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


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).


CONCLUSIONS
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.
Lai
Stephen Y
SY
Departments of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Koppikar
Priya
P
Thomas
Sufi M
SM
Childs
Erin E
EE
Egloff
Ann Marie
AM
Seethala
Raja R
RR
Branstetter
Barton F
BF
Gooding
William E
WE
Muthukrishnan
Ashok
A
Mountz
James M
JM
Lui
Vivian W Y
VW
Shin
Dong M
DM
Agarwala
Sanjiv S
SS
Johnson
Rita
R
Couture
Larry A
LA
Myers
Eugene N
EN
Johnson
Jonas T
JT
Mills
Gordon
G
Argiris
Athanassios
A
Grandis
Jennifer R
JR
D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000628:therapy*; D016373:DNA, Antisense / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D019788:Fluorodeoxyglucose F18; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000737:chemistry / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000032:analysis
D016373:DNA, Antisense; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019788:Fluorodeoxyglucose F18; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt