Large Melanoma Vaccine Trial at Hand

June 1, 1996

WASHINGTON--Final approval by the National Cancer Institute of the largest ever melanoma vaccine trial is near, John M. Kirkwood, MD, of the University of Pittsburgh, said at the American Association for Cancer Research (AACR) meeting. "I think before the summer is through, we should see this trial initiated," added Dr. Kirkwood, principal investigator for the study.

WASHINGTON--Final approval by the National Cancer Institute ofthe largest ever melanoma vaccine trial is near, John M. Kirkwood,MD, of the University of Pittsburgh, said at the American Associationfor Cancer Research (AACR) meeting. "I think before the summeris through, we should see this trial initiated," added Dr.Kirkwood, principal investigator for the study.

The trial of the novel therapeutic vaccine will involve 842 adultmelanoma patients enrolled by more than 100 medical centers inthe United States and perhaps Canada. The randomized, double-blindstudy will compare the vaccine with interferon alfa-2b (IntronA), as adjuvant therapy to prevent relapse in high-risk patientsafter standard treatment.

The phase III trial follows a pilot study by researchers at MemorialSloan-Ket-tering Cancer Center, initiated in 1987, in which asmall group of melanoma patients receiving the vaccine had a 70%lower risk of recurrence than controls after 6 to 7 years of follow-up.

"The eligibility for this trial is identical to the trialsconducted with the interferons over the past decade," Dr.Kirkwood said. Specifically, patients must have a diagnosis ofa deep melanoma, greater than 4 mm in depth, or some lymph nodeinvolvement. All will undergo surgery, and this must occur within56 days of their entry into the trial.

Patients in the vaccine arm will receive treatments for 96 weeks,given weekly for a series, then stretched out to three-monthlyover the last year, Dr. Kirkwood said. Those patients randomizedto the interferon arm will receive daily interferon injectionsfor 4 weeks, then three times weekly for 48 weeks.

Work so far shows that the vaccine produces "very few sideeffects, other than the types you see with immunization-- localswelling and redness at the site of injection," said AlanN. Houghton, MD, of Sloan-Kettering, at a press briefing.

The trial's clear purpose is to reduce melanoma relapse and death.People whose melanomas go 4 mm or more in depth run a 50% chanceof recurrence within 2 to 5 years without adjuvant treatment.The risk rises to 80% with regional node involvement. "Sowe are targeting patients who have a 50% to 80% relapse risk forthis therapy," Dr. Kirkwood said.

The idea of therapeutic cancer vaccines dates back a century."What has happened in the last 10 years is that the scienceof immunology has caught up with the cancer vaccines field,"Dr. Houghton said. "In particular, several researchers haveshown that the immune system can recognize tumor cells targets."

Over the last decade, a far more detailed picture has emergedof how lymphocytes react with antigens on tumors, and the chemicalcomposition of some of these antigens has been determined. "Mostof the action in this field has been in melanoma," Dr. Houghtonsaid.

Trial organizers expect the vaccine to match the effectivenessof interferon, and hope it will prove 10% more effective. On thebasis of the pilot study, the researchers also expect to showthat the vaccine generates a biological marker that predicts thepatient's survival chances.

The vaccine stimulates an antibody response to the GM2 sugar molecule(see box), and the pilot study at Sloan-Ketter-ing correlatedthis response to outcome.

"The antibodies against GM2 strikingly predicted relapse,"Dr. Houghton said. "If you had the antibodies, your chanceof surviving was twice as good." The question researchersseek to answer now is whether this finding will hold up in a muchlarger patient population.

The Make Up of The Melanoma Vaccine

The melanoma vaccine on the verge of its phase III trial (seestory above) consists of a purified surface antigen, a carrierprotein, and an immunological adjuvant.

The antigen is a sugar, GM2, found on the surface of melanomacells and on those of a number of other cancers, Dr. John Kirkwoodsaid at a press briefing.

GM2 is coupled with keyhole limpet hemocyanin (KLH), a proteinextracted from snails that has proved a potent immune system stimulator.This pairing is combined with QS21, a strong immunological adjuvantextracted from the bark of a South American tree.

"This is a very defined, chemically identified complex, whichis really what distinguishes it from all the other vaccines thathave been made with whole cells," Dr. Kirkwood said.