NEWS

Melanoma Treatment Activates Immune System Against Cancer

Christine Theisen

Hoping to overcome a history of false steps and small advances, a research team at the National Cancer Institute recently reported that adoptive transfer—extracting immune cells from a patient, activating the cells to attack tumor cells, and injecting the cells back into the patient—showed clear tumor responses in six of 13 patients with terminal metastatic melanoma.

T lymphocytes, or T cells, are responsible for cell-mediated immunity. The basic premise of this study was to increase the number of T cells within the body. The new method for growing T cells is the most recent step in the decades-long and ongoing search for new ways to treat cancer besides the traditional surgery, chemotherapy, and radiation.

The technologic advance that made this result possible, a new method for growing cells used to replace the body’s immune system, is a "technical tour de force," said David E. Berd, M.D., professor of medicine at Jefferson Medical College in Philadelphia.

Each of the 13 patients in the study had T lymphocytes removed from the site of a single tumor. Called tumor-infiltrating lymphocytes, these T cells, which were already fighting the cancer, were identified by melanoma antigens on their surface. The most reactive of these T cells were stimulated with a growth factor, interleukin 2, and grown into many large colonies of cells. After undergoing non-myeloablative chemotherapy, which suppresses the immune system, each patient was injected with a large population of their own T cells that were modified to replace their immune system with cells reactive to the cancer.

Of the 13 patients treated, six had tumors that showed substantial regression, four had tumors that showed a mixed response, and three had tumors that did not respond at all. The study was reported by NCI’s chief of surgery Steven A. Rosenberg, M.D., Ph.D., and his colleagues in the Sept. 19 online version of Science.



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Dr. Steven Rosenberg

 
"What we’ve been able to do is develop a technique that basically replaces the patient’s immune system with cancer-fighting cells," Rosenberg said.

Rosenberg has studied cancer regression and the human immune system since the start of his career. "I saw a patient when I was a junior resident who had gastric, or stomach, cancer that had undergone a spontaneous regression and that got me thinking about ways the body’s immune system might fight."

Advances were required in many areas before the laboratory technique for growing large numbers of T cells could be considered feasible. Animal models were studied for years for clues of how cancer regression might occur. Lymphocytes had to be identified as the major aspect of the body’s immune system that causes cancer regression. Interleukin 2 was developed as an initial immunotherapeutic treatment for cancer. Genetic study was necessary to identify the genes that code for cancer antigens, or the substance on the surface of the cancer cell recognized by the immune system. And the disease mechanism of metastatic melanoma had to be understood before it was selected as a model.

"The goal was to study melanoma so that we could establish principles that would be broadly applicable to a wide range of tumors," Rosenberg said.

Edgar Engleman, M.D., professor of pathology and of medicine at Stanford University, explained two reasons to use melanoma as a model. "The most important is that several antigens have been identified that are expressed on these tumors (melanomas), and melanoma is unusual in that it develops on a melanocyte, a cell that we don’t need," he said. Melanocytes provide skin pigmentation but are not necessary for survival. "Most of the other tumors—lung, colon, breast—there are no antigens on those tumors that are not also on the tissues of vital organs," Engleman said. "The potential toxicity pales by comparison to the potential benefit."

Another reason to use melanoma as a model for other cancers is that researchers have long recognized it as relatively immunogenic—the body can often recognize a melanoma as abnormal. "There’s a natural tendency for these tumors to have T cell infiltrates," said Engleman. "Tumors are almost the same as normal tissues, so the body cannot recognize them, said Engleman. "Melanoma can be an exception." (See News, July 18, 2001, p. 1047.)

But melanoma can also resist treatment. Each of the 13 patients enrolled in the treatment protocol had received aggressive standard treatment that proved ineffective. All were in the end stage of the disease when they entered the study and had life expectancies of only a few months.

The critical step for this study was an advance in laboratory technique. Earlier in the same line of research, the team had tried numerous methods for growing the enormous number of active T cells needed for successful transplantation into patients in numbers at which T cell levels could be maintained. Each time, they were frustrated in their efforts. They could give the T cells to patients, but the level of T cells in the body would drop quickly.

"You could build up numbers of them to a small extent, maybe one or two percent of the lymphocytes, tiny numbers," said Rosenberg. "You could give lymphocytes, but by the next day you’re down to half a percent, and by a week or two later they’re gone."

The complexity of the laboratory work necessary for the experimental treatment has caused Berd to question its future applicability. Berd remarked on "the enormous amount of work involved in selecting this small amount of cells and expanding them (the cells) from tissue culture" and added that the laboratory technique is "very labor intensive." Rosenberg is more positive: "There are already ways to simplify it that we’re working on."

As with every other step in the process from laboratory to translational science, "We have to interpret the results (of the study) conservatively," said Engleman. "I would assume that others will try to replicate this," he said.

And Rosenberg is hoping that others do try to replicate it. "This particular treatment is only here (at NCI), but now that it is being published obviously a lot of people will begin to look at it. I hope so anyway. We need help," he said.

Rosenberg’s team is working "around the clock" to answer the question of why the treatment was so effective in causing regression of some patients’ tumors and not others. They are also moving forward with changes to improve the protocol suggested by results in the animal model.

Continued research that uses the principles of this study and the results of studies that replicate or build upon it will be needed to move it into a clinical setting. "The field of biologic treatment of cancer is still in its infancy," said Nicholas Restifo, M.D., principal investigator at NCI and coauthor of the study. "We still have a long way to go."


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