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
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.