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Reprogrammed immune cells could fight disease
16 March 2008
From New Scientist Print Edition.
Linda Geddes

Two years ago, on 13 March 2006, six previously healthy young men were left fighting for their lives after being injected with an experimental drug in a safety trial at Northwick Park Hospital in London. The drug was supposed to damp down cells in the immune system whose unwanted activity leads to autoimmune diseases like rheumatoid arthritis. But things went badly wrong, and the volunteers' immune systems started to run out of control, causing damage that led to multiple organ failure.

Though all six survived, the drug, TGN1412, being developed by TeGenero of Würzburg, Germany, was abandoned. However, the principle on which it was based still holds promise for therapies to prevent rejection of transplanted organs, and treatments for autoimmune disease and cancer (see "Cancer's little helpers"). In the past year, some of these therapies have moved into early-stage clinical trials, and while it is too early to say whether they cure disease, initial safety trials have shown none of the disastrous effects seen in the Northwick Park trial.

TGN1412 was supposed to stimulate a type of immune cell called regulatory T-cells (T-regs) that keep in check the "effector" T-cells that mount autoimmune attacks. The new therapies are designed to do the same. In most of them, immune cells are taken from patients or transplant donors, treated in the lab to greatly increase the proportion of T-regs, and then injected back into the patient.

Though this strategy has some drawbacks compared with using a drug to increase the numbers of T-regs within the patient's body (see "Inside or out"), its big advantage is that it gives doctors more control. This should reduce the risk that effector T-cells will become activated at the same time.

At the San Raffaele Telethon Institute in Milan, Italy, Maria Grazia Roncarolo is leading a trial in which this technique is being used to prevent graft versus host disease (GVHD) in people receiving bone marrow transplants. Though T-regs are at the heart of this treatment, it is different from TeGenero's approach. "We are trying to activate T-reg cells and at the same time suppress the effector T-cells," she says.

GVHD occurs when T-cells in the transplanted bone marrow recognise their new host's cells as foreign, and start attacking them. This is similar to what happens in autoimmune diseases, in which T-cells react against the body's own tissues, or in transplant rejection, when they attack the donated tissue. T-regs can directly suppress these attacks. "Regulatory T-cells are our body's own mechanism of preventing it from destroying itself," says Fiona Powrie, an immunologist at the University of Oxford. "We are trying to ramp up the body's natural control system."

Using T-regs would have several advantages over conventional immunosuppressants. These drugs, which often have to be taken for life, have a blanket effect that dampens down the whole immune system. This makes the body more vulnerable to infection, increases the risk of cancer and suppresses the very immune responses that might enable the body to control autoimmunity.

"The current approach of using pharmacological immunosuppression doesn't make any sense at all," says Matthias Edinger at the University Hospital in Regensburg, Germany. T-regs would have a more specific effect, and it could be made more specific still by generating T-regs that target only effector T-cells that react to a particular antigen. This should mean that they only suppress the immune cells that are co-ordinating an immune attack. Furthermore, experiments with mice suggest that a single injection of T-regs is enough to shift the balance of the immune system long-term, perhaps eliminating the need for lifelong drugs.

Like Roncarolo, Edinger is testing T-regs as a way of preventing GVHD in people who have been given bone marrow transplants to treat leukaemia. His team isolates immune cells from the donor and enriches them to increase the proportion of T-regs compared with other immune cells. The cells are then injected into the patient several weeks before the transplant, in the hope they will control donated immune cells and prevent GVHD.

Of the seven people given this therapy prior to receiving bone marrow transplants, none has experienced GVHD. The numbers are too small to say whether the therapy deserves the credit, but "at least there were no adverse events", says Edinger. He presented his results at the International Conference on New Trends in Immunosuppression and Immunotherapy in Berlin, Germany, last month.

Unlike Edinger, Roncarolo is using only a type of T-regs that have been conditioned by exposing them to the antigen outside the body. This makes them specific for the T-cells that are driving an immune reaction. Roncarolo has so far tested the cells in eight people receiving bone marrow transplants, also with no adverse effects - although again it is still too early to say whether the T-regs were responsible for keeping GVHD at bay.

