PHILADELPHIAInjections of vaccinia virus genetically engineered
to deliver the GM-CSF gene proved safe and led to regression of
dermal lesions in patients with stage IV melanoma, said Michael J.
Mastrangelo, MD, professor of medicine, Thomas Jefferson University,
Jefferson Medical College.
The working hypothesis is that if we could enrich the cytokine
environment at the tumor site in vivo in situ, then we could recruit
antigen-presenting cells to this site and perhaps develop systemic
immunity that would be therapeutically effective, Dr.
Mastrangelo said at a symposium on gene therapy at the 35th annual
meeting of the American Society of Clinical Oncology (ASCO) in Atlanta.
The recombinant vaccinia virus carrying the GM-CSF gene is injected
directly into the tumor mass. The virus infects the tumor cells,
dumping the gene into the cytoplasm, he said, where it
functions to make GM-CSF.
Vaccinia was preferable to adenovirus as a vector because of its
larger payload and very good safety record, he said. To
minimize risks, the patients were all revaccinated, he added.
Seven melanoma patients with dermal, subcutaneous, or lymphoid metastases
received twice-weekly injections of escalating doses of the vaccine.
One patient received treatment for 12 months, one for 6 months, and
the rest for 6 weeks.
Two patients showed no response, and both of these patients had a
high tumor load, 1 log greater than the other five patients, Dr.
Mastrangelo said. Three patients experienced a mixed
responseregression of both injected and uninjected dermal
lesions, but no regression at distant tumor sites.
One patient had a partial remission, and one patient who had only
dermal metastases had a complete remission. This patient stayed in
complete remission for 9 months before developing regional lymph node metastases.
Patients suffered only modest local toxicity as well as mild,
flu-like symptoms that resolved within 24 hours. We have not
reached the maximum tolerated dose, Dr. Mastrangelo said.
Infectivity was maintained as long as patients received more than 107
PFU of virus at each site, in spite of the fact that all seven
patients developed antivaccinia antibodies, he said. All of the
patients showed functioning of the GM-CSF gene.
Dr. Mastrangelo concluded that the treatment is safe and nontoxic.
We get regression of injected and uninjected dermal lesions,
but we have yet to see regression of distant visceral disease,
he said. To make that happen, we are going to try to eliminate
the revaccination step; work with a stronger, more concentrated
preparation; and intervene earlier in the course of the disease.