A gene circuit encoded in DNA developed by MIT researchers shows promise for targeted immunotherapy.

A lot of attention is being paid to the development of immuno-oncology treatments, but successes are slow in coming. Identifying specific antigens for specific tumors is difficult. Even when targets are identified, positive responses to therapies may only occur in a small percentage of patients with that type of cancer.

Researchers at the Massachusetts Institute of Technology (MIT) believe they have found a method to more accurately identify cancer cells and more effectively stimulate the immune system to attack them.

Their approach involves the use of a gene circuit encoded in DNA that was inspired by AND gates, which are common in electronic circuitry. With AND gates, two signals must be received before the system will be switched on and an output generated. In the new MIT approach, two cancer-specific biomarkers must be detected before a drug will be activated.

What the approach is not is a combination therapy, in which two different drugs or a drug and a device that can work independently and stimulate different parts of the immune system, are administered simultaneously. The new approach developed at MIT is much more specific, with targeted immunotherapies that work locally at the tumor site stimulating the immune system in different ways, according to Prof. Timothy Lu, Head of the Synthetic Biology Group in MIT’s Research Laboratory of Electronics.

The researchers developed synthetic markers, or promoters, that were then encoded into a circuit and delivered to tumor cells using a virus. Once bound to target proteins in the tumor cells, the promoters activated the circuit, resulting in the expression of both proteins that direct the immune system to kill the cancer cells and a checkpoint inhibitor that limits T-cell activity. In one study, the scientists showed that the circuit could differentiate between ovarian cancer cells from other normal cells. They also showed that in mice, T-cells were activated and killed the cancer cells without harming healthy cells.

One attractive feature of this approach is that the circuit can be designed to target different types of tumors. The MIT team is currently investigating the application of the approach to other cancer models. They also hope it will be effective for the treatment of autoimmune diseases, including rheumatoid arthritis and inflammatory bowel disease. In addition, they are working to develop a manufacturable and easily deliverable version for practical use.