A phase I clinical trial of an adenovirus-mediated endostatin gene (E10A) in patients with solid tumors

Abstract

Purpose. The purpose of the current study were to assess the safety and feasibility of repetitive intratumoral administration of E10A, an adenoviral vector encoding the wild-type endostatin gene, to patients with solid tumors, and to evaluate its biologic effect and the pharmacokinetics of endostatin.Methods. Patients were treated with escalating doses from 1 × 10 10 VP to 1 × 10 12 VP of E10A intratumorally on days 1 and 8. Patients were assessed for toxicity and viral shedding, and antitumor response was evaluated by imaging techniques and tumor biopsy. Circulating levels of endostatin were examined.Results. Fifteen patients received 29 injections of E10A. No dose-limiting toxicity was developed, and the maximum tolerated dose had not yet been reached. Fever and local reaction of injection site were common, but rarely severe. Mild and transient hepatotoxicity was observed in one patient. Minor response of injected tumor was achieved and improvement of the control tumor was observed in one patient with nasopharyngeal carcinoma, and tumor necrosis was occurred in two patients. Sustained elevation of serum endostatin levels was detected.Conclusion. Weekly intratumoral injection of up to 1 × 10 12 VP of E10A to patients with solid tumor is a feasible and well-tolerated procedure that exerts mild antitumor effects. A small and sustained elevation of endogenous endostatin in blood possibly has antitumor activity.

The Current State of Head and Neck Cancer Gene Therapy

“…Although recombinant endostatin is well tolerated, it has a short half-life and repeated dosing is required to achieve antitumor effects (Folkman, 2006). The therapeutic efficacy of an adenoviral expression vector (E10A) engineered to express high levels of endostatin in transduced cells has been tested in HNSCC patients (Lin et al, 2007;Li et al, 2008). Fifteen patients with solid tumors, including 2 patients with HNSCC, were treated with intratumoral injections of up to 10 12 viral particles on days 1 and 8 (Lin et al, 2007).…”

Recent advances in oncolytic adenovirus therapies for cancer

“…Endostatin is a potent inhibitor of angiogenesis and has been safely used in replication-deficient Ad vector (Ad-Endo) in clinical trials for patients with advanced solid tumors. These Ad-Endo trials resulted in one objective response in a patient with nasopharyngeal carcinoma, 12 patients had stable disease, and two had disease progression [24] [25]. Ad-Endo has been used in combination with an Onc.Ad to amplify the endostatin expression in murine xenograft models, and this combination demonstrated more potent anti-tumor and antiangiogenic effects than treatments of either agent alone [26].…”

E10A, an adenovirus-carrying endostatin gene, dramatically increased the tumor drug concentration of metronomic chemotherapy with low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma

“…A phase I clinical trial of E10A gene therapy has already been completed and the safety of this gene therapy has been confirmed. 29 Further, this preclinical study of the combined therapy employing showed no serious general toxicity or specific toxicity evident via histopathological analysis of key organ tissues (Figure 6b) in this mouse model. These findings are encouraging for the clinical application of this combined therapy.…”

“…Endostatin gene therapy using E10A, a replication-deficient recombinant adenovirus containing a wild-type of the human endostatin gene, could directly express the highly bioactive protein in vivo by means of the eukaryotic expression system, and post-translational modification and longterm storage could overcome the need for the cumbersome daily administration of endostatin protein. 29 The antiangiogenic effect of endostatin gene therapy with E10A, and the direct and indirect antitumor activity of metronomic low-dose cisplatin, offer an additive effect for tumor suppression. In this study, we combined intratumoral injections of E10A and intra-peritoneal injections of weekly low-dose cisplatin, and compared the antitumor and antiangiogenic effects of this combined therapy to several single-agent treatments in the H891.…”