NEWS

Melanoma Vaccine Momentum Spurs Interest, Investment

Lou Fintor

With one melanoma vaccine already approved for commercial use in Canada, another recently launched within a global vaccine trial network, and several more nearing the final phases of testing, corporate enterprises are teaming up with hospitals, universities, governments—even each other—in anticipation of potentially huge payoffs.

More than 95 different cancer vaccines are in development by more than 50 companies. Dozens are for melanoma alone, which can be one of the most deadly of all cancers and for which there are few efficacious treatments in advanced disease. With more than 47,000 cases, 8,000 deaths, and incidence rates increasing at approximately 4% annually in the United States over the last 25 years, the potential market is substantial.

Last month the vaccine division of French life sciences giant Aventis entered into a multi-year exclusive commercial marketing agreement with northern California’s Eos Biotechnology. Under the pact, Eos will identify genomic targets for new cancer vaccines designed to prevent cancer recurrence. In return, Eos will receive cash, research and development funding, and royalties. Other cancer vaccine corporate partners include Cambridge, Mass.-based Pangaea Pharmaceuticals and Therion Biologics.

This, the latest in a wave of cooperative agreements and consolidations in the cancer vaccine industry, follows the April launch of Aventis Pasteur’s (formerly Pasteur Merieux Connaught) new Cancer Research Network, a massive Can $350 million (about US $236 million), 10-year research effort aimed at developing therapeutic cancer vaccines for melanoma and other cancers. In addition to hospital-based partnerships, the network has collaborative relationships with researchers at the U.S. National Cancer Institute, Sweden’s Karolinska Institute, Holland’s Leiden University, and a branch of the Ludwig Institute in Brussels, Belgium.



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Aventis Pasteur, whose vaccine laboratory is shown above, is conducting phase I trials of a melanoma vaccine.

 
"The time has come when these vaccines are showing effectiveness. To put this in perspective in the pharmaceutical world, Aventis and other companies are starting to invest significant resources in these therapies," said Neil Berinstein, M.D., assistant vice president for clinical oncology and cancer program director for Aventis Pasteur.

The Canadian government is also contributing up to Can $60 million (about US $40 million) in a repayable technology investment to Aventis Pasteur, that country’s largest vaccine company.

‘Prime-Boost’ Vaccine

Phase I safety studies of the Aventis melanoma vaccine are being conducted at Canada’s Toronto-Sunnybrook Regional Cancer Centre. Researchers hope to recruit up to 36 patients for this phase of the study.

The vaccine is designed to stimulate an immune response to an existing tumor using a novel two-stage "prime-boost" approach. A mutated form of the protein gp100 (involved in the production of melanin) is replicated via the canarypox virus, which does not itself cause human disease. After injection, the immune system is "primed" to begin producing cytotoxic "killer" T lymphocytes and other immune cells that attack the protein. Because the cells recognize small peptide fragments of the protein that have been engineered for enhanced reactivity, the "booster" vaccine consists of these peptides.

"We think these approaches will be a step forward for relatively nontoxic, rational-based treatments that target cancer cells and not normal cells," said Berinstein.

Berinstein said investigators will also evaluate two types of vaccine delivery: traditional intradermal injection versus injecting the vaccine directly into the lymph nodes where the T cells are activated. In addition, he said they have assembled a battery of novel biologic assays that they believe will provide data on immunologic parameters in addition to clinical activity such as tumor shrinkage.

"We believe the most effective way of controlling cancer is by activating the cellular arm of the immune system. The problem has been those assays for monitoring the cellular arm are not as well developed as those monitoring the antibody arm," Berinstein explained.

Approval This Year?

In November, Corixa Corp.’s Melacine® became the first therapeutic melanoma vaccine approved for commercial sale in North America. Phase III clinical trial data showed that Melacine provided improvement in quality of life for patients in late-stage metastatic melanoma compared with a four-drug chemotherapy control. This convinced Canadian regulatory authorities to permit marketing (by Schering-Plough Corp.) of the vaccine in that country. In the United States the vaccine is in phase III clinical trials with company officials hoping to file for full regulatory approval later this year.

The Melacine vaccine consists of two separate melanoma tumor cell lines lysed and combined with a commercial adjuvant (DetoxTM) made up of monophosphoryl lipid A and mycobacterial cell wall skeleton. The vaccine is given in two injections each week for 5 weeks followed by a 2-week break, then five additional weekly injections. Finally, monthly maintenance injections are given to maintain immune response.

In February, Corixa announced the results of a phase III study indicating that Melacine may provide some benefit in preventing recurrence of disease among patients with surgically treated stage II melanoma compared with those receiving no adjuvant. Another phase III study, which began in 1996 and completed accruing patients in January, compares the survival of 252 stage IV melanoma patients randomized to receive Melacine along with recombinant interferon alfa-2b (Intron A) versus Intron A alone. Results are expected later this year.

Although the vast majority of vaccines are allogeneic (nonindividualized), some are autologous (tailor-made to an individual’s tumor); either approach can involve whole tumor cells or antigens that might include DNA, proteins, or protein fragments. Among the other candidates are CancerVax (John Wayne Cancer Center, Santa Monica, Calif.), which comprises allogeneic cell lines and Bacille Calmette-Guerin (BCG), and various ganglioside antigen vaccines that are in phase III clinical trials.



             
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