ASCODelivering normal copies of the p53 tumor-suppressor gene directly into lesions is a novel and promising approach to treating squamous cell carcinoma of the head and neck, John Nemunaitis, MD, of PRN Research Inc., said at the Annual Meeting of the American Society of Clinical Oncology.
In earlier phase I work with the p53 gene, the researchers were able to demonstrate both expression of the transgene and increased apoptosis, as well as evidence of antitumor activity. The protein product of the normal p53 gene also reduces angiogenesis. Dr. Nemunaitis described results of three international phase II trials that used adenovirus as the vector for the wild-type gene.
In the three studies, which used different doses and schedules, virus genetically engineered to carry p53 and not to replicate was injected into the tumors of 170 patients with refractory or recurrent head and neck cancer. All tumors were inoperable but accessible to needle injection. Median size was 5 cm. Patients did not need to demonstrate abnormality in their p53 gene to participate.
In making the injections, the investigators attempted to establish grid patterns across the tumors and to inject the material uniformly throughout the entire tumor, Dr. Nemunaitis said.
Responses were determined by CT scans. Stable disease required a 3-month period of stabilization2 months prior to initial scan and confirmation 1 month later. The investigators encountered no dose-limiting toxicities, Dr. Nemunaitis noted.
There was definitely activity, he said. Complete response occurred in 4% of injected lesions, and 18% of injected lesions decreased in volume by 25% or more.The summary of all patients maintaining stable disease or achieving response is about 30%, he said.
The median overall survival of all groups combined was a little more than 6 months, he said. Higher doses and longer injection schedules were related to longer survival. If you compare the low-dose 3-day schedule vs the high-dose 3-day or 6-day schedule, you can see a difference in median survival, he said, with less than 6 months survival in the lower-dose group and almost 8 months survival in patients receiving the higher-dose, more frequent dosing schedule, suggesting a dose and schedule effect.
The fact that this novel approach, as a single agent, seems to show some therapeutic benefit beyond the 6-month mark is good news, he said.
Toxicities included low-grade fever, mild to moderate pain at the injection site, nausea, and injection-site bleeding. All were easily manageable, and no toxic deaths occurred. Dr. Nemunaitis called the treatment extremely safe.
In conclusion, he said that the studies show that tumor growth can be controlled by injection of the wild-type p53 gene in an adenovirus vector, and that the size of the dose affects survival. We look forward to moving into phase III trials to further test the efficacy of this treatment, Dr. Nemunaitis said.
Because the p53 gene can produce cell-cycle arrest, reverse drug or radiation resistance, and help to reduce angiogenesis, it is indeed an excellent candidate for genetic anticancer therapy, commented discussant Michel Sadelaine, MD, of Memorial Sloan-Kettering Cancer Center. Important questions are how to transfer the gene to more cells within tumors and which tumor-suppressor genes to use for which tumors, he added.