Gene Therapy Kills Prostate Cancer Cells by Replication

BOSTON—Investigators 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 42^nd 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).

How the Virus Works

The prostate-specific enhancer-containing virus CV706 (Calydon, Inc., Sunnyvale, California) is constructed by deleting E3 from an Ad5 adenovirus and adding a minimal promoter-enhancer construct derived from the S´ flank of the human PSA gene, which drives the EIA gene.

The PSA gene acts as a replication trigger, signaling the adenovirus to replicate in tumor cells, which generally contain PSA. Replication continues until the cell lyses, destroying the tumor cell. This process can repeat as long as the replicated virus continues to encounter the targeted cancer cells.

The virus is harmless to normal prostate tissue, which usually contains no PSA, because it replicates far less efficiently in such cells.

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 also obtained.

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 dysfunction.

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.