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Induction of p53-regulated Genes and Tumor Regression in Lung Cancer Patients after Intratumoral Delivery of Adenoviral p53 (INGN 201) and Radiation Therapy¹

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.];

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.

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