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,
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
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
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
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.