Adjuvant Adenovirus-Mediated Delivery of Herpes Simplex Virus Thymidine Kinase Administration Improves Outcome of Liver Transplantation in Patients with Advanced Hepatocellular Carcinoma

Abstract

Purpose: Previous poor results of liver transplantation (LT) have been confirmed in patients with advanced hepatocellular carcinoma (HCC). Adenovirus-mediated delivery of herpes simplex virus thymidine kinase (ADV-TK) therapy is an established adjuvant treatment in cancer, and we evaluated its potential as an adjuvant treatment for HCC patients who underwent LT.Experimental Design: Forty-five HCC patients with tumors >5 cm in diameter participated in the study over a follow-up period of 50 months. Among these patients, 22 received LTonly, and 23 received LTcombined with ADV-TK therapy. All HCC patients enrolled in this study had tumors >5 cm in diameter and no metastasis in lungs or bones was detected by computed tomography or magnetic resonance imaging scans. Results: The recurrence-free survival and the overall survival in the LT plus ADV-TK therapy group were 43.5% and 69.6%, respectively, at 3 years; both values were significantly higher than those in the LT-only group (9.1% and 19.9%, respectively). In the nonvascular invasion subgroup, overall survival was 100% and recurrence-free survival was 83.3% in the patients receiving LT plus ADV-TK, significantly higher than the patients receiving LTonly. Conclusions: HCC patients with no vascular invasion could be selected for LT followed by adjuvant ADV-TK therapy, regardless of intrahepatic huge or diffuse tumor. We propose that the current criteria for LT based on tumor size may be expanded if accompanied by ADV-TK therapy due to improved prognosis.Hepatocellular carcinoma (HCC) is currently the fifth most common neoplasm in the world (1, 2). The majority of HCC (80-90%) are associated with underlying liver diseases related to post-hepatitis cirrhosis, hemochromatosis, or alcohol abuse, and the incidence of HCC continues to increase steadily (3).The population of HCC patients in China is the largest around the world and f230, 000 people die of HCC yearly, counting 53% of the total number of the global death population (4). In the past 30 years, liver transplantation (LT) has become an important technique in HCC treatment because of the triple advantage of removing the tumor, preventing formation of metachronous lesions on underlying cirrhosis, and restoring normal liver function (5). However, high recurrence rates (32-54%) and poor outcomes (5-year survival rate of <40%) were recorded from the first series of transplanted patients. These poor results were mostly related to unrestrictive selection criteria and inclusion of patients with macroscopic vascular invasion, lymph node involvement, and extrahepatic spread (6, 7). The landmark study of Mazzaferro et al. (8) in 1996 established LT as a viable option to treat HCC, based on the poor outcome of advanced HCC patients receiving LT and the limited source of donor organs. Their criteria have come to be known as the Milan criteria (unifocal V5 cm in diameter or V3 foci V3 cm in diameter) and have been widely applied throughout the world in the selection of patients with small HCC for transplantation (9 ...

Recombinant human adenovirus‑p53 improves the outcome of mid‑late stage pancreatic cancer via arterial infusion

“…TP53 gene therapy, particularly adenovirus-mediated rAd-P53 gene therapy, has been used for the clinical treatment of head and neck squamous cell carcinoma, with good clinical outcomes, determined by increased survival times (27,28). The arterial infusion approach can ensure that large amounts of the high-concentration drug can access to tumor cells, with only small amounts of the drug entering the circulation, thus maximizing the therapeutic efficacy and reducing the systemic adverse effects (29). Further laboratory tests showed that there were no significant side effects following adenovirus-mediated rAd-p53 gene therapy by the arterial infusion approach in terms of hematological profiles, and liver and kidney function.…”

A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma

“…This is congruent with the results observed in other clinical studies that had employed Ad.TK/GCV for the treatment of different cancers such as ovarian, prostate, mesothelioma, glioma and metastatic colorectal carcinoma. 11 The experience using Ad.TK/GCV in patients with advanced HCC is scarce, 30 and for secondary liver tumors the results from a single clinical trial in patients with metastatic colorectal carcinoma have been published. 31 In the latter, authors demonstrated the safety of direct injection of up to 10 13 vp of an adenovirus coding for TK into metastatic colorectal liver tumors followed by GCV treatment; nevertheless no objective antitumor responses were reported.…”

Phase I and biodistribution study of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene and ganciclovir administration in patients with head and neck cancer and other malignant tumors

“…[8][9][10][11][12][13][14] There have been no reports evaluating this agent in NPC or head and neck cancer, both of which are common among Chinese people, often relapse locally and are often resistant to radiotherapy and chemotherapy. In this study, the majority of subjects had been diagnosed with NPC or head and neck cancer.…”

“…Phase I/II trials have subsequently been conducted using AdV/TK/GCV in a number of malignant tumors, including ovarian carcinoma, brain tumors, prostate cancer, hepatocellular carcinoma and so on. [9][10][11][12][13][14] All of these trials have shown that the approach is relatively safe, but efficacy has been localized to the injection site, which has limited its use. However, this treatment may be particularly suitable for some tumors that have the tendency to relapse locally, such as head and neck cancer or nasopharyngeal carcinoma (NPC).…”