By David N. Leff

People diagnosed with advanced malignant melanoma spend the rest of their lives on a sort of death row - awaiting almost certain execution within five years after therapy. Surgery is virtually the only treatment of choice, except for high-dose interferon-alpha, introduced about five years ago.

But in New Orleans on Monday afternoon, people attending the 36th annual meeting of the American Society of Clinical Oncology heard a new note of optimism in prolonging the lease on life of melanoma victims. (In the U.S., where melanoma is the 5th commonest cancer, over 40,000 new cases are diagnosed each year, and more than 7,000 people die.)

At a session on melanoma and sarcoma, clinical oncologist David Berd, of Thomas Jefferson University in Philadelphia, presented a poster titled: "Post-surgical treatment of clinical stage III melanoma with autologous, hapten-modified vaccine: Expanded sample size and long-term follow-up."

Berd invented the autologous-cell melanoma vaccine in 1988, and the University licensed it in exclusivity to AVAX Technologies Inc., of Kansas City, Mo., which named it M-Vax. That firm is now conducting a 20-center, 400-patient Phase III randomized trial, comparing Berd's vaccine to FDA-approved high-dose interferon.

"AVAX's randomized pivotal trial," Berd told BioWorld Today, "is based on preliminary data from the Phase II, 214-patient trial we ourselves conducted, and published the first 77-patient cohort in the June 1997 Journal of Clinical Oncology. We entered the first patients at the end of 1989," he recounted, "the last ones just before the AVAX trial began in 1998. This present ASCO report represents an update - more than double the number of patients, and long-term follow-ups out to 10 years." (See BioWorld Today, Oct. 31, 1997, p. 1.)

In early-stage melanoma, surgery attempts to excise - with wide margins - as much and as many as possible of the melanotic tumors that erupt on the skin. Later, as the cancer strikes inward, the immune system's lymph nodes counterattack; they swell with tumor cells and swarm with antibodies and killer T cells. At this advanced stage, surgeons debulk those lymph nodes, and institute interferon chemotherapy aimed at prolonging survival.

Vaccine Doubled Five-Year Survival Rates

In Berd's Phase II study, all 214 subjects had had their lymph-node masses removed, then were treated with the vaccine for eight weeks. The overall five-year survival rate for those with metastasis in only one nodal area was 50 percent, compared with historical survival rates of 20 percent to 25 percent for patients treated with surgery alone. In a group with two debulked nodal areas, survival was 35 percent for vaccinees, 10 percent for those who had surgery alone.

Tumor immunologists have striven over the years to isolate immunogenic antigens from melanoma cells, as targets for candidate vaccines. Berd and his co-workers short-circuited this approach. "We don't know the antigen, and we don't need to know it," he said, "because the antigens that are available today for vaccines don't look that great. If they don't work, you need to go back to the lab and find more antigens. Then, if it takes you five years to work through each one, you have a lifetime of work.

"If you use the whole tumor cell, you don't really need to know what the antigen is. If it turns out that there are individually specific private antigens for each patient's tumor, then you're covered - and maybe have a vaccine."

That was the origin of Berd's autologous-cell vaccine. But it was only the beginning. To convert the native self-tumor cells into an antitumor vaccine, the Jefferson team added a hapten. "A hapten is a small molecule," Berd explained. "By itself it doesn't do anything. But when it sticks on to a protein, it makes that protein more immunogenic."

Haptens are off-the-shelf chemicals. Berd's vaccine employs dinitrophenyl (DNP), "a traditional hapten, used as a test reagent in humans. It's strictly a simple, synthetic chemical. We treat the tumor cells with this DNP hapten, which modifies the protein on the cell - and that's our vaccine. Of course," he added, "we irradiate the cells also, just to make sure they can't grow. Apparently," he went on, "we got a T-cell response against the hapten-modified protein - in our case, hopefully, tumor antigen."

Berd continued: "The T-cell response is measured by a delayed-type hypersensitivity (DTH), which is standard immunological skin testing in clinical medicine. We inject a small amount of tumor cells in the forearm, then wait 36 hours and inspect the arm. If the body has any immunity - and we know this is T-cell immunity - we get a little hive at the injection site and measure the size of it.

"We do the skin testing prior to vaccinating and again at the end of the eight-week course of vaccine, which in the current dosage schedule is approximately eight weeks. Prior to vaccination, almost everybody is zero. Very little baseline immunity. And what we're looking at is a post-vaccine response. As we emphasized pretty strongly in our ASCO presentation, the DTH immune response to the unmodified, native melanoma cells is a very, very strong predictor of clinical outcome."

Vaccinees Who Relapse May Luck In

"One thing that's not in our ASCO report," Berd observed, "is that we found on analysis something interesting. The patients who relapsed - we were treating people who were disease-free, and trying to prevent relapse - may still have long-term survival, particularly if they develop an immune response to the vaccine.

"So if they develop the DTH-aroused immune response to their own tumor cells in the vaccine," he continued, "38 percent of patients who relapse will have five-year survival, as opposed to 20 percent who relapse who don't have the immune response. So that bodes well, we think, for a randomized trial. Because for most post-surgery therapies it's easier to show an effect on relapse-free survivors than overall survival, which doesn't look so good. We think it will have a bigger effect on overall survival," Berd concluded, "because of the immunological mechanism involved here."

"To date," AVAX vice president for preclinical and clinical development, Ernest Yankee, told BioWorld Today, more than 350 melanoma patients have been vaccinated with M-Vax, with no adverse events found." He added, "We expect it to become commercially available to patients in Australia [a global melanoma hot spot] in mid-2000."