Jueves 6 de Noviembre de 2008, Ip nº 253

Cancer special: tumours under lock and key
Por Linda Geddes

They were supposed to be lifesavers. In May 1998, a British man and woman in dire need of a transplant each received a new kidney from a donor who had died from a brain haemorrhage. Just 18 months later, the woman discovered a tumour in her breast, and died within four months. Then, in May 2000, the man developed a lump on his kidney, and a biopsy confirmed that he, too, had cancer.

While the organ donor had been treated for melanoma 15 years earlier, she had been carefully monitored, and there had been no hint that the cancer had returned. "These cancer cells apparently lay in a dormant state for over 15 years," says Rona Mackie of Glasgow University, UK, who treated the two recipients. Yet when the melanoma cells were transplanted along with the donor kidneys, they reawakened with awful consequences.

The man fought off the cancer and survived after being taken off the drugs that had damped down his immune system so that his body would not reject the kidney. As a result, he lost the organ and is now on dialysis.

What happened when his immune system was restored to full capacity holds the key to the entire mystery, Mackie believes. The donor's immune system had presumably kept the melanoma cells in check - only for them to bounce back with a vengeance in the immunosuppressed recipients of the kidneys. Once the man's immune system came back online, he quashed the cancer.

The idea of cancer lying dormant in the body is not new, but only recently has the immune system been implicated in keeping some forms of cancer at bay. If immunologists can learn to mimic this process, people may be able to hold their tumours in check indefinitely.

Fortunately, cases of cancer from a transplanted organ are rare. But there are intriguing hints that many more people may be living with dormant tumours. For example, a team led by Jonathan Uhr of the University of Texas Southwestern Medical Center in Dallas have shown that around one-third of breast cancer survivors have tumour cells circulating in their blood - some up to 22 years after they were successfully treated (Cell Cycle, vol 5, p 1772). Because cancer cells can only survive in the circulation for a few hours, somewhere in the body a microtumour must be constantly shedding cells, says Uhr.

While some studies of the immune system's role in cancer have focused on its role in eliminating individual cancer cells when they first arise (see "You're surrounded"), these mechanisms are thought to be different from those that might keep an established tumour in check.

Now researchers are starting to understand how the immune system controls tumour growth. Variations in an individual's immune response seem to make a difference to how cancer progresses. A team led by Jérôme Galon of the medical research agency INSERM in Paris, France, has shown that for colorectal cancer, the type, density, and location of immune cells within a tumour predicts how likely a patient is to survive; it is even more predictive than standard measures such as the size and invasiveness of the tumour (Cancer Research, vol 67, p 1883). "Even patients with a very small tumour could have a very bad prognosis if they have a weak immune response," says Galon.

While he tries to develop better prognostic tests, what cancer immunologists really want to do is to harness the immune system to halt or reverse cancer growth - making a vaccine that would train the immune system to fight cancer. Despite some promising results in animals, however, progress in people has been slow. "It is a difficult thing to do because a lot of people with cancer have developed tolerance to their tumour," says Peter Johnson, chief clinician with Cancer Research UK. This tolerance may be what enabled the tumour to escape immune control and grow in the first place.

Still, a better understanding of how the immune system responds in people who survive cancer is throwing up new strategies for fighting the disease. From Galon's work, we know that less aggressive tumours contain large numbers of killer T-cells and memory T-cells, which are both powerful weapons of the immune system, suggesting that it is mounting an effective response.

Other research has shown that tumours actively recruit regulatory T-cells, which help dampen down our immune responses. People with larger tumours have more of these "T-regs" in their blood and lymph nodes, and when there are many T-regs in a tumour the prognosis is worse. So by manipulating the balance of T-regs and cancer-fighting T-cells, it may be possible to throw cancer into reverse.

Some of the most impressive results have come from clinical trials using cancer-fighting T-cells from people with melanoma that has spread from the skin to other organs. Tumours shrank in about half of patients after their T-cells were removed, multiplied in the lab and injected back into them.

Preliminary studies also suggest that tumours that have spread to the bone, lymph nodes and elsewhere can be nudged into regression following treatment with a drug called denileukin diftitox, which reduces the number of T-regs. Other researchers are using antibodies to try to block the interactions through which T-regs diminish the other T-cells' effectiveness, in the hope that this will reawaken the cancer-fighting T-cells.

Although some people generate immune cells against their tumour, the numbers are too few to slow the disease. So researchers led by Steven Rosenberg of the National Cancer Institute in Bethesda, Maryland, genetically modify normal T-cells with the help of viruses, getting them to produce receptors specific to the cancer. Then they grow the modified T-cells outside the body before injecting them back in again. When 15 people with melanoma were given this treatment, two responded well (Science, vol 314, p 126) and are still free of cancer two years later.

Rosenberg's team is now running trials in people with other common cancers - including those where there is no evidence that the immune system keeps the tumours dormant naturally.

Mimicking dormancy, rather than eliminating cancer, has become the prime goal - at least in the short term, says Robert Schreiber, an immunologist at Washington University in St Louis, Missouri. "If immunotherapy can't yet be used to cure cancer, maybe it can be used to make cancer a controllable disease instead."

You're surrounded

The immune system is always on the watch for anything unusual - and that includes an aberrant, potentially cancerous cell.

Studies in mice and people suggest that immune surveillance is top-notch in some individuals. In 2003, for instance, Zheng Cui and his colleagues at Wake Forest University in Winston-Salem, North Carolina, announced that they had bred mice whose immune systems would rapidly destroy any cancer cells injected into their bodies.

When tumour cells are injected into these mice, they are rapidly surrounded and destroyed by white blood cells called granulocytes. Since then Cui has been studying human granulocytes, which seem to vary greatly in their ability to fight cancer. "At one end people respond very nicely and at the other end they don't respond at all," he says. "Most people are in between."

Armed with this knowledge, Cui is planning a trial in which granulocytes with high cancer-fighting potential are injected into people with cancer - a strategy that already works for mice.

  22/10/2008. New Scientist Magazine.