CATIONIC LIPID/P53 GENE THERAPY IN LUNG CANCER PATIENTS

DESCRIPTION (As Adapted From the Investigator's Abstract): Lung cancer arises in a bronchial epithelium diffusely damaged by the chronic inhalation of carcinogens in a susceptible host. The p53 gene plays an important role in the lung carcinogenesis process. P53 gene mutations are frequently involved in the progression of bronchial metaplasia to dysplasia. Restoration of p53 function in dysplastic bronchial epithelium by gene transfection technologies using the inhalation route is a logical and technically feasible strategy to prevent or delay the progression of premalignant bronchial epithelial lesions to lung cancer. The applicants have developed a cationic lipid/p53 gene complex (CLp53) that is effective by regional delivery in delaying endobronchial tumor growth in mouse models of p53-null or mutant human lung cancer. They propose to adapt this formulation for aerosol use and to initiate clinical studies with an optimized aerosolized CLp53 formulation (aCLp53). The hypothesis being tested is that restoration of p53 function in the human bronchial epithelium can be safely and effectively accomplished with the inhalation of CLp53 gene complexes. The specific aims of the proposal are: to develop a CLp53 formulation for administration as an aerosol; optimization efforts will focus on particle size, nebulizer type, pH, additives to enhance tissue penetration and CL/gene complex preservation, and potential interactions with bronchial mucus components; to study the preclinical toxicity of CLp53 by intratracheal instillation and aerosolization in mice and rabbits; these studies are essential for IND filing; and, to perform a Phase I clinical study of CLp53 by aerosolization in patients with p53 mutant non-small cell lung cancer (NSCLC). The objectives of the Phase I clinical study are: to determine the maximum tolerated dose, optimum schedule, and dose-limiting toxicity of aCLp53; to generate preliminary information on the ability of aCLp53 to restore p53 function in the human bronchial epithelium; and, to study the deposition and distribution of aCLp53 in the lungs. The results of this study will provide initial but very valuable information on the potential use of this new strategy in the treatment of bronchial premalignancy, carcinoma in situ, and endobronchial lung tumors.