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Adenovirus-Mediated p53 Gene Transfer in Sequence With Cisplatin to Tumors of Patients With Non–Small-Cell Lung Cancer

From US Oncology, Baylor University Medical Center, and Columbia Medical City, Dallas; and Section of Thoracic Molecular Oncology, Departments of Diagnostic Imaging, Pathology, Thoracic/Head and Neck Medical Oncology, and Biomathematics, The University of Texas M.D. Anderson Cancer Center, and Introgen Therapeutics, Inc, Houston, TX.

Address reprint requests to John Nemunaitis, MD, Physician Reliance Network Research, Inc, 3535 Worth St, Collins Building, 5th Floor, Dallas, TX 75246; email j.nemunaitis{at}usoncology.com

PURPOSE: To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10⁶ to 1 x 10¹¹ plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m² on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick–end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay).

RESULTS: Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10¹¹ PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P = .011). Intratumor transgene mRNA was identified in 43% of assessable patients.

CONCLUSION: Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

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