Meanwhile, Benoit Salomon at the Pitié Salpêtrière Hospital in Paris, France, is using T-regs to fight autoimmune uveitis, an inflammation of the eye that can lead to blindness. Salomon, who also presented results in Berlin, says repeated injections of T-regs into the eye cured uveitis in mice, and he hopes to start human trials soon.

One problem still to be resolved is the possibility that T-regs could cause widespread suppression of the immune system, similar to that caused by immunosuppressant drugs. Creating antigen-specific T-regs would help, as they would home in on the rogue T-cells that are mounting an autoimmune attack, but the difficulty here is knowing exactly what antigen the T-cells are reacting against.

Another problem might be that when stimulating the T-regs in a sample taken from a patient there is a risk that the other immune cells will become more numerous too. "If you don't start with a very pure population of T-regs, the effector T-cells will grow and take over," says Salomon. In an extreme case, this could trigger a scenario similar to that seen in the TeGenero trial.

There is also mounting evidence that T-regs are more unstable than was once thought. This raises the possibility that T-regs could differentiate or revert into cells that promote inflammation, making a bad situation worse.

It is hoped the GVHD trials will address some of these issues, but there is still some way to go before widespread clinical trials can start. "Knowing the capabilities of the cell population you are using is going to be very important," says Kathryn Wood at the University of Oxford. "You also need to understand the profile of the patient to make sure that you get the therapy targeted correctly and introduced at the right time."

From issue 2647 of New Scientist magazine, 16 March 2008, page 8-9

Cancer's little helpers A characteristic of cancer cells is their ability to evade attack by the immune system, and it is looking increasingly likely that regulatory T-cells (T-regs) help cancers to do this. "Tumours should be rejected by the immune system," says Tyler Curiel at the San Antonio Cancer Institute in Texas. "Regulatory T-cells dampen immunity that would otherwise be effective." It now appears that people with more extensive tumours have higher numbers of T-regs in their blood and lymph nodes. What's more, the greater the number of T-regs inside a tumour, the more likely it is to prove fatal. Based on this, researchers are hoping that by reducing the number and activity of T-regs, they may be able to boost the immune system's ability to seek out and destroy tumours. Clinical studies are lending support to this idea. Curiel's team has shown that a drug called denileukin diftitox reduces the number of T-regs in people with ovarian, lung, breast and pancreatic cancer, and increases their immune response to the tumour (American Journal of Reproductive Immunology, vol 54, p 369). Unpublished results from 20 patients with ovarian cancer suggest that metastatic tumours in bone, lymph nodes and elsewhere regressed following treatment with denileukin diftitox. Tyler is now investigating whether this was linked to a decrease in the number of T-regs.

Inside or out? While the disastrous TeGenero trial two years ago inevitably raises suspicions over drugs that boost the number of T-reg cells in the body, some researchers still see this approach as preferable to manipulating immune cells outside the body. Fiona Powrie at the University of Oxford points out that the external approach means that every patient's treatment has to be an individually tailored cell therapy. "It isn't so easy," she says. Luckily, there may already be tried and tested drugs that boost T-regs. Infliximab, used by about 1 million people with rheumatoid arthritis, was thought to work by blocking the activity of an inflammatory protein, but it now appears to regenerate healthy regulatory T-cells. People with rheumatoid arthritis often have defective T-regs, which are unable to suppress other immune cells. When Michael Ehrenstein at University College London exposed such patients' T-regs to infliximab, they regained this ability. "It seems our ideas about how infliximab was working may not have been correct," says Ehrenstein, who presented his results in Berlin last month. There is also increasing evidence to suggest that a drug called OKT3, currently in phase 3 trials for treating diabetes, increases the proportion of T-regs and makes the T-cells they suppress more sensitive to their effects. Lucienne Chatenoud of the Necker Hospital in Paris, France, presented findings in Berlin indicating that OKT3 halts the autoimmune attack that causes type 1 diabetes. Four years after patients were injected with the drug, their pancreatic cells retained the ability to produce insulin, significantly reducing the amount of insulin these patients needed compared with those given a placebo.

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