P53 Gene Therapy

Abstract

Based on the frequent inactivation of the p53 gene product in human malignancy, and its functional involvement in tumor suppression, cell cycle control and apoptosis, p53 was identified as an attractive target for somatic gene therapy strategies in cancer. Several pilot and phase I studies explored the intratumoral injection of viral expression vectors encoding the p53 cDNA in patients with advanced cancer. These studies confirmed the safety and feasibility of this approach. Further, vector-specific transgene expression and surrogate markers for biological activity of the transgene were demonstrated. Local tumor regression, or stabilization of tumor growth, were observed in some studies, and were interpreted as evidence for clinical activity. No formal assessment of in vivo transduction efficacy and vector distribution, following intratumoral injection of p53 expression vectors, was performed. The instillation of adenoviral p53 expression vectors into cavitary organs, such as the peritoneum or the bladder, has been studied as an alternative mode of application. Intravesical p53 vector installation, in combination with a transduction-enhancing agent, proved to be safe, feasible and biologically active in a phase I study of patients with bladder cancer. Transgene expression, following vector installation, was superior to intratumoral vector injection in this trial, and effective vector distribution and penetration were achieved by the former treatment. The publication of results from the studies of intraperitoneal vector installation in patients with ovarian cancer is still awaited. To date, only one published phase II study has formally assessed the clinical efficacy of adenovirus-mediated p53 gene transfer in patients with advanced non-small cell lung cancer (NSCLC). No clinically relevant benefit of local p53 gene therapy was identified in patients undergoing systemic chemotherapy when local responses of individual tumor lesions treated with intratumoral vector were compared. The results from additional efficacy studies performed in patients with NSCLC or head and neck cancer are pending. In summary, current studies failed to translate the preclinical success of intratumoral p53 vector injection into the clinic. A major obstacle is the unknown, and probably inefficient, vector delivery following intratumoral injection. In contrast, an effective delivery can be achieved by intravesical instillation of a p53 expression vector in patients with bladder cancer. These results merit further investigation in phase II studies. Recent improvements in vector technology, including targeting techniques, tissue-specific transgene expression andtumor-selective vector replication, will certainly allow investigators to study the efficacy of p53 gene therapy in a next wave of carefully conducted clinical trials.