BOSTONInvestigators at Johns Hopkins University
School of Medicine are testing a common cold virus as a vector for gene therapy
against prostate cancer, Theodore L. DeWeese, MD, reported at the 42nd annual
meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO).
The therapy was found to be safe, and the technique showed signs of antitumor
activity in a phase I trial.
The adenovirus CV706 (formerly CN706) is engineered to target
cells that make PSA and destroy them by continuous replication, Dr. DeWeese
said. In experiments with mice, the technique had been shown to kill prostate
cancer cells while sparing normal cells (see box).
The adenovirus was injected into the prostate using a modified
brachytherapy technique in 20 patients who had locally recurring adenocarcinoma
of the prostate after radiation therapy.
"For patients who have prostate cancer that is locally
recurrent after radiation, there really is no standard therapy to date,"
Dr. DeWeese said, explaining why the researchers decided to study the virus
with this group initially.
Patients had to have escalating PSA rates, but no sign of
metastasis to be admitted to the study. The median pretreatment PSA level was
12 ng/mL, he said, and some patients had PSAs higher than 20 ng/mL. All were
healthy except for prostate cancer.
All 20 patients experienced fluctuating PSA rates during the
experiment. Three patients met the criterion for dose response: a 50% decrease
in PSA over 4 weeks. Two others came close to that mark.
All of the responses occurred in the last two of five doses in
this standard dose-escalation study. Dr. DeWeese said that 9 of 11 patients in
the final two dose levels of the trial had greater than 30% reductions in their
PSA from pretreatment levels.
At biopsy on day 22, 60% of biopsies showed a significant
reduction in PSA staining, and viral replication has been confirmed by electron
microscopy of samples from post-treatment biopsies.
Therapy Well Tolerated
The primary objective of the trial was to define the
maximum-tolerated dose and toxicities. Patients were hospitalized for 24 hours
for observation on the first day of treatment. Follow-up included biopsies on
days 4 and 22 and at the end of 3 months. Serial urine and serum samples were
Overall, the doctors found the treatment well tolerated with no
irreversible grade 3 toxicity and no grade 4 toxicity. Consistent reactions
included a fever (grade 2 or less) that was treated with acetaminophen on the
first day, and urinary irritation in the majority of patients. Dr. DeWeese
attributed the latter in part to the virus, but noted that the patients blamed
it on a Foley catheter that they were required to use for 14 days.
No patient experienced grade 2 or greater elevation of liver
transaminases; two had hypertension, and three had blood clots in their urine.
After 21 days, there were no systemic toxicities, Dr. DeWeese said, but one
patient who was potent before treatment had some symptoms of erectile
The researchers have gone on to phase I-II trials using a more
potent sister virus called CV787. This agent is being tested in organ-confined
disease and in patients with hormone-refractory metastatic prostate cancer.