Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints.

Abstract

Replication-selective oncolytic adenoviruses are being developed for the treatment of cancer, but the safety and feasibility of repeated adenovirus delivery to tumors via the bloodstream was unknown, particularly in light of a patient death after hepatic artery infusion of a replication-defective adenovirus vector. We performed a Phase II trial of an oncolytic replication-selective adenovirus (dl1520, also known as Onyx-015) administered by hepatic artery infusion in patients with gastrointestinal carcinoma metastatic to the liver (n = 27). dl1520 was infused into the hepatic artery (2 x 10(12) particles) on days 1 and 8 as a single agent, and thereafter starting on day 22 in combination with i.v. 5-fluorouracil and leucovorin every 28 days. Repeated viral infusions were feasible, and no deaths occurred on study; reversible grade 3/4 hyperbilirubinemia occurred in 2 patients. Systemic inflammatory cytokine responses varied greatly between patients and even between cycles within a given patient. Proinflammatory cytokines [e.g., tumor necrosis factor, IFN-gamma, and interleukin (IL) 6] typically rose within 3 h and were followed at 18 h by a rise in IL-10. However, in the single patient who suffered a severe but reversible systemic inflammatory response, a unique cytokine profile was detected: marked acute increases of IL-6 (20-fold higher than average for all of the patients) and inhibition of IL-10 production. Delayed secondary peaks of viremia were reproducibly detected 3-6 days after treatment, even in the presence of high level neutralizing antibody titers and antiviral cytokines. Mathematical modeling was used to calculate the number of virus particles produced and shed into the blood with each replication cycle. The combination of virotherapy and chemotherapy had antitumoral activity in some chemotherapy-resistant colorectal tumors. The intra-arterial infusion of oncolytic adenoviruses warrants additional study.

• Authors: Tony Reid, Eva Galanis, James Abbruzzese, Dan Sze, Lawrence M Wein, James Andrews, Britta Randlev, Carla Heise, Margaret Uprichard, Michael Hatfield, Larry Rome, Joseph Rubin, David Kirn
• Journal: Cancer research (Cancer Res) Vol. 62 Issue 21 Pg. 6070-9 (Nov 01 2002) ISSN: 0008-5472 [Print] United States
• PMID: 12414631 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article)

Chemical References

• Antibodies, Viral
• Cytokines
• Leucovorin
• Fluorouracil

Topics

• Adenoviruses, Human (genetics, physiology)
• Adult
• Aged
• Antibodies, Viral (biosynthesis)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Colorectal Neoplasms (drug therapy, immunology, pathology, virology)
• Combined Modality Therapy
• Cytokines (biosynthesis, immunology)
• Female
• Fluorouracil (administration & dosage)
• Genome, Viral
• Hepatic Artery
• Humans
• Infusions, Intra-Arterial
• Leucovorin (administration & dosage)
• Liver Neoplasms (drug therapy, immunology, secondary, virology)
• Male
• Middle Aged
• Virus Replication