Domain-Swapping Technique May Increase Safety of Tumor-Specific T-Cell Receptor (TCR) Gene Therapy

The human body produces T cells to recognize and fight disease. Each T cell has a unique T cell receptor (TCR) on its surface that surveils small fragments of proteins presented by other cells. Upon detecting evidence of cancer or infection, a subset of T cells binds the diseased cells and orchestrates their elimination. When tumors and infections cannot be eradicated naturally, researchers employ immunotherapies to boost the immune system's effectiveness. By inserting genes encoding a tumor-specific TCR into a patient's T cells, researchers can engineer a large population of T cells to target tumor cells. This approach, called TCR gene therapy, has yielded clinical successes where conventional cancer treatments have failed. However, TCR gene therapy is not without risk. The introduced receptor can become tangled with the resident receptor in each engineered T cell, causing some of these cells to attack healthy cells. A new technique developed by Caltech researchers prevents this from happening, increasing the safety of TCR gene therapy. The technique, called domain swapping, was developed in the laboratory of Nobel laureate David Baltimore, President Emeritus and the Robert Andrews Millikan Professor of Biology at Cal Tech. A paper describing the findings was published online on November 8, 2016 in the journal eLife. The specificity of the TCR in each T cell results from the pairing of two protein chains--called an alpha chain and a beta chain--each of which has constant domains (shared among all TCRs) and variable domains (unique to each T cell). Normally, each T cell encodes only one alpha chain and one beta chain, which pair to form a single TCR. In TCR gene therapy, the introduction of genes encoding a tumor-reactive TCR results in T cells that express two alpha chains and two beta chains, with four possible pairings.
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