Modified T-Cells Attack Tumors without Triggering Autoimmune Disease

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 (or TCR). 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.

Cancer cells are 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 - T-cell receptor gene therapy - modifies T-cells to destroy cancer cells by transfecting them with genes that encode a tumor-specific TCR.

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.

Investigators at the California Institute of Technology (Pasadena, CA, USA) devised a new strategy to prevent T-cell receptors from mispairing. They altered the arrangement of particular regions in a cancer-specific T-cell receptor to make a new receptor called a domain-swapped T-cell receptor (dsTCR). 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.

They reported in the November 8, 2016, online edition of the journal eLife that 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.

"As T-cells are produced, the immune system "auditions" them, eliminating those that react to healthy cells and selecting those with potential to recognize diseased cells," said first author Dr. Michael Bethune, a postdoctoral researcher in biology and biological engineering at the California Institute of Technology. "However, in T-cells engineered to express a second TCR, the introduced chains can mispair with the resident chains, resulting in TCRs with unintended and unpredictable specificity. These mispaired TCRs are not auditioned by the immune system, and some will target healthy cells causing autoimmunity."

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California Institute of Technology