Gene Therapy Halts Two Cases Of Melanoma

BETHESDA, Md., Aug. 31 -- In two men with advanced melanoma, genetically altered T-cells wiped out their cancer, leaving them disease-free a year and half after treatment, researchers here said.

But the therapy did not work in 15 other patients, according to Steven Rosenberg, M.D., Ph.D., of the National Cancer Institute, who led the research team.

Nevertheless, Dr. Rosenberg and colleagues reported online in Science, the finding shows that gene therapy can be used to combat cancer. It "represents the first time that gene manipulations have been shown to cause tumor regression in humans," Dr. Rosenberg said in a statement.

Dr. Rosenberg is a pioneer in trying to induce the immune system to attack and defeat cancer and has reported some success with a method in which a patient's T-cells are extracted, multiplied in culture, and then reinfused.

But that method depends on the patient having T-cells whose receptors react to tumor-associated antigens (TAAs), he and colleagues said. Another obstacle is that even if the cells exist, it is sometimes difficult to identify them.

To overcome those barriers, Dr. Rosenberg said, the researchers decided to create T-cells that would attack tumor cells, rather than trying to find and expand them.

They extracted peripheral blood lymphocytes from each of 17 patients, and transferred the genes encoding the T-cell receptor specific to the MART-1 antigen found on melanocytes. The cells were then grown in culture and reinfused into each patient.

"We can take normal lymphocytes from patients and convert them to tumor-reactive cells," Dr. Rosenberg said.

In most of the patients, the transferred T-cells appeared not to last long enough to have a significant effect, the researchers reported but in two patients, the effect was striking:

• A 52-year-old man had previously been treated to no avail with alpha interferon, lymph node dissection, an experimental vaccine, and high-dose interleukin-2. He developed large tumors in his liver and axilla. But after the T-cell treatment, the axillary mass regressed completely and the liver mass shrunk to the point where it could be removed surgically. After 19 months, he was clinically free of disease.
• A 30-year-old man, previously treated with alpha interferon, lymph node dissection, and high-dose interleukin-2, had developed a large and growing mass in the lung. After T-cell treatment, the mass regressed completely, and 18 months after therapy he was clinically free of disease.

While the results in the two patients were encouraging, it's "undeniable the response here is rather disappointing," Michel Sadelain, M.D., Ph.D., of Memorial Sloan-Kettering Cancer Center in New York told a press agency.

But, he added, the work is "a significant technical advance" that should fuel interest and enthusiasm for cancer gene therapy.

Dr. Rosenberg said the technique could, in theory, be used to combat any form of cancer, not just melanoma, since the genes that encode T-cell receptors for many cancer types are known.

He and colleagues are now searching for ways to fine-tune the treatment so that more of the modified T-cells will survive and continue expressing the receptor genes.