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Replacing Defective p53 Gene May Slow Progression of NSCLC

Replacing Defective p53 Gene May Slow Progression of NSCLC

SAN DIEGO--A therapy for advanced lung cancer patients who have not responded to other treatments is showing promise in studies at M.D. Anderson Cancer Center. In this phase I trial, 18 patients with non-small-cell lung cancer (NSCLC) and missing or defective copies of the tumor-suppressor p53 gene have received injections directly into their tumors of an adenovirus containing the p53 wildtype gene.

Most of the patients had previously failed almost all traditional therapies, including chemotherapy and radiation therapy. "It was a difficult population to look at," Stephen G. Swisher, MD, said at the American Association for Cancer Research annual meeting.

Patients received varying dosages once a month for up to six months. "We were especially interested in later gene deliveries," Dr. Swisher said, to look not only for late responses but also for the possible neutralizing effects of viral-induced antibodies that may develop with subsequent injections.

Indeed, the study showed a definite rise in antibody levels after the first treatment. "The average serum antibody level rose from 1:700 before treatment to approximately 1:25,000 following treatment. This was a dramatic rise, and it was maintained throughout the treatment period," he said. Despite the high antibody levels, the researchers saw minimal toxicity associated with injection of the disabled cold virus.

"We saw maybe a transient fever that would occur after the injection and last about 24 hours," Dr. Swisher said. He speculated that the mild toxicity could be explained, in part, because the treatment was a local, regional delivery into the tumor rather than systemic.

The high antibody levels also did not appear to interfere with expression of the wildtype p53 gene. Biopsies of the lung tumors, before and after treatment, were analyzed for vector DNA by polymerase chain reaction (PCR) and for gene expression by RT (reverse transcriptase)-PCR and immunohistochemistry.

"We clearly saw evidence of the adenoviral vector within the tumor tissue in the majority of patients with evaluable samples, even with subsequent serial dosages," Dr. Swisher said. "We were also able to see trans gene expression both with immunohistochemistry and RT-PCR. . . . The tumor cells were able to express this wildtype p53 even in the face of high antibodies."

Dosages were escalated from 106 pfu (plaque forming units) in log increments to 109 pfu, and there did appear to be a dose-response effect. Four of the six patients who received the highest doses experienced disease stabilization and another had a partial response.

"The numbers at this time are too small to look at response correlations," warned study head Jack A. Roth, MD. "We don't want to emphasize response rates in a phase I study."

Dr. Roth said he was especially encouraged by the finding that "replacement of a single genetic defect is able to drive the apoptotic process in cancer cells. While further research is required, we believe this may prove to be an advantage in our ability to fine tune or control p53-mediated apoptosis."

The Texas researchers are currently in the late planning stage for a phase II trial, expected to include about 100 patients.

 
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