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Melanoma Regresses After GM-CSF Gene Therapy

Melanoma Regresses After GM-CSF Gene Therapy

PHILADELPHIA—Injections 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 response—regression 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.”

 
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