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

Jennifer R. Grandis, 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

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1235-1242
Number of pages8
JournalJournal of Clinical Oncology
Volume27
Issue number8
DOIs
StatePublished - Mar 10 2009
Externally publishedYes

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Antisense DNA
Head and Neck Neoplasms
Epidermal Growth Factor Receptor
Genetic Therapy
erbB-1 Genes
Clinical Trials, Phase I
Injections
Maximum Tolerated Dose
Therapeutics
Tumor Burden
Neoplasms
Up-Regulation
Immunohistochemistry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Intratumoral epidermal growth factor receptor antisense DNA therapy in head and neck cancer : first human application and potential antitumor mechanisms. / Grandis, Jennifer R.; Lai, Stephen Y.; Koppikar, Priya; Thomas, Sufi M.; Childs, Erin E.; Egloff, Ann Marie; Seethala, Raja R.; Branstetter, Barton F.; Gooding, William E.; Muthukrishnan, Ashok; Mountz, James M.; Lui, Vivian W Y; Shin, Dong M.; Agarwala, Sanjiv S.; Johnson, Rita; Couture, Larry A.; Myers, Eugene N.; Johnson, Jonas T.; Mills, Gordon; Argiris, Athanassios.

In: Journal of Clinical Oncology, Vol. 27, No. 8, 10.03.2009, p. 1235-1242.

Research output: Contribution to journalArticle

Grandis, JR, Lai, SY, Koppikar, P, Thomas, SM, Childs, EE, Egloff, AM, Seethala, RR, Branstetter, BF, Gooding, WE, Muthukrishnan, A, Mountz, JM, Lui, VWY, Shin, DM, Agarwala, SS, Johnson, R, Couture, LA, Myers, EN, Johnson, JT, Mills, G & Argiris, A 2009, 'Intratumoral epidermal growth factor receptor antisense DNA therapy in head and neck cancer: first human application and potential antitumor mechanisms', Journal of Clinical Oncology, vol. 27, no. 8, pp. 1235-1242. https://doi.org/10.1200/JCO.2008.17.8251
Grandis, Jennifer R. ; Lai, Stephen Y. ; Koppikar, Priya ; Thomas, Sufi M. ; Childs, Erin E. ; Egloff, Ann Marie ; Seethala, Raja R. ; Branstetter, Barton F. ; Gooding, William E. ; Muthukrishnan, Ashok ; Mountz, James M. ; Lui, Vivian W Y ; Shin, Dong M. ; Agarwala, Sanjiv S. ; Johnson, Rita ; Couture, Larry A. ; Myers, Eugene N. ; Johnson, Jonas T. ; Mills, Gordon ; Argiris, Athanassios. / Intratumoral epidermal growth factor receptor antisense DNA therapy in head and neck cancer : first human application and potential antitumor mechanisms. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 8. pp. 1235-1242.
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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 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.",
author = "Grandis, {Jennifer R.} and Lai, {Stephen Y.} and Priya Koppikar and Thomas, {Sufi M.} and Childs, {Erin E.} and Egloff, {Ann Marie} and Seethala, {Raja R.} and Branstetter, {Barton F.} and Gooding, {William E.} and Ashok Muthukrishnan and Mountz, {James M.} and Lui, {Vivian W Y} and Shin, {Dong M.} and Agarwala, {Sanjiv S.} and Rita Johnson and Couture, {Larry A.} and Myers, {Eugene N.} and Johnson, {Jonas T.} and Gordon Mills and Athanassios Argiris",
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T1 - Intratumoral epidermal growth factor receptor antisense DNA therapy in head and neck cancer

T2 - first human application and potential antitumor mechanisms

AU - Grandis, Jennifer R.

AU - Lai, Stephen Y.

AU - Koppikar, Priya

AU - Thomas, Sufi M.

AU - Childs, Erin E.

AU - Egloff, Ann Marie

AU - Seethala, Raja R.

AU - Branstetter, Barton F.

AU - Gooding, William E.

AU - Muthukrishnan, Ashok

AU - Mountz, James M.

AU - Lui, Vivian W Y

AU - Shin, Dong M.

AU - Agarwala, Sanjiv S.

AU - Johnson, Rita

AU - Couture, Larry A.

AU - Myers, Eugene N.

AU - Johnson, Jonas T.

AU - Mills, Gordon

AU - Argiris, Athanassios

PY - 2009/3/10

Y1 - 2009/3/10

N2 - 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.

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