Therapeutic gene suspected to cause cancer

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One of the few gene therapy studies that had ever been successful was terminated in 2003, because several of the treated children had developed leukemia.

The cancer of the blood was induced by activation of an oncogene. Christof von Kalle, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), jointly with colleagues from the Salk Institute, La Jolla, California, has now shown that the transferred human gene itself has cancer-promoting properties.

The life of children suffering from X-SCID (X-chromosomal severe combined immunodeficiency) is constantly in danger, because their immune system is unable to fend off infections by pathogens. This is caused by a defect in the gene coding for the gamma chain of the interleukin-2 receptor (IL2RG). This protein, which is found on the surface of many immune cells, controls a multitude of maturation and differentiation processes of the body’s defense system.

In 1999, a gene therapy study was started at the H?al Necker, France, under the leadership of Alain Fischer. The study included children suffering from X-SCID, in whom the defective IL2RG gene was replaced by a healthy copy. The immune functions of study subjects improved significantly. Nevertheless, the study was terminated in 2003, when three of the 27 children treated within such studies developed leukemia within two to three years after the gene transfer. Subsequent investigations by Christof von Kalle showed that this is caused by the fact that the IL2RG gene was inserted close to the LMO2 oncogene in the genetic material of the patients. As a result of the close vicinity of the very active therapeutic gene, the oncogene was activated, causing uncontrolled cell growth.

In their new study, which is published in the science magazine Nature, Professor Christof von Kalle, German Cancer Research Center and National Center for Tumor Diseases (NCT) Heidelberg, jointly with colleagues of the Salk Institute, showed that IL2RG itself can also have a cancer-promoting effect.

The researchers observed mice after IL2RG gene therapy over a period of 18 months. As vehicles for the IL2R gene they used lentiviruses, which do not activate neighboring genes when inserted in the genetic material of the cell and are, thus, expected to minimize cancer risk. Nevertheless, about one third of animals developed T-cell lymphomas within four to eight months after receiving the treatment. Molecular-genetic analyses of the animals confirmed that the cancer of the lymphatic system was not caused by direct activation of oncogenes. The gamma chain of the interleukin-2 receptor is also inserted at the cellular docking sites of many other messenger substances of the immune system. Binding of these messenger substances to the receptors on the cell surface frequently means a growth signal to the cell. The authors presume that misregulations in one of these signaling pathways might be responsible for the derailing of T cell growth in the affected animals.

“The study shows two things,” comments von Kalle. “Before starting gene therapies in human patients, it is necessary to observe tested animals over a sufficiently long period of time to assess possible late effects. In the past, mice were observed sometimes no more than six months prior to therapy trials. The good news is: It is not the gene therapy as such or the vector for the therapeutic gene that causes T-cell lymphomas, but the interleukin-2 receptor itself. If genes are transferred whose products do not have growth-promoting properties, then the risk of malignant transformation of treated cells may be lower.”

http://www.dkfz.de

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