Induction of p53-regulated Genes and Tumor Regression in Lung Cancer Patients after Intratumoral Delivery of Adenoviral p53 (INGN 201) and Radiation Therapy 1 Stephen G. Swisher, 2 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 Herbst, Armando 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, Jr., Arcenio J. Sarabia, Thomas Shelton, Craig Stevens, Daniel M. Shin, William R. Smythe, Ara A. Vaporciyan, Garrett L. Walsh, and Min Yin Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery[S. G. S., J. A. R., J. G., A. M. C., M. D., R. F., J. B. P., A. J. S., W. R. S., A. A. V., G. L. W., M. Y.], Department of Radiation Therapy [R. K., Z. L., C. S.], Department of Diagnostic Imaging [M. H., K. A., F. M., R. Mu., T. S.], and Department of Pathology [J. Y. R., A. K. E-N., B. K.], and Department of Thoracic/Head and Neck Medical Oncology [W. K. H., F. F., B. G., R. H., F. R. K., J. M. K., R. Mo., V. P., K. M. W. P., D. M. S.], Department of Pulmonary Medicine [A. H.]; Department of Molecular Pathology and Research [T. J. M.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Introgen Therapeutics, Inc., Houston, Texas 77030 [J. A. M.]; Department of Biomathematics [J. J. L., N. E. A.]; Aventis, Bridgewater, New Jersey [L. D.]; Biotechwrite: Biomedical and Science Communications, Houston, Texas 77079 [S. G.]; 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 radi- ation therapy in patients with non-small cell lung cancer. Experimental Design: Nineteen patients with nonmeta- static 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 outpa- tients. The most common adverse events were grade 1 or 2 fevers (79%) and chills (53%). Three months after comple- tion 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%), pro- gressive 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) injec- tion 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 pri- mary injected tumor. Serial biopsies of the tumor suggest that BAK gene expression is most closely related to Ad-p53 (INGN 201) gene transfer. INTRODUCTION Many genes involved in signal transduction, cell cycle control, and apoptosis have been implicated in the etiology of 1 This work was partially supported by grants from the National Cancer Institute and the National Institutes of Health Grants 01 CA78778-01A1 (to J. A. R.) and SPORE 2P50-CA70970-04); by gifts to the Division of Surgery from Tenneco and Exxon for the Core Laboratory Facility; by the University of Texas M. D. Anderson Cancer Center Support Core Grant CA 16672; by donations from the Charles Rogers Memorial and Gene Therapy Donor funds; by a grant from the Tobacco Settlement Funds as appropriated by the Texas State Legislature (Project 8); the W. M. Keck Foundation; and sponsored research agreement (SR93- 004-1) with Introgen Therapeutics, Inc. J. G. is a University of Texas M. D. Anderson Odyssey Program Fellow supported by the Kimberly- Clark Endowment for New and Innovative Research. The University of Texas and J. A. M. are shareholders in Introgen Therapeutics, Inc., the sponsor of this study. J. A. R. is an advisor and paid consultant to Introgen Therapeutics, Inc. Received 5/17/02; revised 8/13/02; accepted 8/20/02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 2 To whom requests for reprints should be addressed, at The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, #445, Houston, TX 77030. Phone: (713) 792-8659; E-mail: sswisher@ mdanderson.org. 93 Vol. 9, 93–101, January 2003 Clinical Cancer Research Cancer Research. on December 3, 2021. © 2003 American Association for clincancerres.aacrjournals.org Downloaded from