A phase I clinical trial of intrahepatic artery delivery of TG6002 in combination with oral 5-fluorocytosine in patients with liver-dominant metastatic colorectal cancer
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Effective treatment for patients with metastatic cancer is limited, particularly for colorectal cancer patients with metastatic liver lesions (mCRC), where accessibility to numerous tumours is essential for favourable clinical outcomes. Oncolytic viruses (OVs) selectively replicate in cancer cells; however, direct targeting of inaccessible lesions is limited when using conventional intravenous ( i.v. ) or intratumoural ( i.t. ) administration routes.
Methods
We conducted a multi-centre, dose-escalation, phase I study of vaccinia virus, TG6002, via intrahepatic artery (IHA) delivery in combination with the oral pro-drug 5-fluorocytosine (5-FC) to fifteen mCRC patients.
Results
Successful IHA delivery of replication-competent TG6002 was achieved, as demonstrated by virus within tumour biopsies. Functional transcription of the FCU1 transgene indicates viral replication within the tumour, with higher plasma concentrations of 5-fluorouracil (5-FU) associated with patients receiving the highest dose of TG6002. IHA delivery of TG6002 correlated with a robust systemic peripheral immune response to virus with activation of peripheral blood mononuclear cells, associated with a proinflammatory cytokine response and release of calreticulin, potentially indicating immunogenic cell death. Gene Ontology analyses of differentially-expressed genes reveal a significant immune response at the transcriptional level in response to treatment. Moreover, an increase in the number and frequency of T cell receptor clones against both cancer- and neo-antigens, with elevated functional activity, may be associated with improved anti-cancer activity. Despite these findings, no clinical efficacy was observed.
Conclusions
In summary, these data demonstrate delivery of OV to tumour via IHA administration, associated with viral replication and significant peripheral immune activation. Collectively, the data supports the need for future studies using IHA administration of OVs.
SUMMARY
A phase Ia study of TG6002 oncolytic vaccinia virus administration via the hepatic artery in patients with colorectal cancer liver metastases. Virus was delivered to tumour with functional activity of the virus-encoded FCU1 transgene, eliciting innate and adaptive anti-cancer immunity.
