Related Experiment Videos
A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung
M Schuler1, C Rochlitz, J A Horowitz
1Department of Medicine III, Johannes Gutenberg University, Mainz, Germany.
Abstract:
Mutations of the tumor suppressor gene p53 are the most common genetic alterations observed in human cancer. Loss of wild-type p53 function impairs cell cycle arrest as well as repair mechanisms involved in response to DNA damage. Further, apoptotic pathways as induced by radio- or chemotherapy are also abrogated. Gene transfer of wild-type p53 was shown to reverse these deficiencies and to induce apoptosis in vitro and in preclinical in vivo tumor models. A phase I dose escalation study of a single intratumoral injection of a replication-defective adenoviral expression vector encoding wild-type p53 was carried out in patients with incurable non-small cell lung cancer. All patients enrolled had p53 protein overexpression as a marker of mutant p53 status in pretreatment tumor biopsies. Treatment was performed either by bronchoscopic intratumoral injection or by CT-guided percutaneous intratumoral injection of the vector solution. Fifteen patients were enrolled in two centers, and were treated at four different dose levels ranging from 10(7) to 10(10) PFU (7.5 x 10(9) to 7.5 x 10(12) particles). No clinically significant toxicity was observed. Successful transfer of wild-type p53 was achieved only with higher vector doses. Vector-specific wild-type p53 RNA sequences could be demonstrated in posttreatment biopsies of six patients. Transient local disease control by a single intratumoral injection of the vector solution was observed in four of those six successfully transduced patients. There was no evidence of clinical responses at untreated tumor sites. Wild-type p53 gene therapy by intratumoral injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective in patients with advanced non-small cell lung cancer.
Insights
Wild-type p53 gene therapy using an adenoviral vector is safe and effective for non-small cell lung cancer. Intratumoral injection of this gene therapy showed transient disease control in patients with advanced cancer.
Area of Science:
- Oncology
- Gene Therapy
- Cancer Genetics
Background:
- Mutations in the tumor suppressor gene p53 are common in human cancers.
- Loss of wild-type p53 function compromises DNA repair, cell cycle arrest, and apoptosis.
- Gene transfer of wild-type p53 can restore these functions and induce cancer cell death.
Purpose of the Study:
- To evaluate the safety and efficacy of intratumoral delivery of a wild-type p53 gene therapy in patients with advanced non-small cell lung cancer.
- To determine the maximum tolerated dose and biological activity of the adenoviral vector encoding wild-type p53.
Main Methods:
- Phase I dose escalation study involving intratumoral injection of a replication-defective adenoviral vector carrying wild-type p53.
- Patients with non-small cell lung cancer and p53 overexpression received vector injections via bronchoscopy or CT-guidance.
- Doses ranged from 10^7 to 10^10 PFU, with safety and biological markers assessed.
Main Results:
- The gene therapy was safe and well-tolerated, with no significant toxicity observed.
- Successful wild-type p53 gene transfer was achieved at higher vector doses, confirmed by RNA detection in biopsies.
- Transient local disease control was observed in a subset of successfully transduced patients.
Conclusions:
- Intratumoral administration of wild-type p53 gene therapy via an adenoviral vector is a safe and feasible approach for advanced non-small cell lung cancer.
- The therapy demonstrated biological activity and potential for local tumor control.
- Further investigation in larger trials is warranted to explore its therapeutic potential.