Twenty years of Gendicine® rAd-p53 cancer gene therapy: The first-in-class human cancer gene therapy in the era of personalized oncology

Abstract

Genetic mutations in TP53 contribute to human malignancies through various means. To date, there have been a variety of therapeutic strategies targeting p53, including gene therapy to restore normal p53 function, mutant p53 rescue, inhibiting the MDM2-p53 interaction, p53-based vaccines, and a number of other approaches. This review focuses on the functions of TP53 and discusses the aberrant roles of mutant p53 in various types of cancer. Recombinant human p53 adenovirus, trademarked as Gendicine, which is the first anti-tumor gene therapy drug, has made tremendous progress in cancer gene therapy. We herein discuss the biological mechanisms by which Gendicine exerts its effects and describe the clinical responses reported in clinical trials. Notably, the clinical studies suggest that the combination of Gendicine with chemotherapy and/or radiotherapy may produce more pronounced efficacy in slowing tumor growth and progression than gene therapy/chemotherapy alone. Finally, we summarize the methods of administration of recombinant human p53 adenovirus for different cancer types to provide a reference for future clinical trials.

Keywords: Gendicine; Gene therapy; Recombinant p53 adenovirus; TP53; p53 mutation.

Figure 1

Milestones of TP53 gene targeting therapy. Since p53 was first described in 1979, its biological function has been widely and intensively investigated. In 1989, the tumor suppression function of p53 was confirmed. In the following year, TP53 germline mutation was found in Li-Fraumeni syndrome. MDM2-p53 interaction is great meaningful for drug target. Also, the drugs for mutant p53 rescue are developed. “Recombinant human p53 adenovirus injection” (Gendicine) was developed in 1998 by SiBiono GeneTech Co, Shenzhen, China, and has been applied in clinic since it was approved by Drug Administration in 2003.

Figure 2

The p53 interacted protein network. P53 (center) interacts with multiple proteins and involves in many distinct pathways. Each node represents a gene. Each node directly or indirectly interacts with TP53. The pathways are depicted with different colors. For one node, multiple color coating suggest that it is involved in multiple distinct pathways. Top 15 enriched KEGG pathways are depicted. Figure is generated based on String (https://cn.string-db.org/).

Figure 3

Presentive p53 functions and the drugs targeting P53-MDM2 complex. MDM2 protein binds to the N-terminal transactivation domain of p53, inhibiting its transcriptional activity as a tumor suppressor. Those drugs that inhibit MDM2 and MDM2-p53 interaction contribute to p53 normal function rescue.

Figure 4

Clinical application summary of Gendicine. (A) Objective responses of Gendicine application in different cancer types. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. (B) Side effect incidence of Gendicine in different cancer types. (C) Objective responses when Gendicine was injected with different modes.