A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer

Hum Gene Ther. 1998 Sep 20;9(14):2075-82. doi: 10.1089/hum.1998.9.14-2075.

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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Adolescent
  • Adult
  • Aged
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Transfer Techniques / adverse effects
  • Genes, p53 / genetics*
  • Genetic Therapy / adverse effects
  • Genetic Therapy / statistics & numerical data*
  • Genetic Vectors / genetics
  • Humans
  • Injections / methods
  • Lung Neoplasms / genetics*
  • Male
  • Middle Aged
  • Mortality
  • RNA, Messenger / genetics
  • Treatment Outcome

Substances

  • RNA, Messenger