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.
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All Authors
West, EJ.
Sadoun, A.
Bendjama, K.
Erbs, P.
Smolenschi, C.
Cassier, PA.
de Baere, T.
Sainte-Croix, S.
Brandely, M.
Melcher, AA.
LTHT Author
Bennett, Angela
Kent, Sarah
Hammond, Christopher
Patel, Chirag
Collinson, Fiona
Twelves, Chris
Swinson, Daniel
Samson, Adel
Kent, Sarah
Hammond, Christopher
Patel, Chirag
Collinson, Fiona
Twelves, Chris
Swinson, Daniel
Samson, Adel
LTHT Department
Oncology
Medical Physics & Engineering
Radiology
Nuclear Medicine
Leeds Cancer Centre
Medical Physics & Engineering
Radiology
Nuclear Medicine
Leeds Cancer Centre
Non Medic
Research Nurse
Lead Research Nurse
Lead Research Nurse
Publication Date
2025
Item Type
Journal Article
Clinical Trial
Multicenter Study
Clinical Trial
Multicenter Study
Language
Subject
Subject Headings
Abstract
PURPOSE: Effective treatment for patients with metastatic cancer is limited, particularly for those with colorectal cancer with metastatic liver lesions, in which accessibility to numerous tumors is essential for favorable clinical outcomes. Oncolytic viruses (OV) selectively replicate in cancer cells; however, direct targeting of inaccessible lesions is limited when using conventional intravenous or intratumoral administration routes.
PATIENTS AND METHODS: We conducted a multicenter, dose-escalation, phase I study of vaccinia virus, TG6002, via intrahepatic artery (IHA) delivery in combination with the oral prodrug 5-fluorocytosine to 15 patients with metastatic colorectal cancer.
RESULTS: Successful IHA delivery of replication-competent TG6002 was achieved, as demonstrated by the virus within tumor biopsies. Functional transcription of the FCU1 transgene indicates viral replication within the tumor, with higher plasma 5-fluorouracil associated with patients receiving the highest dose of TG6002. IHA delivery of TG6002 correlated with a robust systemic peripheral immune response to the 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 antigens and neoantigens, with elevated functional activity, may be associated with improved anticancer activity. Despite these findings, no clinical efficacy was observed.
CONCLUSIONS: In summary, these data demonstrate the delivery of OV to tumor via IHA administration, associated with viral replication and significant peripheral immune activation. Collectively, the data support the need for future studies using IHA administration of OVs.
Journal
Clinical Cancer Research