Intratumoral epidermal growth factor receptor antisense DNA therapy in head and neck cancer: first human application and potential antitumor mechanisms.

Abstract

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 microg/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.

• Authors: Stephen Y Lai, Priya Koppikar, Sufi M Thomas, Erin E Childs, Ann Marie Egloff, Raja R Seethala, Barton F Branstetter, William E Gooding, Ashok Muthukrishnan, James M Mountz, Vivian W Y Lui, Dong M Shin, Sanjiv S Agarwala, Rita Johnson, Larry A Couture, Eugene N Myers, Jonas T Johnson, Gordon Mills, Athanassios Argiris, Jennifer R Grandis
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 8 Pg. 1235-42 (Mar 10 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19204206 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• DNA, Antisense
• STAT3 Transcription Factor
• STAT3 protein, human
• Fluorodeoxyglucose F18
• ErbB Receptors
• Proto-Oncogene Proteins c-akt

Topics

• Aged
• Carcinoma, Squamous Cell (chemistry, therapy)
• DNA, Antisense (therapeutic use)
• ErbB Receptors (analysis, antagonists & inhibitors, genetics)
• Female
• Fluorodeoxyglucose F18
• Genetic Therapy
• Head and Neck Neoplasms (chemistry, therapy)
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Positron-Emission Tomography
• Proto-Oncogene Proteins c-akt (analysis)
• STAT3 Transcription Factor (analysis)