Blood stem cell grafts: a possible treatment for an ever-wider range of cancers

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The rejection of transplanted tissue by the recipient body is often life-threatening, but it can, in controlled form, be exactly what the doctors are looking for. New cancer therapies using transplanted blood stem cells are based on exploiting graft-versus-host reactions to attack the disease.

A few years ago, Anders Hedström developed repeated stomach pain; after several visits to hospital, doctors decided to X-ray him, and it was discovered that he had cancer of the pancreas. Anders had developed a cancer type that usually has a very poor prognosis, and was invited to take part in a small stem-cell study at Karolinska University Hospital in Huddinge.

"I knew that the mortality rate was almost 100 per cent and so didn't hesitate to take part in the study," says Anders. "I only have one sibling, a sister, and luckily she was suitable as a stem cell donor."

A group of patients with pancreatic cancer, which eventually consisted of only two individuals, were to obtain blood stem cells from a sibling once their tumours had been surgically removed. The treatment is completely new, and exploits the fact that grafted cells react to and attack tissue in the host body in what is known as a graft-versus-host (GvH) reaction. In acute cases, this is a serous inflammatory reaction, which appears within three months of treatment. In its most severe form, it is highly lethal.

If, however, the reaction happens three months or more after transplantation, it is called chronic, and it is this chronic reaction that the scientists are now trying to exploit as a form of therapy. The transplanted cells now attack the tumour, in what is called a graft-versus-cancer reaction. In order that they can slow down the reaction when necessary and avoid damage to healthy tissue, doctors administer immunosuppressant drugs, such as ciclosporin.

The results from the treatment of Anders Hedström and the other patient were compared with a control group of five patients who had no sibling from which to obtain blood stem cells. For someone to be a successful donor, his or her tissue type must match that of the host.

Two years after treatment, Anders Hedström shows no signs of having any remaining cancer cells in his body. The same applies to the other patient who received blood stem cells. All control group patients have since died.

The study is unique in its kind, but the group was so small that no reliable conclusions can yet be drawn. However, the results are promising, according to Olle Ringdén, professor of transplantation immunology at the Department of Laboratory Medicine at Karolinska Institutet and senior physician and medical director at the Centre for Allogen Transplantation (CAST) at Karolinska University Hospital in Huddinge.

"Most patients who develop pancreatic cancer don't survive," says Professor Ringdén. "Our results are encouraging, but we usually reckon with a time threshold of at least five years after treatment before we can say that the patient has been cured."

The study was led by Dr Brigitta Omazic MD at the Department of Laboratory Medicine at Karolinska Institutet.

It is still unclear exactly what causes the positive effects of the graft-versus-cancer reaction. Certain types of immune system T cells and the proteins they secrete are thought to have a key part to play in the mechanism. This has become an important branch of research in its own right, and the group working under Professor Ringdén are world-leaders in the field.

"Mr Hedström and the other patient with pancreatic cancer, who are both still cancer free two years after the stem cell graft, experienced a more powerful reaction to the tumour cells from the stem cells than they did from normal chemotherapy," says Professor Ringdén. "A number of studies are now being conducted based on the same graft-versus-cancer reaction principle. Patients who have undergone a liver transplantation as a treatment for liver cancer have been given a blood stem cell graft to prevent a relapse."

One study is looking into developing prostate-specific cytotoxic T cells (killer T cells) for patients who have undergone blood stem cells grafts for prostate cancer. The killer T cells are enriched, prior to being administered to the patient, to attack substances found both on the prostate and on the tumour cells. Similar procedures are to be tried for pancreatic cancer and ovarian cancer.

Treatment using grafted blood stem cells from a donor is an already established method for leukaemias, anaemic diseases, and metabolic diseases. In the case of acute leukaemias, for instance, high doses of chemotherapy followed by stem cell transplantation lead to long-term survival or complete cure for 50 to 80 per cent of the patients. The new stem cells produce life-essential white and red blood cells, and thrombocytes, which prevent haemorrhaging.

It is not yet fully known exactly how stem cell therapy using the graft-versus-cancer reaction will feature in the treatment of "solid" cancers, such as pancreatic, prostate, liver, kidney and breast cancer.

"Many new drugs are being produced for the solid cancers, and it's hard to say what place stem cell transplantation will occupy in the field," says Professor Ringdén. "Leukaemia treatment is also now more and more about drugs; before, for example, patients with chronic myeloid leukaemia received blood stem cells, but these days we only see the patients who have developed a resistance to their medication."

Whether stem cell transplantation is to become an established form of therapy for solid as well as non-solid cancers depends very much on how successful scientists are in controlling the adverse reactions that are always associated with grafts. Professor Ringdén's research group has devoted considerable time to studying ways of dealing with acute GvH reactions, using, in part, connective tissue (mesenchymal) stem cells. These cells are also produced by the bone marrow and can mature into a range of tissues, such as bone, cartilage and fat.

Whether a combination of mesenchymal stem cells and blood stem cells can prevent acute GvH reactions is now being tested in a randomised study led by Professor Katarina Le Blanc, a colleague of Professor Ringdén at the Department of Laboratory Medicine. Mesenchymal stem cells produce certain growth factors that can influence blood formation and that also have an immunosuppressive effect.

"The first time that mesenchymal stem cells were tested on a patient was in the early 2000s, and it was very much a shot in the dark," says Professor Ringdén, even if test-tube studies had already shown that mesenchymal stem cells have immunological effects.

"Our first patients was a six-year old Norwegian boy with acute leukaemia, who had developed a severe GvH reaction and received all conceivable treatment, without success," says Professor Ringdén.

"We extracted bone marrow from the boy's mother and cultivated mesenchymal cells from it, which we then gave to the boy. He responded dramatically to the treatment. For instance, his dysentery stopped and he started producing normal stools."

The boy did not survive. After 18 months he contracted a severe infection that he was unable to beat. Infections are the second type of serious adverse reaction associated with stem cell transplantations, and much of the research being carried out today is about reducing this risk. Virus infections, pneumonia and Epstein-Barr lymphoma, which is caused by the Epstein-Barr herpes virus, are three such side-effects.

"In one project, being led by Michael Uhlin at the Microbiology and Tumour Biology Centre at Karolinska Institutet, the objective is to produce specific T cells in the graft from a donor that react to both the Epstein-Barr virus and the lymphoma," continues Professor Ringdén. "We've had, for example, a woman with lymphoma in several organs who received T cells from her mother, with successful results."

"But we don't have enough cases of certain complications - one to two cases of Epstein-Barr lymphoma a year, for example - to single-handedly develop the high-tech solutions required. So well try to set up an internal laboratory as a shared resource for all Nordic centres. We're currently looking into ways of financing this."

Text: Peter Örn. Published in Medical Science, no. 2/ 2009.

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