Cytokine-Transduced Melanoma Cells Promising Vaccine

VIENNA—Individually tailored vaccines made by transducing a patient’s own melanoma cells with the gene for GM-CSF have proven feasible and safe in a study conducted at the Netherlands Cancer Institute, Amsterdam.

Although median survival was only nine months for the population of advanced melanoma patients entered into this study, some vaccinated patients lived as long as 22 to 27 months, investigator Elaine M. Rankin, MD, of the Department of Immunology, said in her presentation at the 21st Congress of the European Society for Medical Oncology (ESMO).

“Looking at it simply, we do get results,” Dr. Rankin said. “We mustn’t think we’re doing souped-up chemotherapy, however. It takes a long time to switch on the immune system, so don’t dismiss tumor progression very early on, but carry on with vaccinating,” she recommended.

The 65 participants in the Amsterdam study were typical, unselected stage IV melanoma patients, many of whom had been heavily pretreated with chemotherapy with or without radiotherapy.

Most patients had lung, liver, or visceral soft-tissue metastases, although central nervous system (CNS) metastases were grounds for exclusion from the study.

In eight patients, it proved impossible to grow the autologous tumor cells required for the vaccine, and a number of other patients progressed during the eight to 10 weeks necessary for manufacture of the vaccine.

More Vaccinations?

Dr. Rankin said that, thus far, 24 patients have been randomized to vaccination with three doses of either 5 × 106 or 50 × 106 autologous GM-CSF-transduced and irradiated tumor cells administered subcutaneously and intradermally every three weeks.

“In retrospect, I think three vaccination doses is probably insufficient, and we should be moving toward protocols that involve a greater number of vaccinations,” she said.

Toxicity was mild and transient, consisting of itching at the vaccination site, fatigue, headache, and fever on the day of vaccination; erythema and considerable localized edema peaking at 36 hours at the vaccination site with the higher dose; and occasional local or regional lymphadenopathy.

Patients’ vital signs, organ function, and electrocardiograms remained unchanged by vaccination.

Biopsies taken after eight days revealed very heavy cellular infiltrates with marked eosinophilia and nuclear debris indicative of dying immune cells.

Signs of Immunomodulation

Conversion of the delayed hypersensitivity reaction was shown in all patients, irrespective of dose. “At distant metas-tases, we also saw signs of immunomodulation,” Dr. Rankin said.

Vaccination resulted in an increase in the number of circulating CD8 cytotoxic lymphocytes (CTLs) in some patients. In one patient, she said, a decrease in CTLs in the blood was paralleled by a rise in tumor-specific CTLs at the site of distant metastases. Dr. Rankin said that the therapy does seem to be having some impact on the disease, “and based on this evidence, we feel that further exploration of this therapy is appropriate.”