NCI researchers, led by Dr. Steven A. Rosenberg, chief of surgery in NCI's Center for Clinical Research (CCR), achieved sustained regression of advanced melanoma by genetically engineering a patient's own white blood cells to recognize and attack cancer cells, as reported online August 31 in Science.

The treatment resulted in tumor regression for 2 of 17 patients: a 52-year-old man with advanced melanoma that had spread subcutaneously and to his liver, and a 30-year-old man whose melanoma had metastasized to his lymph nodes. Both men have remained disease-free more than a year after their treatment.

This represents a promising advance in the use of gene therapy to treat cancer. "Technical issues remain to be resolved, but the relative ease of this gene therapy approach will allow for testing in a broad array of tumors other than melanoma," said Dr. Lee Helman, acting scientific director for clinical science in CCR. "Application to other cancers is a very exciting possibility."

The two patients who experienced regression of their melanomas maintained high levels of genetically altered lymphocytes over the course of the study. Two months after receiving gene therapy, all patients in the last two of three treatment groups still had 9 to 56 percent of their genetically modified lymphocytes. No patients experienced toxic side effects attributed to the gene therapy treatment.

The researchers converted each person's own white blood cells, or autologous lymphocytes, into cancer-fighting cells in the laboratory. They accomplished this by drawing a small sample of blood containing normal lymphocytes from each patient and infecting the cells with a retrovirus. The retrovirus delivers genes that encode T-cell receptors (TCRs) into cells.

When the genes are turned on, TCRs are manufactured and line the outer surface of the lymphocytes. The TCRs then recognize and bind to certain molecules on the surface of tumor cells and activate the lymphocytes to destroy the tumor cells.

In a process called adoptive cell transfer, the newly engineered autologous lymphocytes were infused back into 17 patients with advanced metastatic melanoma. The first of three patient groups consisted of three patients who showed no delay in the progression of their disease. As the study evolved, the researchers improved the treatment process of lymphocytes in the lab so that the cells could be administered in their most active growth phase, resulting in successful therapy for two patients in the second and third groups.

Approaches to increase the expression and function of the engineered TCRs, including the development of TCRs that can bind more tightly to tumor cells, as well as further improving delivery methods using retroviruses, are under investigation. The researchers have also isolated TCRs that recognize cancers other than melanoma.

"At present, we are treating advanced melanoma patients using adoptive transfer of genetically altered lymphocytes, and we have now expressed other lymphocyte receptors that recognize breast, lung, and other cancers," said Dr. Rosenberg.

By Heather Maisey