New hope for treatment of melanoma

An experimental cancer therapy that uses immune-system cells to target and kill tumors holds promise for treating patients with advanced melanoma, a potentially fatal form of skin cancer.

The treatment, which infuses a patient's own immune cells that are triggered to react against melanoma cells, halted tumor growth in more than half of those who underwent therapy.

Researchers are optimistic that with further refinement, the technique, although not a cure, could provide new options for those who do not achieve a complete response to primary therapy.

The work was led by Dr. Cassian Yee of the Clinical Research Division and appeared in the Dec. 10 issue of the Proceedings of the National Academy of Sciences. Coauthors included Drs. John Thompson and David Byrd at the University of Washington, Dr. Phil Greenberg of the Clinical Research Division and collaborators at the Mayo Clinic in Rochester, Minn.

The study was one of the first to apply this type of immunotherapy, known as adoptive T-cell therapy, to a solid tumor and was more comprehensive than prior analyses, Yee said.

"In addition to looking at tumor response, we measured a number of other immune-system parameters that will help guide our efforts to improve the procedure," he said.

Such parameters included survival of the infused cells in the body and assessment of whether the cells migrate to tumor sites.

T cells are white blood cells that contain receptor proteins on their surface that specifically recognize and bind to markers displayed on other cell types, much like a key fits a lock. Upon recognition of a non-self or abnormal marker, T cells initiate an immune response that can result in destruction of cells displaying the aberrant protein.

Vast repertoire

The human immune system contains a vast repertoire of T cells, each recognizing a different target, but under normal conditions there are only a few of each type of T cell present in the body.

In adoptive T-cell therapy, a patient's T cells are extracted, and those that recognize a desired target, such as a protein on the surface of cancer cells, are identified and stimulated to divide.

This population of identical cells, or clones, is then infused back into the patient.

Yee's study involved 10 patients with metastatic melanoma who had failed conventional therapy. Each had T cells extracted prior to the start of their conventional therapy. Patients received infusions of T cells specific for either of two proteins, called MART1/MelanA and gp100, which are commonly produced by melanoma tumor cells. Patients received four such infusions and also were treated with low doses of interleukin-2 (IL-2), an immune system molecule that stimulates T-cell activity.

Researchers found that the transferred T cells survived an average of 16 days after transfusion and migrated to tumor sites. Disease progression stabilized in five of the patients and partially stabilized in three other patients for up to 21 months. Typically, patients with such advanced disease have a median survival of four or fewer months.

Though most patients had slight fever, aches and pains that subsided within three days, no major toxic side effects were linked to treatment.

Encouraging results

Yee said that while the study involved only a small number of patients, the results have encouraged the team to explore strategies to enhance the technique's effectiveness.

"Next, we'd like to use T cells that recognize additional tumor-specific proteins since not all tumor cells display the same array of markers," he said.

"We also need to determine the additional immune system components required for these T cells to survive and perform with maximum efficiency. The idea is to mimic the normal physiological conditions under which the T cells function as closely as we can."