A Phase I Study of Adenovirus-Mediated Wild-Type <i>p53</i> Gene Transfer in Patients with Advanced Non-Small Cell Lung Cancer

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 107 to 1010 PFU (7.5 × 109 to 7.5 × 1012 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. Gene transfer of the human wild-type (wt) p53 tumor suppressor gene into p53 mutant tumors has been shown to have antiproliferative and apoptotic effects in vitro and in vivo. Schuler et al. report on a phase I clinical study of local wt p53 gene therapy in patients with advanced non-small cell lung cancer. A recombinant replication-deficient adenovirus carrying the complete human wt p53 cDNA under the control of the CMV immediate/early gene promoter was devised as expression vector. Gene transfer was achieved at higher virus doses without occurrence of any relevant treatment-related toxicity. In addition, clinical effects suggestive of a moderate local antiproliferative activity were observed in some patients.