Adenoviral p53 gene therapy for lung cancer
119_229.pdf 462 KB
To determine the feasibility, safety, humoral immune response, and biological activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non-small cell lung cancer (NSCLC). Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled into this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 × 109 to 1 × 1011 plaque-forming units[PFU]) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m2). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response. Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing anti-adenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting ≥9 months, and 2 patients had progressive disease. Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.
アデノウイルスベクター (adenovirus vector)
肺癌 (lung cancer)
臨床試験 (clinical trial)
Okayama Medical Association
|Eprints Journal Name||
2) Saunders M, Dische S, Barrett A, et al. : Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer : a randomised multicentre trial. CHART Steering Committee. Lancet (1997) 350, 161-165.
3) Fearon ER, Vogelstein B : A genetic model for colorectal tumorigenesis. Cell (1990) 61, 759-767.
4) Finlay CA, Hinds PW, Levine AJ : The p53 proto-oncogene can act as a suppressor of transformation. Cell (1989) 57, 1083-1093.
5) Levine AJ : p53, the cellular gatekeeper for growth and division. Cell (1997) 88, 323-331.
6) Ohtani S, Kagawa S, Tokunaga N, et al. : Quantitative analysis of p53-targeted gene expression and visualization of p53 transcriptional activity following intratumoral administration of adenoviral p53 in vivo. Mol Cancer Ther (2004) 3, 93-100.
7) Zhang WW, Alemany R, Wang J, et al. : Safety evaluation of Ad5CMV-p53 in vitro and in vivo. Hum Gene Ther (1995) 6, 155-164.
8) Fujiwara T, Grimm EA, Mukhopadhyay T, et al. : Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res (1994) 54, 2287-2291.
9) Nishizaki M, Fujiwara T, Tanida T, et al. : Recombinant adenovirus expressing wild-type p53 is antiangiogenic : a proposed mechanism for bystander effect. Clin Cancer Res (1999) 5, 1015-1023.
10) Waku T, Fujiwara T, Shao J, et al. : Contribution of CD95 ligand-induced neutrophil infiltration to the bystander effect in p53 gene therapy for human cancer. J Immunol (2000) 165, 5884-5890.
11) Fujiwara T, Tanaka N, Kanazawa S, et al. : Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 (ADVEXIN) in patients with advanced non-small cell lung cancer. J Clin Oncol (2006) 24, 1689-1699.