Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy

Stephen G. Swisher, Jack A. Roth, Ritsuko Komaki, Jian Gu, J. Jack Lee, Marshall Hicks, Jae Y. Ro, Waun K. Hong, James A. Merritt, Kamaran Ahrar, N. Edward Atkinson, Arlene M. Correa, Marcelo Dolormente, Linda Dreiling, Adel K. El-Naggar, Frank Fossella, Rhodette Francisco, Bonnie Glisson, Susan Grammer, Roy HerbstArmando Huaringa, Bonnie Kemp, Fadlo R. Khuri, Jonathan M. Kurie, Zhongxio Liao, Timothy J. McDonnell, Rudolfo Morice, Frank Morello, Reginald Munden, Vassiliki Papadimitrakopoulou, Katherine M.W. Pisters, Joe B. Putnam, Arcenio J. Sarabia, Thomas Shelton, Craig Stevens, Daniel M. Shin, William R. Smythe, Ara A. Vaporciyan, Garrett L. Walsh, Min Yin

Research output: Contribution to journalArticle

204 Scopus citations

Abstract

Purpose: We designed a prospective single arm Phase II study to evaluate the feasibility and mechanisms of apoptosis induction after Ad-p53 (INGN 201) gene transfer and radiation therapy in patients with non-small cell lung cancer. Experimental Design: Nineteen patients with nonmetastatic non-small cell lung cancer who were not eligible for chemoradiation or surgery were treated as outpatients with radiation therapy to 60 Gy over 6 weeks in conjunction with three intratumoral injections of Ad-p53 (INGN 201) on days 1, 18, and 32. Results: Seventeen of 19 patients completed all planned radiation and Ad-p53 (INGN 201) gene therapy as outpatients. The most common adverse events were grade 1 or 2 fevers (79%) and chills (53%). Three months after completion of therapy, pathologic biopsies of the primary tumor revealed no viable tumor (12 of 19 patients, 63%), viable tumor (3 of 19 patients, 16%), and not assessed (4 of 19 patients, 21%). Computed tomography and bronchoscopic findings at the primary injected tumor revealed complete response (1 of 19 patients, 5%), partial response (11 of 19 patients, 58%), stable disease (3 of 19 patients, 16%), progressive disease (2 of 19 patients, 11%), and not evaluable (2 of 19 patients, 11%). Quantitative reverse transcription-PCR analysis of the four p53 related genes [p21 (CDKN1A), FAS, BAK, and MDM2] revealed that Bak expression was increased significantly 24 h after Ad-p53 (INGN 201) injection and levels of CDKN1A and MDM2 expression were increased over the course of treatment. Conclusions: Intratumoral injection of Ad-p53 (INGN 201) in combination with radiation therapy is well tolerated and demonstrates evidence of tumor regression at the primary injected tumor. Serial biopsies of the tumor suggest that BAK gene expression is most closely related to Ad-p53 (INGN 201) gene transfer.

Original languageEnglish (US)
Pages (from-to)93-101
Number of pages9
JournalClinical Cancer Research
Volume9
Issue number1 I
StatePublished - Jan 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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