T Cell triumph

IMMUNOTHERAPY MAY HAVE FINALLY TURNED A CORNER BY DIANE MARTINDALE, 2003

A TREATMENT

IN WAITING

Despite the recent success, immune cell therapy Is still highly

experimental. Side effects were serious In some cases: they

Included vitlilgo (white patches of skin where normal pigment cells

were attacked by the tumor­ infiltrating lymphocytes) and

opportunistic Infections. This is not like a drug you can just pull

off the shelf.  Every cell we give is basically a different drug because it’s unique to that patient. And every patient has a different kind of tumor,”  sags Steven A. Rosenberg of the National Cancer Institute, who is  still trying to understand why the therapy works in some and not in others.  Rosenberg thinks it will be at least two years before the therapy is ready for other types of cancer patients.

Immunotherapy for cancer is a targeted treatment that uses a patient’s own immune cells to attack and destroy tumors. Highly touted when it was conceived in the early 1980s, the approach has met with little suc­cess. Now researchers think they may have gotten over the hump: they have successfully treated several cases of a deadly skin cancer with immune cells taken from the patients, grown in large numbers in the laboratory and then given back to them. “We can now repop­ulate the body’s immune system with cells that fight the cancer,” says Steven A. Rosenberg of the National Cancer Institute, who pio­neered immunotherapy.

The idea is to exploit a subset of T cells, the so-called tumor-infiltrating lymphocytes (TILs), found deep inside cancerous tis­sue. These killer T cells at­tack the rapidly dividing cells and provide a natural protection against cancer. But the body seldom makes enough to keep the disease in check.

Rosenberg first isolated and grew TILs and gave them to patients in the 1980s, in a pro­cess called adoptive T cell therapy. Although the T cells retained their antitumor properties, they did not proliferate or survive long enough in patients to kill their tumor cells. The recent success came when Rosenberg’s team altered its method in two crucial ways. First, the sci­entists improved the way antitumor T cells are generated. TILs were isolated from multiple samples of each patient’s tumor and grown in the lab. The group then tested up to 50 dif­ferent samples against each patient’s cancer cells and chose the most reactive T cells to ex­pand and reinfuse into the patients. Previous­ly, cells were simply extracted from the tu­mors without any type of selection.

Second, the researchers changed the way patients are prepared be­fore the treatment. This time subjects underwent robust chemotherapy to wipe out their immune sys­tems temporarily and thereby make room for the incoming tumor-killing T cells. The procedure may have removed suppressor cells (made by the immune system or the tumor), which prevent T cells from proliferating, Rosenberg says. After the reinfusion, patients received repeated doses of interleukin 2, a potent immune system hormone that stimulates the growth of T cells.

The study relied on 13 individuals with advanced metastatic melanoma, a skin cancer that eventually spreads to other organs.  The patients, who had exhausted all other treat­ments, including surgery, received on average 80 billion of their own TILs—enough to give them a new immune system. As of December 2002, 10 of those subjects were still alive: six had major remissions of their cancer, and four had some of their tumors shrink.

Analysis of patients’ blood and tumor samples showed that the TILs multiplied and then attacked the tumor tissue. “In the past when we transferred cells, maybe 1 or 2 per­cent survived,” Rosenberg explains. “Now we have 80 percent that survive for months, and when that happens the cancer disappears.

“The good news about Rosenberg’s work is that as a proof of principle, it’s extraordi­nary,” says Robert A. Figlin, an oncologist at the University of California at Los Angeles School of Medicine. “The bad news is that it’s not easily extrapolated to a large group of patients.” Moreover, “we are asking a lot of these T cells to treat patients with very large tu­mor burdens,” says Cassian Yee, an immunol­ogist who has developed a similar T cell trans­fer therapy at the Fred Hutchinson Cancer Re­search Center in Seattle. “The T cell therapy might be more effective with smaller tumors and with repeated treatments over time.

According to Figlin, the key to immuno­therapy is selecting the right patients. “There will be a smaller number of patients that have a higher response, and not the other way around,” he explains. “That’s the reality un­til we understand the subtleties of the immune response.

Diane Martindale is based in Toronto.

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