Gene therapy success for metastatic melanoma

The research was conducted by Steven A. Rosenberg, M.D., Ph.D., and a team of investigators at the National Cancer Institute (NCI).

Dr. Rosenberg's group previously had identified immune cells, which they labeled tumor-infiltrating lymphocytes, which were reactive against the cancer in patients with metastatic melanoma. They extracted and expanded these cell populations, then reinfused the cells.

The problem is that not all patients have this anti-cancer subset of lymphocytes, while others may have T-cells with receptors that do not home in on and bind so tightly to cancerous cells. Researchers sought to improve on nature.

The process extracts a patient's normal lymphocytes, which have no ability to recognize cancer, and uses viral vectors in the lab to insert into the lymphocyte DNA the gene for a T-cell surface receptor that better recognizes melanoma. The modified lymphocytes are then grown in the laboratory in great numbers and infused back into the patient.

Two patients clear

The first trial included 17 patients with metastatic melanoma who were refractory to all other treatments.

"In two patients, we saw regression of cancer, and both are disease-free now, almost at two years. The disease disappeared in the liver and the lung," Dr. Rosenberg says.

"It is very important to deplete, get rid of the normal lymphocytes first, before you replace them," he explains. "We use chemotherapy to knock down the immune system. It has no impact on the cancer; it prepares the patient to accept the infused cells. It's just a temporary ablation. The patient's normal lymphocytes recover after about 10 days, but that gives adequate time for the infused cells to engraft.

"They are all autologous, so the cells engraft very easily, with no risk of rejection," he says. "It's a living treatment, different than radiation or chemotherapy, because those cells survive and thrive in that patient."

"Cancer regression in patients after transfer of genetically engineered lymphocytes" first appeared in the online edition of the journal Science on Aug. 31.

Better receptor

Once they had established the proof of principle, the NCI team set about tweaking various aspects of the approach to make it better.

Dr. Rosenberg says the initial trial used a gene for a lymphocyte receptor with a fairly weak affinity for cancer-specific cell surface molecules.

Over the ensuing two years they have gained a better understanding of cell receptors, and now have a much better candidate, "a receptor that is at least 10 times better able to recognize the antigens."

That trial is about to start enrolling patients.

"One of the side effects of the gene therapy is that about a quarter of patients develop vitiligo, a depigmentation of the skin, as normal melanocytes are destroyed," Dr. Rosenberg says. "It is a relatively minor side effect for Caucasians. It can be very cosmetically problematic for African Americans, but they tend not to get melanoma."

Current trials are limited to patients with metastatic melanoma who are refractory to all other treatments, but with experience and a greater level of effectiveness the risk/benefit ratio will shift and he anticipates that the therapeutic approach will be used earlier in the course of disease.

Vaccine boosts effect

Dr. Rosenberg says animal models have shown that a therapeutic vaccine, administered along with genetically engineered lymphocytes, generates an even better anticancer response.

The hope is to move the combination approach into human trials as quickly as possible.

"But perhaps the most exciting part is that we now have receptors that recognize other types of cancers, so I think this approach can be extended beyond melanoma to patients with very common kinds of cancers," he says.

Marc D. Brown, M.D., professor of dermatology at Rochester University, Rochester, N.Y., was excited by this first successful use of gene therapy to treat cancer.

"Even though it is only two of 17 patients, the problem with melanoma is that we have no good treatment once it spreads beyond the site, so any progress is good," he says. "A different receptor that better recognizes the antigen is likely to be even more effective."

Should the next round of trials prove efficacious, he believes that a major use of this therapeutic approach will be as an adjunct to surgery in the 15 percent to 20 percent of high-risk patients in whom the tumor is deeper than 4 mm or for whom there is a positive sentinel lymph node biopsy.