Originally published as JCO Early Release 10.1200/JCO.2008.17.8251 on February 9 2009

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Intratumoral Epidermal Growth Factor Receptor Antisense DNA Therapy in Head and Neck Cancer: First Human Application and Potential Antitumor Mechanisms

From the Departments of Otolaryngology, Pharmacology, Pathology, Radiology, and Medicine, University of Pittsburgh Medical Center; and Biostatistics Facilities, University of Pittsburgh Cancer Institute, Pittsburgh, PA; Departments of Head and Neck Surgery and Molecular Therapeutics, University of Texas, The M. D. Anderson Cancer Center, Houston, TX; State Key Laboratory of Oncology in Southern China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Chinese University of Hong Kong, Shatin, Hong Kong; Department of Hematology/Oncology, Emory University, Winship Cancer Institute, Atlanta, GA; and National Gene Vector Laboratory, Center for Biomedicine and Genetics, City of Hope National Medical Center, Duarte, CA.

Corresponding author: Jennifer R. Grandis, MD, Eye and Ear Institute, 200 Lothrop St, Suite 500, Pittsburgh, PA 15213; e-mail: jgrandis{at}pitt.edu.

Purpose Squamous cell carcinoma of the head and neck (SCCHN) is characterized by upregulation of the epidermal growth factor receptor (EGFR). We developed a novel strategy to target EGFR by using a therapeutic gene that consisted of an EGFR antisense (AS) gene sequence under U6 promoter control. A phase I clinical trial was conducted to evaluate the safety and biologic effects of EGFR AS.

Patients and Methods Patients with advanced SCCHN who were refractory to standard therapies and who had at least one assessable and accessible lesion were enrolled. The EGFR AS dose was escalated in successive cohorts (six dose levels; 60 to 1,920 µg/injection). Patients received four weekly intratumoral EGFR AS injections. Tumor biopsies were performed before and after completion of therapy. Treatment response was assessed by tumor volume measurements (positron emission tomography/computed tomography), and levels of target proteins were assessed by immunohistochemistry.

Results Seventeen assessable patients were treated. No grades 3 to 4 or dose-limiting toxicities were noted, and a maximum-tolerated dose was not reached. Five patients (29%) achieved a clinical response, which included two complete responses (CRs) and three partial responses (PRs); two additional patients had stable disease (SD) as the best response. Patients with disease control (CR + PR + SD) had tumors with higher EGFR and lower STAT3 expression at baseline compared with patients who had progressive disease (P = .0312 and P = .095, respectively).

Conclusion Intratumoral EGFR AS was safe and resulted in antitumor activity in patients with advanced SCCHN. Baseline levels of high EGFR and low STAT3 may be associated with antitumor effects.

Presented in part at the 43rd American Society of Clinical Oncology Annual Meeting, June 1-5, 2007, Chicago, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00009841 [ClinicalTrials.gov] .

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