Progress and Future of p53 Gene Therapy in China

张珊文
Peking University School of Oncology Zhang Shan-wen

P53 tumor suppresser gene well known for its structure and function, widely regarded as the genome guardian of cells, plays a key role in cell cycle control, apoptosis, and inhibition of tumor cell proliferation; especially as a transcription factor, in cellular responses to DNA damage.

Wild-type p53 gene promotes cell cycle arrest and apoptosis of tumor cells after irradiation, but mutated p53 abrogates this response and induces resistance to radiation. Replacement with normal p53 gene using viral vectors results in suppression and/or reversal of the malignant phenotype. P53 gene transfer induces radiosensitization: a stratege to convert a radio-resistant phenotype into a radio-sensitive one.

Adp53 is an E1 substituted replication-incompetent recombinant adenovirus encoding the human p53 gene.

Recombinat human p53 adenovirus injection (trademarked as Gendicine) was approved to market by the SFDA in October 2003. Although the product is primary used for nasopharyngeal carcinoma and other head-and-neck cancers, and is off-label used for cervix, pancreas, liver and other cancers at a late-stage, especially for sarcoma which cannot be easily treated by conventional methods. Adp53 is normally injected into solid tumors, although intra-locoregional arterial infusion, and intrathoracic /intraperitoneal infusion are also used. Now p53 gene therapy mostly in combination with radiotherapy, hyperthermia, or chemotherapy. Up to now, more than 3000 patients with cancer have been treated with Adp53 in china.

Study of Clinical mechanism： Expression of p53 gene and p53 target gene assayed by immunohistochemistry (IHC) in tumor simple taken 48h after intratumoral injection of Adp53. Up-regulation of cell cycle relative gene p21 and apoptosis relative gene Bax and down-regulation of VEGF were observed in postinjection tumor biopsy by using IHC. Adp53-specific p53 mRNA was detected by RT-PCR analyses of tissue samples in 16 (94.1%) of 17 assessable samples taken 48h after intratumoral injection of Adp53.

Clinical Study: Between Oct. 2001 to May. 2003, a randomized controlled clinical trial on Adp53 combined with radiotherapy (GRT group) in 42 patients with nasopharyngeal carcinoma (NPC) was compared with a control group of 40 patients with NPC treated with radiotherapy alone (RT group). In the GRT group, Adp53 was intratumorally injected once a week for 8 weeks. Concurrent RT (70Gy in 35 fractions) was given to nasopharygeal tumor and neck lymph node. Patients and tumors were monitored for adverse events and response, respectively.

Complete response rate in the GRT group was observed at 2.73 times that of RT group (66.7% vs. 24.4%). Six-year follow-up data showed that Adp53 significantly increased the 5-year locoregional tumor control rate by 25.3% for patients with NPC treated with irradiation (P=0.002). The 5-year overall survival rate and 5-year disease-free survival rate of GRT group were 7.5% (P=0.34) and 11.7% (P=0.21) higher than that of RT group. No dose-limiting toxicity and adverse events appeared, except for transient fever following Adp53 administration.

15 patients with cervix cancer at a late-stage IIB or IIIB treated by Adp53 in combination with radiation totally got complete response. 5-year survival rate was 87.3% (6/7) higher than that of radiotherapy alone before.

p53 gene was mutated in 70% of patients with pancreas cancer induces high malignant phenotype, high recurrent rate, and very low 5-year survival rate (only 1 to 3%). So 9 patients with unresectable pancreas cancer ( 4 primary and 5 metastasis) treated with Adp53 in combination with radiation got a good response, mean survival time was 13.2 months, that equate to results of surgery for patients with pancreas cancer at a early stage .

High incidence rate of p53 gene mutation was significantly correlated to worse survival and successful Adp53 gene transfer synergistically inhibited growth and metastasis in patients with bladder cancer and prostate cancer. A new strategy of Adp53 to increase locoregional control for urology tumors should be suggested.

Referance:   J Clin Oncol. 2008 Dec 22. [Epub ahead of print]

Pan JJ, Zhang SW*, Chen CB, Xiao SW, Sun Y, Liu CQ, Su X, Li DM, Xu G, Xu B, Lv YY