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.
Subject(s)
Neoplasms/therapy , Oncolytic Virotherapy , Oncolytic Viruses/physiology , Poxviridae/physiology , Adult , Aged , Aged, 80 and over , DNA, Viral/blood , Female , Gene Expression Regulation, Enzymologic , Humans , Infusions, Intravenous , Male , Middle Aged , Neoplasms/pathology , Neoplasms/surgery , Neoplasms/virology , Organisms, Genetically Modified/physiology , Transgenes/genetics , beta-Galactosidase/genetics , beta-Galactosidase/metabolismABSTRACT
Efforts to selectively target and disrupt established tumor vasculature have largely failed to date. We hypothesized that a vaccinia virus engineered to target cells with activation of the ras/MAPK signaling pathway (JX-594) could specifically infect and express transgenes (hGM-CSF, ß-galactosidase) in tumor-associated vascular endothelial cells in humans. Efficient replication and transgene expression in normal human endothelial cells in vitro required either VEGF or FGF-2 stimulation. Intravenous infusion in mice resulted in virus replication in tumor-associated endothelial cells, disruption of tumor blood flow, and hypoxia within 48 hours; massive tumor necrosis ensued within 5 days. Normal vessels were not affected. In patients treated with intravenous JX-594 in a phase I clinical trial, we showed dose-dependent endothelial cell infection and transgene expression in tumor biopsies of diverse histologies. Finally, patients with advanced hepatocellular carcinoma, a hypervascular and VEGF-rich tumor type, were treated with JX-594 on phase II clinical trials. JX-594 treatment caused disruption of tumor perfusion as early as 5 days in both VEGF receptor inhibitor-naïve and -refractory patients. Toxicities to normal blood vessels or to wound healing were not evident clinically or on MRI scans. This platform technology opens up the possibility of multifunctional engineered vaccinia products that selectively target and infect tumor-associated endothelial cells, as well as cancer cells, resulting in transgene expression, vasculature disruption, and tumor destruction in humans systemically.
Subject(s)
Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Neovascularization, Pathologic/prevention & control , Oncolytic Viruses/physiology , Vaccinia virus/physiology , Animals , Blotting, Western , Carcinoma, Hepatocellular/blood supply , Carcinoma, Hepatocellular/virology , Cell Line, Tumor , Cells, Cultured , Clinical Trials, Phase I as Topic , Endothelial Cells/drug effects , Endothelial Cells/physiology , Endothelial Cells/virology , Female , Fibroblast Growth Factor 2/pharmacology , Humans , Liver Neoplasms/blood supply , Liver Neoplasms/virology , Magnetic Resonance Imaging , Mice , Mice, Inbred BALB C , Neoplasms, Experimental/blood supply , Neoplasms, Experimental/therapy , Neoplasms, Experimental/virology , Neovascularization, Pathologic/virology , Oncolytic Virotherapy/methods , Oncolytic Viruses/genetics , Rabbits , Receptors, Vascular Endothelial Growth Factor/metabolism , Time Factors , Treatment Outcome , Vaccinia virus/genetics , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/pharmacology , Virus ReplicationABSTRACT
Oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear. JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus. To determine the optimal JX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomized phase 2 dose-finding trial (n=30). Radiologists infused low- or high-dose JX-594 into liver tumors (days 1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes. Objective intrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%) response rates and intrahepatic disease control (50%) were equivalent in injected and distant noninjected tumors at both doses. JX-594 replication and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression preceded the induction of anticancer immunity. In contrast to tumor response rate and immune endpoints, subject survival duration was significantly related to dose (median survival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio 0.39; P=0.020). JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses and dose-related survival in individuals with HCC.