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%,
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.