeneity in clinical response remains a challenge [2][3][4] . To this end, it has been long recognized that improvements to therapeutic efficacy either through viral engineering or through combination therapies will be critical to the success of these platforms 2,5 .…”

Model-based rational design of an oncolytic virus with improved therapeutic potential

“…Whether a patient receives therapeutic virus intravenously 15 or through direct intratumoural injection 16 , the quantity of virus that reaches the tumour bed is vastly outnumbered by the number of target cells found in the malignancy 17 . Successful OV therapies thus rely upon the ability of a relatively small number of virus particles to initiate an infection and spread within a population of cancer cells.…”

Oncolytic viruses: From bench to bedside with a focus on safety

“…132 Also, in clinical trials, live JX-594 was detected in throat swabs and skin pustules of patients up to one week after administration. 133 Theoretically, recombination between oncolytic recombinant VV and wildtype VV is possible, however, since VV vaccination is not practiced on a large scale anymore, this is highly unlikely.…”