A PHASE-I STUDY OF ADENOVIRUS-MEDIATED WILD-TYPE P53 GENE-TRANSFER INPATIENTS WITH ADVANCED NONSMALL CELL LUNG-CANCER

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 res ponse 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 stu dy of a single intratumoral injection of a replication-defective adeno viral expression vector encoding wild-type p53 was carried out in pati ents with incurable non-small cell lung cancer. All patients enrolled had p53 protein overexpression as a marker of mutant p53 status in pre treatment tumor biopsies. Treatment was performed either by bronchosco pic intratumoral injection or by CT-guided percutaneous intratumoral i njection 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 clinic ally significant toxicity was observed. Successful transfer of wild-ty pe p53 was achieved only with higher vector doses. Vector-specific wil d-type p53 RNA sequences could be demonstrated in posttreatment biopsi es of six patients. Transient local disease control by a single intrat umoral injection of the vector solution was observed in four of those six successfully transduced patients. There was no evidence of clinica l responses at untreated tumor sites. Wild-type p53 gene therapy by in tratumoral injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective in patients with advanced non-small cell lung cancer.