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Toward Specific Immune Therapy

Then along came genetic engineering and the recognition of its value in identifying and manufacturing proteins called cytokines. Some of these can act as anticancer agents because they regulate the activation of immune cells. They essentially put the immune system at a higher state of alertness so that it can better detect tumor cells. Researchers had discovered some cytokines in the mid 1970s, before the era of genetic engineering, but that technology made possible the production of a large enough quantity of the proteins for study and treatment.

Over the years, investigators have identified several cytokines that lead to the destruction of tumor cells. Indeed, the U.S. Food and Drug Administration has approved the intravenous use of the cytokine interleukin-2 for this purpose against kidney cancer. Researchers have also found this cytokine can help against one form of leukemia and malignant melanoma, and are studying its efficacy against a broad range of other cancers. And scientists have discovered that the cytokine alpha interferon can activate immune cells against a form of leukemia. Although for reasons not yet understood investigators have found that cytokine injections generally induce responses in only 20 to 30 percent of patients, researchers worldwide are continuing to explore which of a large variety of tumors, prognostic factors, doses, and dose schedules work best with particular cytokines.

Meanwhile, following some early work injecting cytokines to fight cancer, some scientists recognized that the amount of immune-cell activation that can take place in the body through cytokine injection is limited by the dose of cytokines that can be administered that way. The treatment’s side effects, such as alternating fever and chills, low blood pressure, and difficulty in breathing, can become severe enough that patients need to stop the therapy. The investigators thought a way to raise the amount of activated immune cells would be to identify some of those cells, remove a few from the body, and mix them with a high dose of cytokines in a test tube. The idea was that the resulting large mass of activated immune cells, when infused back into the body, would travel to tumor sites and destroy cancer cells.

In 1982 Elizabeth Grimm, then a cancer expert at the National Cancer Institute (NCI), and two colleagues were the first to identify a kind of immune cell-which they labeled a lymphokine-activated killer (LAK) cell-that led to the death of tumor cells. Using the cytokine interleukin-2, the team next activated quantities of LAK cells in test tubes. Working in the laboratory of Steven Rosenberg, chief of NCI’s surgery branch, the group ultimately found that LAK infusions destroyed cancer cells, especially those associated with malignant melanoma and kidney cancer. But other researchers concluded that the effects were no stronger than those seen from simply injecting interleukin-2. Apparently generating LAK cells outside the body was no more effective that creating them within the body through infusions of interleukin-2.

Then in 1986 Rosenberg isolated an immune cell from inside a tumor itself. Calling this cell a tumor-infiltrating lymphocyte (TIL), he postulated that it recognizes proteins unique to a tumor, moves into that entity, and attempts to generate an immune response. He extracted TIL cells from a surgically removed tumor and, in a test tube using interleukin-2, stimulated their growth up to about 100 times their original number. After this process, which took three weeks, Rosenberg injected the complete mass of TIL cells into animal models and later patients. The therapy was more potent than LAK treatments, with the tumors in 11 of 20 patients shrinking or disappearing altogether.

In follow-up research to determine why the TIL technique didn’t always work as expected, however, in 1990 Richard Barth of the same laboratory determined that TIL cells do not kill tumor cells directly. Instead, after traveling to the tumor site they secrete more cytokines, such as tumor necrosis factor (TNF) and gamma interferon. These presumably recruit still other elements of the immune system in an attempt to destroy the tumor-an operation analogous to a reconnaissance team finding an enemy and then firing flares to bring reinforcements. Armed with this knowledge, in a subsequent experiment the lab tried to genetically engineer TIL cells to raise their secretion of TNF and gamma interferon. The idea was that the manufactured material, after being injected into the body, would home to areas surrounding malignant melanoma tumors-a particularly virulent form of cancer. But the researchers couldn’t consistently engineer the TIL cells as they wanted to.

Interest in the method, as well as in injecting amplified but unaltered TIL, has subsequently waned because of such practical difficulties. Moreover, growing TIL cells is costly because of extensive involvement of lab technicians over three to six weeks, and contamination of cultures with bacteria or fungi is always possible. Repeated surgeries are also required to provide tumor cells to stimulate continual TIL growth. Still, the notion underlying Barth’s research-genetically manipulating tumor cells-has provided the intellectual impetus for the next stage of work: cancer vaccines.

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