By David N. Leff

As of last Friday, 47 men had signed on to a Phase II trial of the most advanced vaccine yet against prostate cancer. Their ranks soon will reach 60 - the number of prostate patients planned to take part in a seven-center clinical study of the vaccine, said tumor immunologist Howard Kaufman, who heads the vaccine therapy program at Albert Einstein College of Medicine in Bronx, N.Y.

Kaufman directs the multicenter project, which besides Albert Einstein lines up Beth Israel Deaconess Hospital in Boston; the Cancer Institute of New Jersey in New Brunswick; Fox Chase Cancer Center in Philadelphia; the Indiana University Medical center in Indianapolis; and the University of Wisconsin in Madison. All are members of ECOG - the Eastern Cooperative Oncology Group.

The group's prostate cancer vaccine trial takes off from a Phase I study, just reported in the May issue of the National Cancer Institute (NCI) journal, Clinical Cancer Research. The paper's title: "A Phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen [PSA] in advanced prostate cancer."

That vaccine was developed over the past half-decade by Therion Biologics Corp. in Cambridge, Mass., jointly with NCI tumor immunologist Jeffrey Schlom, a co-author of the journal article.

The vaccine's epitope - or antigenic bull's-eye target of the prostate tumor cells - explained Therion's president and CEO, molecular biologist Dennis Panicali, "is the entire prostate-specific antigen molecule, so the vaccine in the vaccinia virus vector expresses the complete PSA sequence. Our theory," he told BioWorld Today, "is to try to induce a killer T-cell response to all of the PSA epitopes, not just one or two. And we have done work, not in the clinic yet, where we've made some modifications in the PSA protein to increase its immunogenicity."

The vaccine's Phase I trial, which set the stage for ECOG's Phase II study, Panicali observed, "started a couple of years ago at the Dana-Farber Cancer Institute in Boston, and ended last October. It enrolled 33 men with rising PSA levels after radical prostatectomy, radiation therapy or metastatic disease." He said, "PSA levels are presumed to correlate with the progression of the disease.

"A salient point of that NCI paper," Panicali observed, "was that while we saw stabilization in a significant percentage of the men, in terms of measuring PSA levels, most of them went on to a rise in their PSA, which we assume coincided with progression of their disease."

They received three injections of the vaccinia/PSA vaccine, one month apart. Most of the immune response occurred after the first dose, then gradually declined.

No Vaccinia Virus Virgins Need Apply

Another condition of acceptance into the study was that only men who had had smallpox vaccinations - when these were still being given a quarter-century ago - were eligible. Panicali explained the rationale: "It was a sort of unintended fact of nature that everyone over the age of 25 or so was immunized against smallpox, so is already vaccinia-immune and therefore has some immunity to the vector. FDA likes the idea that people who have already been smallpox-vaccinated should therefore be less susceptible to any adverse reaction, so it placed the condition as an added sort of safety mechanism."

Kaufman put the dilemma this way: "The vaccinia virus is a very potent T-cell stimulant - probably the most potent one around. And we have put the PSA gene directly in the vaccinia vector so that when we immunize the patient, he's seeing not only the vaccinia virus, but also the PSA. And this should really trigger a very strong T-cell response.

"Look at infectious disease, for example, measles," he went on. "There, vaccination is very effective if given before exposure to the disease. But vaccines are completely ineffective once the infection is already developed. When someone has had measles for a week, you wouldn't think of giving him or her a vaccine.

"However, in cancer," Kaufman continued, "we're starting with patients who not only have disease, but have disease that's spread and failed other types of therapy. These are not really the patients in whom we expect to see tremendous immune responses. If one sees anything it's truly amazing.

"We're slowly working our way forward," he recounted, "and in fact the ECOG study, I think, is the first step toward going in that direction. And that's why we actually get prostate scans that show there's no disease, but there is a rising PSA. These are clearly patients who are at risk for recurrent disease. Most likely they have tumors which are just too small to be seen."

Limiting their patient cohort to men whose immune systems already "know" the vaccinia virus is an FDA requirement, which Kaufman and his ECOG collaborators are trying to get relaxed. "Since most of our patients are older," he pointed out, "they've all pretty much had that vaccinia exposure, but there are some concerns about the potential for complications from that virus. And although we expect that patients who are vaccinia-naove would probably respond better, we're not able to enroll them right now in any vaccinia study."

'Prime-Boost' Strategy Outwits Vaccinia Blackmail

To circumvent that Catch-22, Therion and its clinical collaborators are enlisting a quite different pox virus, hitherto unknown to man - at least immunologically. This is the nonreplicating avian fowlpox virus, used by poultry farmers to vaccinate chickens against related viral infections.

The new prostate strategy essentially is - after an initial high-potency vaccinia priming injection - subsequent booster shots that use the fowlpox virus as vector to maintain the PSA protein response. Thus, the ongoing ECOG study will divide its 60 patients into four dosage-arm cohorts, Kaufman said.

"In one arm," he related, "the patients will get four injections of just fowlpox. The second, a single vaccinia virus shot followed by three fowlpox injections. The third arm, three fowlpox boosters followed by a single vaccinia virus.

"That way we'll know if vaccinia really helps, compared to fowlpox alone - which we know we can give repeatedly, whereas vaccinia we can't. And then we'll know whether giving the vaccinia first or last makes a difference." Kaufman expects this Phase II trial to end in November, if not sooner, to be followed, Panicali anticipates, "by a Phase III trial - perhaps in the fourth quarter of 2001."