Technology evaluation: tgDCC-E1A, targeted genetics/MD Anderson.

Abstract

Targeted Genetics is developing, tgDCC-E1A, a E1A tumor suppressor gene therapy formulated in a non-viral, lipid-based delivery system as a potential treatment for solid tumors which overexpress the her-2/neu oncogene [221611]. Fournier is the European development partner [244180]. Preclinical studies of E1A in mouse models for human breast and ovarian cancer demonstrated inhibition of expression of the her-2/neu oncogene, a significant reduction in tumors and increased survival rate in the treated animals [244180]. Results of a phase I study of intratumoral liposomal-E1A gene therapy in patients with recurrent/refractory breast cancer and head and neck cancer were presented at the 1998 American Society of Clinical Oncology (ASCO) meeting. Results demonstrated that intratumoral delivery of the E1A gene caused a subsequent downregulation of HER-2/neu expression and tumor response. The phase I dose-escalation study treated nine patients with recurrent breast cancer and nine patients with head and neck cancer. In 16 patients evaluable for response, nine had stable disease, five had progressive disease and two had minor responses despite tumor progression at other sites. In one of six patients who had repeat biopsies of treated tumors, no pathological evidence of tumor was found. In four of seven patients evaluated to date (May 1998), evidence of downregulation of HER-2/neu was reported [287387,290118]. The first phase I trial in patients with breast and ovarian cancer was completed by the end of 1997. The second phase I trial, enrolling 12 to 24 patients with solid tumors, was initiated in April 1997. Its aim was to determine dosing and safety of tgDCC-E1A and evaluate levels of gene transfer and tumor response. Patients were administered tgDCC-E1A by intratumoral injections. The company completed this trial by the end of 1997. In October 1998, Targeted Genetics initiated a multicenter, open-label phase II clinical trial of tgDCC-E1A in patients with recurrent head and neck squamous cell carcinoma who have exhibited disease progression despite standard therapies. The study to be conducted at six medical institutions in the US will enrole up to 60 patients with an interim analysis scheduled to be performed after the first 20 evaluable patients have been enrolled. Patients will be treated with ten direct intratumoral injections of the E1A gene over a period of 8 weeks, with follow-up performed at week 12. Patients who demonstrate a response will be eligible for continued treatment and will be monitored for 1 year [300424]. Targeted Genetics has issued three patents covering methods and compositions of use of the E1A and LTgenes (qv) to treat a variety of cancers. US-05651964 covers the use of the E1A gene, US-05643567 and US-05641484 cover the use of either the E1A gene or the LT gene as cancer therapies. These three patents provide the company with broad patent protection for tgDCC-E1A and all future products based on the use of the E1A or LT gene as tumor suppressors [259808].