A modified T cell receptor (Image credit: Caltech)

Arming immune cells against cancer

Modified receptors make an anti-cancer gene therapy safer.

T cells enable the immune system to recognize invading microbes and diseased cells while ignoring healthy cells. The ability of a T cell to recognize a specific microbe or diseased cell is determined by two proteins that pair to form its “T cell receptor.” The paired receptors are exported to the surface of the T cell, where they bind to infected or cancerous cells. Those T cells that produce receptors that bind healthy cells are eliminated during development.

T cells can generally distinguish between the body’s own cells and the cells of invading bacteria or other microbes. However, cancer cells are more difficult to identify because they are similar to healthy cells. Efforts to develop therapies that enhance the immune system’s ability to recognize cancer cells have had only limited success. One successful approach — known as T cell receptor gene therapy — modifies T cells to destroy cancer cells by arming them with a cancer-specific T cell receptor.

This technique produces T cells possessing two T cell receptors — the cancer-specific receptor and the one it had originally — so it is possible for proteins from the two receptors to mispair. This impedes the correct pairing of the cancer-specific T cell receptor, reducing the effectiveness of the therapy. More importantly, mispaired T cell receptors may cause the immune cells to attack healthy cells in the body, leading to autoimmune disease. To make T cell receptor gene therapy safe, the cancer-specific receptor must not mispair with the resident receptor.

Michael Bethune and colleagues now describe a new strategy to prevent T cell receptors from mispairing. The strategy involves altering the arrangement of particular regions in a cancer-specific T cell receptor to make a new receptor called a domain-swapped T cell receptor (or dsTCR for short). Like normal T cell receptors, the dsTCRs were exported to the T cell surface and were able to interact with other proteins involved in immune responses. Furthermore, T cells armed with dsTCRs were able to kill cancer cells and prevent tumor growth in mice. Unlike other cancer-specific receptors, dsTCRs did not mispair with the resident T cell receptors in mouse or human cells, and did not cause autoimmune disease in mice.

The findings of Bethune and colleagues show that the structure of the T cell receptor is unexpectedly robust, in that it still works even if it is modified. The next step is to study dsTCRs in more detail with the aim of optimizing them so that they might be used in human clinical trials in the future.

To find out more

Read the eLife research paper on which this eLife digest is based: Domain-swapped T cell receptors improve the safety of TCR gene therapy(November 8, 2016).
eLife is an open-access journal that publishes outstanding research in the life sciences and biomedicine.
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