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

Background: Preclinical studies in animal models have demonstrated tumor re gression following intratumoral administration of an adenovirus vector cont aining wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I cl inical trial, we administered Ad-p53 to 28 patients with nonsmall-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments. Me thods: Patients received up to six, monthly intratumoral injections of Ad-p 53 by use of computed tomography- guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU. Results: Polymerase chain reacti on (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specif ic p53 messenger RNA was detected by means of reverse transcription-PCR ana lysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was dem onstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment b iopsy specimens from 11 patients. Vector-related toxicity was minimal (Nati onal Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; gr ade 4 = no patients) in 84 courses of treatment, despite repeated injection s (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 inject ions of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of pat ients with advanced NSCLC.