Improving immuno-oncology with electronics-inspired gene 'circuits'

Immunotherapy is promising, but identifying tumor-specific antigens for immuno-oncology treatments to target has proven challenging. Even in some of the most successful tests, such treatments only elicit responses in small proportions of patients, so multiple efforts are underway to improve immuno-oncology approaches. Now scientists at the Massachusetts Institute of Technology (MIT) believe they have figured out a way to identify cancer cells more accurately and stimulate the immune system more effectively.

The new approach—a gene circuit encoded in DNA—is inspired by a simple concept used in electronics known as "AND gates." The idea is that only when two inputs are present will the system be switched on and yield an output. To translate it into oncology: The therapy will only be activated when two cancer-specific biomarkers are detected.

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But this isn't just another combination therapy. With an ordinary combo treatment, each part of the drug could potentially work on its own, stimulating different aspects of the immune system to produce a systemic response.

By using the AND gate, the result is “much more specific, targeted immunotherapies that work locally at the tumor site” folded into a single package, which can at the same time “stimulate the immune system in multiple different ways,” said Prof. Timothy Lu, who heads the Synthetic Biology Group in MIT’s Research Laboratory of Electronics, in a statement.

Lu and his team at MIT developed synthetic markers, or “promoters,” encoded them into the circuit, and delivered them to cells in the affected body area using a virus. The promoters bind to certain proteins in tumor cells, then activate the circuit to express proteins that direct the immune system to kill the cells, plus a checkpoint inhibitor that lifts the brakes off T-cell activity.

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According to a paper the team published in the journal Cell, in an in vitro study, the circuit could differentiate ovarian cancer cells from other normal cells. A test in mice with implanted ovarian cancer also showed that it could trigger T cells to find and kill the cancer cells without harming other cells.

The circuit can be customized to different types of tumors. So the researchers, encouraged by the results, plan to test the therapy in different cancer models and to develop a delivery system that’s flexible and easy to manufacture and use. They also hope to expand the use of the approach to treat autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease.