Selective intra-arterial infusion of rAd-p53 with chemotherapy for advanced oral cancer: a randomized clinical trial

Abstract

BackgroundIn this study, a combination of recombinant adenoviral p53 (rAd-p53) gene therapy and intra-arterial delivery of chemotherapeutic agents for treatment of oral squamous cell carcinoma was evaluated.MethodsIn total, 99 patients with stage III or IV oral carcinoma who had refused or were ineligible for surgery were enrolled in a randomized, placebo-controlled, double-blind, phase III clinical trial. They were randomly assigned to group I (n = 35; intra-arterial infusion of rAd-p53 plus chemotherapy), group II (n = 33; intra-arterial infusion of rAd-p53 plus placebo chemotherapy), or group III (n = 31; intra-arterial infusion of placebo rAd-p53 plus chemotherapy).ResultsThe median length of follow-up was 36 months (range, 3 to 86 months). During follow-up, 16 patients in group I, 20 in group II, and 22 in group III died. Group I (48.5%) had a higher complete response rate than groups II (16.7%) and III (17.2%) (P = 0.006). The rate of non-responders in group I was significantly lower than that in groups II and III (P < 0.020). A log-rank test for survival rate indicated that group I had a significantly higher survival rate than group III (P = 0.019). The survival rate of patients with stage III but not stage IV oral cancer was significantly higher in group I than in group III (P = 0.015, P = 0.200, respectively). The survival rate of patients with stage IV did not differ significantly among the three groups. Or the 99 patients, 63 patients experienced adverse events of either transient flu-like symptoms or bone marrow suppression, while 13 patients had both these conditions together. No replication-deficient virus was detected in patient serum, urine, or sputum. rAd-p53 treatment increased Bax expression in the primary tumor of 80% of patients, as shown by immunohistochemical staining.ConclusionsIntra-arterial infusion of combined rAd-p53 and chemotherapy significantly increased the survival rate of patients with stage III but not stage IV oral cancer, compared with intra-arterial chemotherapy. Intra-arterial infusion of combined rAd-p53 and chemotherapy may represent a promising alternative treatment for oral squamous cell carcinoma.Trial registrationChiCTR-TRC-09000392 (Date of registration: 2009-05-18).

Historical and Clinical Experiences of Gene Therapy for Solid Cancers in China

“…Between 2000 and 2012, all gene therapy clinical trials were carried out in China, and Chinese researchers and physicians acquired a lot of experience in the associated procedures. A total of 16 controlled clinical trials of rAd-p53 (Gendicine TM ) have been carried out for the treatments of advanced cancers, including head and neck cancer, hepatic cell carcinoma, NSCLC, malignant glioma, and epithelial ovarian carcinoma [22,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38] (Table 1). Overall, the outcomes of the present clinical trials have been satisfying, and the overall response rates and survival rates were better in the rAd-p53 treatment groups, than those in the control groups.…”

“…The patients in the combined group had a lower incidence of gastrointestinal symptoms ( p < 0.05), and a higher survival rate ( p = 0.0002) [26]. Li et al administrated rAd-p53 and chemotherapeutic drugs to the patients of advanced oral squamous cell carcinoma, via selective intra-arterial infusion in a randomized, controlled clinical trial, and the patients in the combined group had a significantly higher survival rate than either the chemotherapy-only or gene therapy-only group ( p = 0.019), and the most frequent vector-related complication was a transient fever [27]. …”

“…However, clinical results have shown that these two treatment strategies do not yield satisfactory results for patients, especially for solid tumors, which may explain the lack of significant improvements in the overall survival rate over the last 30 years [47]. With the development of gene therapy, we have found that this alternative form of therapy can play an important role in the combined therapeutic strategy [27]. For example, a synergistic relationship between p53, and chemo- and radio-therapy has been suggested.…”

“…Therefore, it is meaningful in clinical practice to combine chemo- and radiotherapy with rAd-p53 gene therapy in order to correct the gene defects and mutations, which should reduce the treatment resistance and produce other benefits for cancer patients. Furthermore, the WT p53 protein could mitigate the toxicity of chemotherapeutic drugs by at least one of the following pathways: (1) p53 proteins interacting with DNA helicase; (2) increasing of ribonucleotide reductase by p53; and/or (3) the 3′→5′ exonuclease activity of the p53 protein [27]. …”

Antitumor effects of recombinant human adenovirus-p53 against human cutaneous squamous cell carcinoma in mice

“…Hence, the reconstitution of a wild-type p53 (wt-p53) gene is a promising anticancer therapy against cSCC. Gendicine, a recombinant human serotype 5 adenovirus (rAd/p53) in which the E1 region has been replaced by a human wt-p53 expression cassette, is the first commercial gene therapy product against multiple cancer (7). The therapeutic p53 gene in Gendicine can be delivered into the cytoplasm and the cell nucleus of the tumor target cells via an adenoviral particle infecting the tumor cells.…”