Stem Cells: treatment for Leukaemia

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Let’s talk with the specialist

Last week we defined what the Stem Cells are (“Something about stem cells”), their biological properties (“The plasticity of Stem Cells”) and the ethical issues they rise  (“Ethical issues related to stem cell research”). Today I report an interview to Doctor Benjamin Uttenthal a Clinical Research Training Fellow at the University College London. He explains how Haematopoietic Stem Cells that reside in the bone marrow can be used to treat patients affected by Leukaemia. He also introduces some of the more advanced immunological treatments for Leukaemia studied in his laboratory.

Which are the most common types of leukaemia and how do they differ from each others?

Leukaemias are cancers of the blood or bone marrow, and all result in an abnormal proliferation of white cells in the blood. The commonest leukaemias can be divided into four categories: acute or chronic, and lymphoid or myeloid.

Acute leukaemias cause a rapid increase in immature white cells in the bone marrow. These immature cells crowd out the production of normal blood cells, and spill out into the peripheral blood. Because the abnormal cells in acute leukaemias are proliferating rapidly, acute leukaemias need to be treated quickly and with more aggressive chemotherapy. However, rapidly dividing cells are more easily killed by chemotherapy, and acute leukaemias can often be cured. Acute lymphoblastic leukaemia is the commonest leukaemia in childhood, and with better treatments the cure rate has increased to over 80% in recent years. Acute myeloid leukaemia is more often seen in adults.

Chronic leukaemias cause proliferation of more mature, but still abnormal, white cells. They progress less rapidly than acute leukaemias, and in the commonest leukaemia of all, chronic lymphocytic leukaemia, a period of observation is often required to decide whether treatment is needed at all. Chronic leukaemias can affect people of any age, but are most frequently seen in adults.

Which are the treatment approaches generally used?

The mainstay of treatment for leukaemias remains chemotherapy. Traditional chemotherapy drugs preferentially target rapidly dividing cells, and hence often affect normal cells in the body as well as cancer cells. This causes many of the side-effects of chemotherapy. For instance, the normal bone marrow contains many cells which divide rapidly to replenish red cells, white cells and platelets in the blood. Traditional chemotherapy will affect these cells as well as any cancer cells, and so patients undergoing chemotherapy frequently have low numbers of these normal blood cells.

As our understanding of the biology of specific cancers has improved, more targeted treatments have been developed. These are exemplified by imatinib (Glivec), a molecule which specifically targets an enzyme (tyrosine kinase) that is abnormally switched on in chronic myeloid leukaemia cells and drives their proliferation. Imatinib, the first tyrosine kinase inhibitor, is available in tablet form and has revolutionized treatment for chronic myeloid leukaemia, with 95% of patients achieving a complete haematologic response (normal blood counts) after a year of treatment.

Can you tell us something about immunotherapy of leukaemia?

Immunotherapy is an umbrella term for all treatments which harness the body’s immune system to treat disease. A form of immunotherapy which has been used for a long time to treat leukaemia is the transplantation of bone marrow or peripheral blood stem cells from a separate donor to a patient (allogeneic bone marrow/stem cell transplantation). For many years it was thought that the beneficial effects of bone marrow transplantation arose from the chemotherapy or radiotherapy given to the patient, and that bone marrow transplantation simply allowed high doses of chemotherapy to be used to treat the leukaemia, followed by ‘rescue’ of the patient’s bone marrow by transplantation from a donor. However, more recently it has been recognized that immune cells within the transplanted bone marrow themselves play an important part in clearing leukaemia cells that remain, recognizing them as ‘foreign’ and attacking them in a response known as ‘graft-versus-leukaemia’ or GVL. However, this response against ‘foreign’ cells may also be directed against the normal tissues of the bone marrow recipient, causing a potentially severe complication of bone marrow transplantation called ‘graft-versus-host disease’ or GvHD. For this reason, research aimed at improving immunotherapy in leukaemia has often focused on ways of improving the GVL response while limiting any GvHD. One way of doing this is to develop immune cells which specifically recognise and attack leukaemic cells but not the normal cells of the patient. In our research group we have done this by using gene therapy to target the immune cells against a molecule called WT-1, which is found at high levels on acute myeloid leukaemia cells. The aim is to give these cells to patients with acute myeloid leukaemia, a process known as adoptive cellular immunotherapy. A similar approach has already met with some success in patients with metastatic melanoma, a skin cancer, and we are optimistic that we will soon be able to start clinical trials in a small and selected number of patients.

To know more check: Uttenthal BJ et al. “Adoptive therapy with redirected antigen-specific primary regulatory T cells is a potential novel cellular therapy for graft-versus-host disease” Human Gene Therapy 21:507-525 (2010)

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• Bone marrow transplant – All Information (umm.edu)