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Published on: March 22, 2011
Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer
S G Swisher1, J A Roth, J Nemunaitis
1Department of Thoracic and Cardiovascular Surgery, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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 non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments.
Methods:
Patients received up to six, monthly intratumoral injections of Ad-p53 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 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 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 patients with advanced NSCLC.
Insights
Intratumoral administration of Ad-p53 gene therapy showed minimal toxicity and antitumor activity in patients with advanced non-small-cell lung cancer. This novel treatment demonstrated p53 transgene expression and disease stabilization in a significant portion of participants.
Area of Science:
- Oncology
- Gene Therapy
- Viral Vectors
Background:
- Preclinical studies showed tumor regression with Ad-p53.
- A phase I clinical trial was conducted for advanced non-small-cell lung cancer (NSCLC).
Purpose of the Study:
- To evaluate the safety and efficacy of Ad-p53 gene therapy.
- To assess Ad-p53 delivery and antitumor activity in NSCLC patients.
Main Methods:
- 28 NSCLC patients received up to six monthly intratumoral Ad-p53 injections.
- Doses ranged from 10^6 to 10^11 PFU via CT-guided or bronchoscopic delivery.
- Evaluated vector DNA presence, p53 mRNA expression, apoptosis, toxicity, and therapeutic response.
Main Results:
- Adenovirus vector DNA detected in 86% of patients; p53 mRNA in 46%.
- Apoptosis observed in 11 patients; vector-related toxicity was minimal.
- Partial responses in 8% and disease stabilization in 64% of evaluable patients.
Conclusions:
- Repeated Ad-p53 injections are well-tolerated in advanced NSCLC.
- Ad-p53 mediates antitumor activity and transgene expression in a subset of patients.
- Supports further investigation of Ad-p53 for NSCLC treatment.
