When prostate cancer, one of the leading causes of cancer death among men, spreads in the body, it most often goes to the bone where it is particularly difficult to treat. Metastasis to the bone is implicated in over 70% of prostate cancer deaths. Prof. Zelig Eshhar, Head of the Immunology Department at the Weizmann Institute of Science, has now shown how a treatment that works on cancer in the prostate can be redirected to the bones.
The treatment, which was developed in Eshhar’s lab a number of years ago, is based on cells that have been engineered to combine two different types of weapons used by the immune system to fight invaders. Antibodies are best at recognizing foreign or altered molecules such as antigens on the outer walls of bacteria, viruses or cancer cells. T cells are better at killing unwanted cells, but not as adept at identification, especially of tricky cancer cells that may already have developed methods of evading detection by the immune system. By attaching an antibody-based structure designed to recognize specific cancer cells directly to a T cell receptor, Eshhar produced custom-modified cells, dubbed T bodies, which are proficient at both finding and killing cancer cells.
However, getting T bodies into the bone to treat metastasized cancer was another story. The cancer in this case is likely to be spread throughout the bone, in hard to reach places. When Eshhar’s research team first injected T bodies into immunodeficient mice in which human prostate cancer developed in the leg bones, they saw no real improvement, indicating to them that the cells were not getting to the cancer in significant enough quantities to have an effect.
To address the problem, the Weizmann team, which included Dr. Jehonathan Pinthus of Sheba Medical Center, Tel Hashomer, “preconditioned” the mice using one of two strategies already in use in some forms of cancer therapy: low doses of radiation or a specific chemotherapy drug. Both treatments cause some disruption in the bone marrow, the intended target of the T bodies. In response, the bone marrow sends out a chemical distress signal to the immune system. This signal not only alerts immune cells such as T cells to the danger, but assists them in homing in on the problem area and in passing through barriers that might otherwise prevent them from getting into the bone marrow tissue.
Mice treated with either therapy 24 hours prior to being injected with T bodies showed a significant drop in the tumor marker, PSA (an indicator of cancer levels), a reduction in the tumor load and prolonged survival. Because the method holds promise for treating disseminated cancers that are resistant to other forms of therapy, Eshhar hopes to move it into clinical trials in the near future.
Prof. Zelig Eshhar's research is supported by the M.D. Moross Institute for Cancer Research and the Crown Endowment Fund for Immunological Research.
Prof. Eshhar is the incumbent of the Marshall & Renette Ezralow Professorial Chair of Chemical & Cellular Immunology.
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