By David N. Leff

A cruel and convoluted Catch-22 confronts men with advanced cancer of the prostate.

Once the tumor has spread beyond the wall of the gland, it's too late to remove the organ surgically, too late for radiation to help, but not yet time to start the last-ditch hormonal treatment that aims at slowing the malignancy's inexorable growth. (See BioWorld Today, June 12, 1997, p. 1; Oct. 16, 1996, p. 1.)

In the time it takes to read this issue of BioWorld Today -- say, 15 minutes -- another American man will die of terminal prostate cancer. Mortality in 1997 will reach an estimated 42,100.

With surgery, radiation and chemotherapy found wanting for advanced disease, research oncologists are turning to gene therapy.

On this front, new optimism is at hand in today's issue of the journal Cancer Research, dated July 1, 1997. Its title: "Prostate-attenuated replication-competent adenovirus (ARCA™) CN706: A selective cytotoxic for prostate-specific antigen-positive prostate cancer cells."

In this report, the two key terms are "adenovirus" (AV) and "prostate-specific antigen," better known as PSA.

PSA is the highly prostate-specific protein in common use as a blood-test marker to monitor the presence and progress of suspected or actual cancer. It's about to get an uncommon use as the target of an anti-PSA gene sequence, delivered to active tumor by an adenoviral vector.

That construct's creator is molecular biologist and virologist Daniel Henderson, one of the journal paper's two senior authors. The other is his clinical collaborator, oncologist Jonathan Simons, who directs the genetic medicine program for prostate cancer at Johns Hopkins University, in Baltimore.

Henderson is president and CEO of Calydon Inc., in Menlo Park, Calif. "What we've done," he told BioWorld Today, "is taken a normal, wild-type adenovirus, not genetically engineered in any way, and inserted our prostate-specific cancer enhancer gene (PSE) into its genome. It thus controls E1A, the only gene the virus makes during the first two and one-half hours of infection.

"E1A in turn," he continued, "starts to turn on a whole bunch of other viral genes. So E1A is the one we are controlling, and hence attenuating -- that is, restricting AV replication to PSA-producing tissue."

AV infections usually cause the common cold or pink-eye, but can have more serious consequences in the gastrointestinal tract and in neonates.

The whole virus is 35 kilobases of DNA long, Henderson noted. "We have deleted a 3-kilobase region, which is not necessary for replication. This makes space in the genome for our 1.5 kilobase PSE gene, which controls AV's E1A gene. All the remainder of the viral genome is retained in our gene therapy vector."

Targeting AV To Prostate Tumor Cells Only

What makes the construct specific to the prostate, Henderson explained, is "the fact that the E1A gene, by virtue of being controlled by our PSE, is made only in cells that produce PSA -- the prostate-specific antigen, which it kills."

As Henderson reported in Cancer Research, he and his co-authors at Calydon inoculated cohorts of nude mice subcutaneously with a human prostate cancer cell line. "We injected the mice with a million of these cells," he recounted, "and waited four weeks until they all had nice big tumors growing on their backs, all resistant to chemotherapy, radiation and hormonal treatment."

At that point, the animals received injections of the AV viral vector, named CN706. "Six or seven weeks later," Henderson went on, "the average tumor size was down to 16 percent of start. And of the ten mice in that group, five were visually free of tumor, which is unprecedented. Meanwhile, their PSA blood levels, which mirror prostate malignancy, had dropped to zero."

What about the other five animals with visible residual tumors? In similar experiments since submitting his paper to the journal, Henderson related, "If we have an animal with a visual tumor left, but not making PSA, we asked: What does that tumor consist of?"

The answer: "It appears to be scar tissue, not producing PSA cells any more. We're delighted to have scar tissue," he observed. "That we can live with -- literally."

He and his co-senior author, Jonathan Simons, at Hopkins, hope that prostate cancer patients will be able to live with scar tissue, or no tumor at all.

"That's why there's great scientific interest here at Hopkins now," Simons told BioWorld Today, "in moving very swiftly into a Phase I trial of this gene-therapy approach, because the opportunity to learn more about the entire direction of cancer therapy is best addressed by actually treating patients."

There's another, prostate-specific, reason for moving directly from Calydon's mice to Hopkins' prostate patients, without pausing for any more intermediate preclinical studies.

"The PSA gene," Henderson pointed out, "does not exist below primates, for reasons of which we have no idea. And second, the adenoviruses don't replicate in any but higher primate cells. Thus, the notion of doing rats, cats and dogs goes out the window. So we're going to go right to people. We already have our GMP [good manufacturing practice], lots of CN706 manufactured, and are in the process of FDA approval."

Simons observed: "Since the AV is an entirely novel gene-delivery construct, it needs to go through the appropriate safety testing, which means a Phase I dose-escalation trial. We're in active discussion with the Food and Drug Administration [FDA], and hopeful that we can start accruing patients by the end of 1997.

"The patients we would treat," he added, "in prostate cancer stage T-3, would have had a recurrence of locally advanced malignancy, after radiation therapy, and for whom there is no effective treatment at this time."

"Basically, there's not much you can do for people in T-3 stage," Henderson added. "They're no longer candidates for surgery, but not yet candidates for hormones, because their bones haven't started to hurt yet."

Immune Reaction Affects Treatment

The main hang-up in the Hopkins-Calydon strategy is a sub-Catch 22: If the initial gene therapy falls short of total tumor eradication, a return engagement of CN706 will engage the patient's immune system to attack the adenoviral protein.

"I think everyone in the AV field understands," Simons said, "that multiple dosing over weeks in a patient is going to mount antiviral immune responses that are going to block its therapeutic effects ultimately. Trying to optimize the schedule for maximum dose early is what we're actually working on. Even the Phase I trial is designed to answer some of those questions.

"Coming in at a high dose," Simons continued, "and treating rapidly, several times in the first week, before the immune response is mounted, one might see a great deal of antineoplastic activity."

Built into the viral vector itself is an astronomical antineoplastic potential, as Simons explained: "What you actually see is amplification of the treatment effect. If the tumor is affected, you get a boost by the restricted replication of the virus itself. For every prostate cancer cell infected with the CN706 construct that makes prostate-specific antigen, you get 10,000 more viral particles beyond the site of administration."

It's planned to inject the vector directly into the clearly imaged prostate malignancy.

Simons summed up his and Henderson's philosophy: "If it's good science, it could turn into good medicine. If it's good medicine, it could turn into good business." *