Gene therapy with a T cell receptor targeting a single cancer-specific point mutation is being used to eradicate large solid tumors, according to a recent study in the Journal of Clinical Investigation.1
This approach uses T cell receptors, which scan the surfaces of all body cells for antigens. Antigens are protein fragments and are usually derived from pathogens. If T cells recognize the foreign origins of antigens, the T cells will kill the cells that have the antigens. This research sought to use T cells to target mutant proteins produced by cancer cells.
Typically, T cells in tumors are usually inactive and therapeutically almost useless, explained Matthias Leisegang, PhD, of the Institute of Immunology in Berlin, Germany, and lead author of the study.
“But it is possible to obtain fresh T cells from a patient’s blood and transfer tumor-specific T cell receptors into them,” said Leisegang. “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.”
The importance of preliminary animal studies to the success of mutation-specific therapies was shown by this work. Tests in cell cultures showed that some mutations appeared to be appropriate targets, but those can have disappointing results in the real context of a patient’s body. A humanized mouse model was able to analyze the antigens and clearly distinguish between good and bad T cell targets.
“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.
The patient individualized treatment is not yet ready for use in humans, despite successes in mice, emphasized Leisegang. While clinical tests of similar methods are ongoing, they are targeting only antigens without mutations and may have T cells also attacking healthy tissues. Fewer side effects would result from targeting cancer-specific mutations. However, the new method is also much more complex, as it must be individualized for each patient.
1. Leisegang M, Kammertoens T, Uckert W, Blankenstein T. Targeting human melanoma neoantigens by T cell receptor gene therapy [published online ahead of print January 25, 2016]. J Clin Invest. doi:10.1172/JCI83465.