A week ago last Friday, at the National Cancer Institute in Bethesda,Md., a woman with late-stage malignant melanoma got a shot in thearm.

She was the first patient in the first clinical trial of an experimentalvaccine for treating this lethal cancer. And last week, two more suchmetastatic-melanoma victims received intramuscular injections of thenovel gene-therapy construct.

Malignant melanoma begins when a mole on the skin suddenlychanges color, size or shape. It ends, with aggressive rapidity, aftermelanotic tumors invade the body's internal organs, from lymphnodes and viscera to bone and brain.

Once such metastases erupt, a victim's median life expectancy istypically six to 11 months.

What gives a cutaneous mole its dark color is melanin, the pigmentthat also tints hair and skin fair, brown or black. Melanocytes in thebasal layer of the epidermis secrete melanin; melanoma turns thesecells malignant.

Too much sunshine beating down on light skin, especially inchildhood, is deemed the prime cause of melanoma, but heredity alsoplays a part in the cancer, which may lie low for years beforeshowing its cloven hoof. (See BioWorld Today, June 14, 1996, p. 1.)

This year, about 38,000 Americans will learn that they havemalignant melanoma. That incidence is going up 4 percent a year.Overall, according to 1996 data from the American Cancer Society,"about 87 percent of people diagnosed with melanoma survive forfive years or more." This death-defying figure jumps to "94 percentwhen the lesion has not spread beyond its original site," and so isamenable to local surgical excision.

The five-year survival rate drops to 16 percent "of people diagnosedwhen distant metastases have occurred." By then, "Stage IV" onmelanoma's four-point scale, clinical trials are the last best hope oftreatment. Melanoma is the first cancer to be treated with genetherapy.

At the National Cancer Institute (NCI), Steven Rosenberg, chief ofthe Surgery Branch, has been practicing experimental immunotherapysince the mid-1980s. His key strategy is to sic the body's immune-system tumor-infiltrating lymphocytes (TIL) on to melanotic cells,and to beef up these TILs with interleukin-2 cytokines.

His initial successful outcome came 12 years ago: "The first patientwith widespread melanoma to respond," Rosenberg told BioWorldToday, "back in November 1984, is still completely disease-free. Histumors never recurred."

Since then, Rosenberg and his NCI colleagues have netted more than200 complete and partial clinical responses, using various strategiesbased on their TILs.

From Whole-Cell Targets To Tumor Antigens

Within the past year, their discovery of two melanoma-associatedantigens, MART1 and gp100 _ which they have expressed in miceand patients by gene therapy _ further brightens this outlook.

"It's only now that we have these genes available," Rosenbergpointed out, "that we can do highly specific cancer trials. Up untilnow, we've had to use whole cancer cell extracts. Now for the firsttime we can actually immunize against unique gene products."

His Phase I/II trial that got going last week will test the vaccine forsafety, optimization of dose and route of administration, assay forimmune response "and of course clinical response to the therapy."Rosenberg expects it will take about a year to recruit between 30 and40 Stage IV melanoma patients for the trial. Each will receive aninitial vaccine shot followed by a booster four weeks later.

"And then," he said, "if patients are showing a clinical response, wecan repeat the course of vaccination with two more injections."

In this gene vaccine construct, the tumor-killing bullet is not amonoclonal antibody, but the body's own smart TIL-cell clone,programmed against MART1, one of those two recombinantantigenic peptides. MART1 stands for "Melanoma AntigenRecognized by T Cells."

The novelty within this novelty is the viral vector that aims and firesthe gene, which expresses the antigenic protein in the patient. There,it teaches the endogenous antigen-seeking cytotoxic T cells to fixtheir sights on a tumor antigen they couldn't properly see before.

That gene delivery vehicle is the fowlpox virus (FPV), an avianmember of the poxvirus family, which includes canarypox (seeBioWorld Today, May 28, 1996, p. 1), vaccinia and variola _ whichused to deliver smallpox. Rosenberg had previously treated 33melanoma patients with an adenovirus supplied by Genzyme Corp.,of Cambridge, Mass.

Virus Delivers, But Doesn't Replicate

Therion Biologics Corp., of Cambridge, Mass., provided the NCIteam with its recombinant fowlpox virus, driven by a vaccinia viruspromoter to encode the MART1 antigen gene.

"Our FPV is very efficient at infecting human cells," Therion'spresident and CEO, Dennis Panicalli, told BioWorld Today, "butbecause it's of avian, not mammalian, origin, it does not replicate inmammals. So it will not spread from cell to cell in the patient."

MART1 antigen lurks not only in malignant melanoma cells, but inperfectly normal melanocytes throughout the healthy body.

There's another arrow in NCI/Therion's melanoma vaccine quiver:

"The way this trial is designed," Rosenberg explained, "patients willfirst be receiving the virus vaccine. Then, only when we achievemaximal dose, will they start getting interleukin-2, a T-cell growthfactor, in conjunction with it."

Systemic IL-2, he observed, enhances the antitumor effects of theimmunization, but no one knows exactly how it does this."Presumably," he hypothesized, "the immunization increases thenumber of activated lymphocytes that are reactive with the tumor,and IL-2 can expand those clones to large numbers."

Rosenberg added that "this experience with IL-2 is the only approvedtreatment for patients with metastatic kidney cancer approved byFDA."

He concluded: "Now that we've been able to clone the genes thatencode cancer antigens _ that is, parts of the tumor that the immunesystem recognizes _ and now that we have the genes available, weare exploring new opportunities for cancer vaccines very vigorously.It's hard to know how effective they'll be, but it's a whole new areaof investigation."

Therion, Panicalli said, "aims to initiate trials of its FPV vaccineagainst prostate, breast, lung and other cancers before the end of thisyear and next." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.