Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: Results of a phase I clinical trial

Animal studies have shown that direct injection of an adenoviral vector (Ad v.RSV-tk) expressing the herpes thymidine kinase gene into established tumo rs in the liver, followed by systemic ganciclovir administration, was effec tive in inducing tumor necrosis. Toxicities were minimal at therapeutically effective vector doses, although severe hepatic necroinflammation was seen at much higher supratherapeutic doses. We conducted a clinical phase I tri al in patients with metastatic colorectal adenocarcinoma in the liver to as sess the safety of intratumoral Adv.RSV-tk injection (escalating doses) fol lowed by intravenous ganciclovir (fixed dose). The vector was injected into a metastatic tumor in the liver under local anesthesia by percutaneous nee dle placement with concurrent ultrasonographic monitoring to prevent inject ion or leakage into adjacent normal liver structures. We treated 16 patient s in five dose level cohorts of Adv.RSV-tk, from 1.0 x 10(10) to 1.0 x 10(1 3) virus particles per patient. Hepatic toxicities were low, with transient grade 1 elevations in serum aminotransferase levels in 3 of 16 patients. O ther toxicities were also transient: grade 2-3 fevers in 5 of 16 patients, grade 3 thrombocytopenia in 1 of 16 patients, and grade 2 leucopenia in 3 o f 16 patients. These results indicate that Adv.RSV-tk can be safely adminis tered by percutaneous intratumoral injection in patients with hepatic metas tases at doses up to 1.0 x 10(13) virus particles per patient, and can prov ide the basis for future clinical trials involving intratumoral adenoviral vector injection.