Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer

Stephen G. Swisher, Jack A. Roth, John Nemunaitis, David D. Lawrence, Bonnie L. Kemp, Cesar H. Carrasco, Dee G. Connors, Adel K. El-Naggar, Frank Fossella, Bonnie S. Glisson, Waun K. Hong, Fadlo R. Khuri, Jonathan M. Kurie, Jack J. Lee, Jin S. Lee, Michael Mack, James A. Merritt, Dao M. Nguyen, Jonathan C. Nesbitt, Roman Perez-SolerKatherine M.W. Pisters, Joe B. Putnam, William R. Richli, Michael Savin, David S. Schrump, Dong M. Shin, Allan Shulkin, Garrett L. Walsh, Juliette Wait, David Weill, M. Kimberly A. Waugh

Research output: Contribution to journalArticle

437 Scopus citations

Abstract

Background: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with nonsmall-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments. Methods: Patients received up to six, monthly intratumoral injections of Adp53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 106 plaque-forming units (PFU) to 1011 PFU. Results: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2- 14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression. Conclusions: Repeated intratumoral injections of Adp53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.

Original languageEnglish (US)
Pages (from-to)763-771
Number of pages9
JournalJournal of the National Cancer Institute
Volume91
Issue number9
DOIs
StatePublished - May 5 1999
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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