To train the immune system to attack tumour cells, cancer researchers and molecular biologist stake new hopes on a certain group of immune cells called dendritic cells. After special treatment in the laboratory, these cells seem to stimulate the immune system much more efficiently than genetically engineered cancer cells or cells of the connective tissue. At the 4th Symposium on Gene Therapy in Berlin, several scientists from the US and Germany reported on modern strategies using dendritic cells for anti-cancer-therapy. The concepts, some of which have already been tested in clinical trials, aim at special kinds of blood cancer, melanoma and kidney cell carcinomas.
For a long time, cancer researchers have dreamt of fighting tumours by mobilizing the body’s own defence system. Unfortunately, malignant cells hardly ever arouse efficient immune responses - a problem both the human body and various anti-cancer trials using gene therapy fail to overcome. As many oncologists see it, the immune system is very capable of recognizing tumour cells due to specific alterations on their surfaces. However, the abnormal cells use various strategies to suppress an adequate immune response.
Nevertheless, cancer researchers believe that the immune system could be effectively stimulated with the appropriate impulses. Many scientists think that dendritic cells are the best candidates for doing this job because they are specialized in training the immune army to fight against abnormal cells, for instance virus-infected cells. To show the immune system which cells it has to attack, dendritic cells take up specific fragments of defective cells and present them on their own surface as antigens. Antigens whose structure differs from the structures on healthy cells can activate cytotoxic T-cells, a group of immune cells which cancer researchers regard as the most important troop in the battle against tumours because cytotoxic T-cells are able to destroy tumour cells.
Some researchers want to utilize the potential of dendritic cells as “antigen-presenting-cells“ to train T-cells against specific types of tumours. They plan to develop a kind of vaccination with dendritic cells isolated from blood or bone marrow. After these cells have been multiplied in the lab, the scientists supply them with an antigen specific for the respective tumour. Finally, they transfer the manipulated cells back into the patients body. Some scientists even intend to train cytotoxic T-cells outside the human body by mixing them with manipulated dendritic cells in the lab - and to treat the patient merely with his own, “educated“ cytotoxic T-cells.
Any effort to use dendritic cells for anti-cancer therapy requires one essential prerequisite: the availability of an antigen specific for the tumour to be treated. For certain kinds of melanoma and blood cancer, Prof. Pezzutto from the Department of Medical Oncology and Tumor immunology at the Robert Rössle Klinik at the MDC reported that scientists have been able to identify such tumour specific fragments. Some scientists presume that also certain types of kidney cell carcinoma bear appropriate antigens which they might soon be able to identify. The German oncologist is actually developing a new strategy to treat chronic myeloid leukemia (CML). In his project, he and his co-workers use an antigen which constitutes a certain part of a protein (called BCR-ABL-protein) specifically produced by CML-cells. The tumour cells of about 90 percent of all CML-patients synthesize this abnormal protein. However, even if the strategy should prove to be successful, only about 30 percent of the patients can possibly profit from the therapy due to different tissue properties of human individuals (HLA structure).
The researchers think, that once a specific immune response has been initiated, the patient’s immune system will not require further support from the lab because the “trained“ cytotoxic T-cells will conduct all the necessary steps for tumour cell destruction.
Recent experiments by Prof. Micheal Lotze and Dr. Walter Storkus from the Cancer Institute of Pittsburgh seem to justify these hopes. The researchers succeeded to show (J. Exp. Med., Vol. 183, Jan. 1996, p. 283-287) that vaccinating mice with specifically supplied dendritic cells protects the animals from developing a specific tumour. Treated animals were able to destroy tumour cells which were implanted after the vaccination. In non-vaccinated animals, the cancer cells formed malignant tumours.
Moreover, the researchers observed a suprising effect in an additional experiment. Following vaccination and subsequent destruction of tumour cells, the animals were also protected from another tumour variant closely related to the first even though this second tumour type lacked the antigen used for the vaccination. The scientists presume, that in the course of destroying the first tumour, the animals’ immune system developed additional cytotoxic T-cells against other antigens of this tumour type. Some of the T-cells had probably specialized for antigens both tumour variants share.
A team of scientists directed by Dr. Ronald Levy from the Division of Oncology, Stanford University, California, has already started to treat patients with cancer of the lymphnode called B cell lymphoma. In January (NATURE MEDICINE Vol.2, No.1, 1996, p. 52-58) the researchers reported that two years after completion of the therapy, two of the four patients treated didn’t have any detectable signs of illness. Partial tumour regression was observed in the other two patients. According to the scientists, they didn’t observe side-effects of the treatment.
Various obstacles must be overcome to use dendritic cells as an anti-cancer vaccine. For instance, nobody can tell whether in certain cases vaccinating patients with their own antigens might arouse autoimmune reactions, in which the immune system attacks healthy tissue. The most challenging problem is the lack of appropriate antigens because specific antigens have not yet been identified for the majority of tumour types. Even so, Prof. Pezzutto is optimistic for the future. Since common immunological strategies, mainly using antibody-techniques, turned out to be inadequate for the identification of tumour specific antigens, cancer researchers have recently changed their approach. Certain biochemical techniques allowing the isolation of tumour cell fragments directly from tissue samples offer novel opportunity to identify new tumour specific antigens and characterize them more quickly.
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