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

• Published in: Journal of clinical oncology Vol. 18; no. 3; pp. 609 - 622
• Main Authors: NEMUNAITIS, J, SWISHER, S. G, FOSSELLA, F, GLISSON, B. S, HONG, W. K, KHURI, F. R, KURIE, J. M, LEE, J. J, LEE, J. S, NGUYEN, D. M, NESBITT, J. C, PEREZ-SOLER, R, TIMMONS, T, PISTERS, K. M. W, PUTNAM, J. B, RICHLI, W. R, SHIN, D. M, WALSH, G. L, MERRITT, J, ROTH, J, CONNORS, D, MACK, M, DOERKSEN, L, WEILL, D, WAIT, J, LAWRENCE, D. D, KEMP, B. L
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 01.02.2000; Lippincott Williams & Wilkins
• Subjects: Adenoviruses, Human - genetics; Adenoviruses, Human - immunology; Adult; Aged; Antibodies, Viral - biosynthesis; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - therapy; Cisplatin - adverse effects; Cisplatin - therapeutic use; Combined Modality Therapy; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); DNA Mutational Analysis; DNA, Neoplasm - genetics; Female; Gene Transfer Techniques - adverse effects; Genes, p53; Genetic Vectors - genetics; Humans; In Situ Nick-End Labeling; Injections, Intralesional; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Male; Medical sciences; Middle Aged; Organ Specificity - genetics; Pharmacology. Drug treatments; Staining and Labeling; Antineoplastic agent; Adenoviridae; Intravenous administration; Bronchopulmonary; TP53 Gene; Bronchus disease; Advanced stage; Vector; Non small cell carcinoma; Tumor suppressor gene; Platinum II Complexes; Human; Lung disease; Respiratory disease; Intratumoral administration; Malignant tumor; Cisplatin; Genetic transfer; Virus; Chemotherapy; Phase I trial; Genetic engineering; Combined treatment; Transduction; Gene therapy
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2000.18.3.609

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 with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) 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). Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) 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. Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.