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Patients' Melanoma Cells Engineered to Secrete GM-CSF

Patients' Melanoma Cells Engineered to Secrete GM-CSF

ASCO--Injections of an irradiated autologous melanoma vaccine genetically engineered to secrete GM-CSF proved safe and capable of eliciting an antitumor response in patients with advanced tumor burden, Robert Soiffer, MD, of the Dana-Farber Cancer Institute and Massachusetts General Hospital, said at an ASCO scientific session.

Of the 20 evaluable patients, four had a small decrease in the size of tumor deposits, and some patients with no observed decrease in tumor size had extensive tumor necrosis on pathologic exam. "This might suggest that perhaps we need to rethink how we measure response in this particular circumstance," he said.

At a median of 14 months' follow-up, 14 patients remain alive. Four patients with stable or responding disease are currently being re-treated with another vaccination course. "Three patients who have been rendered surgically NED are not being treated and have been free of disease for over two years," he said.

The phase I trial was conducted by Drs. Soiffer, Thomas Lynch, and Glenn Dranoff, and their colleagues in collaboration with Somatix Therapy Corporation, Alameda, Calif.

The study enrolled 32 stage IV metastatic melanoma patients. The source of the vaccine was generally soft tissue mass or lymph node (22 patients), though tumor was also removed from the lung, liver, and adrenal gland. Harvested melanoma cells were expanded in culture and transduced with a replication-defective retrovirus expressing the GM-CSF gene.

Of 32 tumors harvested, 28 vaccines were successfully prepared, and these cells secreted a median of 280 ng/million cells of GM-CSF over 24 hours. Of these 28 patients, 25 actually received vaccination.

The interval between harvest and vaccination was 10 weeks (range, 8 to 32 weeks), "but almost all received their first vaccination between 8 and 13 weeks," Dr. Soiffer said. Five patients withdrew early because of progressive disease that occurred primarily during this harvest-vaccination interval.

Patients received 107 irradiated tumor cells monthly for a total of three injections, every 14 days for a total of six injections, or weekly for a total of 12 injections. Dr. Soiffer noted that the frequency of vaccination may be an important variable because the intensity of the pathologic reactions (described below) was greater at skin vaccination sites with more frequent injections.

There was little toxicity, he said, except for local skin erythema and induration at the injection site.

A number of patients with subcutaneous metastasis developed significant clinical signs of inflammation around these tumor deposits. "When we looked at these specimens histologically, we found a significant rim of fibrosis with underlying central tumor necrosis," he said. "When we looked more carefully, we saw lymphocytes invading and destroying blood vessels that were supplying the tumor, as well as melanoma cells surrounded by lymphocytes."

These tumor-infiltrating lymphocytes were extracted from these tumor deposits, and their ability to kill the patients' own melanoma cells was evaluated in the lab. In one patient, the T cells were able to specifically lyse her own tumor but did not lyse another patient's tumor, suggesting some degree of specificity.

Serologic changes were also observed. "Prior to vaccination, there was very little reactivity with melanoma cell panels, but after vaccination, we saw an increase in antibody production that reacted with patients' melanoma cells," he said.

The clinical significance of these vaccine-induced responses needs to be evaluated in future efficacy studies, Dr. Soiffer said. The researchers are planning ultimately to look at patients with a smaller tumor burden, perhaps in an adjuvant setting, and are examining new adenoviral vectors in hopes of increasing the efficiency of gene insertion and thus decreasing the interval between tumor harvest and initiation of therapy.

 
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