The T cell receptor on T cells might recognize antigens derived from mutated proteins in cancer cells. Once a foreign “non-self” antigen is detected, the T cell will kill the cancer cell. Credit: Matthias Leisegang.
T cell therapies with less side effects. An international team has successfully modified immune cells to recognize and specifically target tumor cells in mice. Cancer treatments based on the findings would likely have fewer side effects than standard therapies. Although T cells migrate into tumors and recognize antigens, the defense mechanism seems to fail during the formation of tumors. T cells in the tumors are usually inactive and therapeutically almost useless. “But it is possible to obtain fresh T cells from a patient’s blood and transfer tumor-specific T cell receptors into them,” Leisegang says. “The transfer of the T cell receptor is carried out using genetically modified and functionally inactivated viruses that can insert their genetic material into millions of T cells. When these modified cells are infused into the patient, they are able to fight the tumor.”
Hans Schreiber’s research team at the University of Chicago analyzed gene therapy with T cell receptors in mice. They identified a mutation that occurred in all regions of the tumor and also found its way to the surface as an antigen. T cells were taken from the mouse, armed with a T cell receptor that would target this antigen, and were then administered to the animal. The cells almost completely destroyed the tumor. However, T cell therapy had to be combined with local radiation to eliminate the tumor in the long term.
Now, the Berlin researchers show the importance of preliminary animal studies to ensure the final success of mutation-specific therapies. The research group of Thomas Blankenstein and Wolfgang Uckert were able to analyze the antigens and clearly distinguish between “good” and “bad” T cell targets by using a humanized mouse model. “This means that we have developed an animal model to test the therapeutic suitability of T cell receptors and antigens, which is an important prerequisite for clinical applications,” Leisegang said.
Although the efforts of Matthias Leisegang and his colleagues to train immune cells to fight cancer by targeting mutations were successful in mice, he emphasized that the patient individualized treatment is not yet ready for use in humans. Clinical tests based on similar methods are currently underway, but so far targeting only antigens without mutations. In those cases, T cells may also attack healthy tissue. Targeting cancer-specific mutations, the researchers say, would cause fewer side effects. But the new method is also much more complex because it has to be individualized for each individual patient. With support from the BIH, the groups are now working with other teams at the MDC and Charité to apply their research to the clinic. https://insights.mdc-berlin.de/en/2016/02/gene-therapy-t-cells-target-mutations-to-fight-tumors/
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