A research team at MIT has used synthetic biology to create a gene circuit that triggers the immune system to attack cancer when it first detects the signs of the disease.

The circuit works by only activating the immune response when two specific cancer biomarkers are detected. The new study was published in the journal Cell this week and represents an exciting step forward for synthetic biology and cancer research.

The potential of immunotherapy

Cancer is primarily a disease of aging caused by genomic instability, and immunotherapy is widely regarded as having great potential in combating this disease. Anyone interested in aging should be equally interested in cancer research, as the two are closely linked, and if we are to hope to live longer lives, a solution to cancer must be found.

Approaches such as blocking checkpoint inhibitors are also promising. Cancer cells use checkpoint inhibitors to hide from the immune system and appear to be healthy cells to escape destruction. Blocking the checkpoint inhibitor allows the immune system to see the cancer and attack, and this approach is showing great potential in tests.







Unfortunately, despite some successes, immunotherapy is still limited by the lack of tumor-specific antigens – substances that alert the immune system to the presence of a particular type of cancer. Another problem is the toxicity of certain therapies, which can do more harm than good.

Because cancers are all genomically unique, this presents a huge problem for traditional one-size-fits-all approaches, and, in some cases, only 30 to 40 percent of patients respond to a treatment. One recent immunotherapy approach gets around this by creating a customized cancer vaccine matched to the unique genetic makeup of a patient’s tumor.

Another problem with cancer is that it can often adapt to an approach. For example, if a therapy knocks out a checkpoint inhibitor signal the cancer can sometimes respond by using a backup signal to survive. This has led researchers to explore the use of combination immunotherapies to combat the disease and encourage the immune system to attack.

Creating locally targeted multiple-payload immunotherapies

The research team in this study believes that there is a need to develop more specific and localized immunotherapies instead of treating the body systemically. They are also interested in including multiple immunotherapies in a single package that can stimulate the immune system in several ways rather than just one, in case the cancer adapts to treatment.







To achieve this, Dr. Lu’s MIT team has created a gene circuit encoded in DNA which is designed to detect cancerous and noncancerous cells. The circuit can also be customised to respond to different kinds of tumors and uses the same principle that AND gates in electronics use. These biological AND gates only switch on the circuit when the two specified inputs are detected.

Cancer cells are genomically different to normal healthy cells and have a different gene expression pattern. The researchers created synthetic promoters, which are DNA sequences that initiate gene expression only in cancer cells, and they are similar to the method used in the CellAge project we hosted last year at Lifespan.io.

This customised circuit is delivered to local cells in the affected region of the body using gene therapy. The synthetic promoters then bind to target proteins that are present only in tumor cells, causing the promoters to activate.

The DNA circuit itself only switches on when two of these cancer promoters are activated. This means the circuit can specifically target tumors with higher accuracy than existing therapies, and it is safer because it requires two cancer-specific inputs to activate the circuit.

When the circuit is activated, it secretes proteins that attract the cells of the immune system and directs them to attack the tumor cells. This includes surface T cell engagers, which direct the T Cells to destroy the cancer cells. Additionally, the circuit expresses a checkpoint inhibitor that removes the barrier to T cell activity, allowing it to spot the cancer cells and move in for the kill.







When the researchers tested the circuit during in vitro studies, they discovered it was able to detect ovarian cancer cells hiding among healthy ovarian cells and even other cell types.

The next step was to test the system in mice implanted with ovarian cancer cells; the research team showed that the circuit could trigger T cells to seek and destroy the cancer cells without harming the healthy cells around them.

Lastly, the team demonstrated that the circuit could be easily converted to target other kinds of cancer cells by changing the required inputs to trigger it. They identified promoters that were selective for breast cancer, which allowed the immune system to focus on that type of cancer over others.

The researchers are ambitious; they are not just setting their sights on cancer, they are keen to see their approach adapted to combat other diseases, such as rheumatoid arthritis, inflammatory bowel disease, and other autoimmune diseases.

Conclusion







The next step for the team is to test the circuit on other types of cancer and develop a circuit delivery system that is easy to use, adapt and manufacture. This could greatly increase the cost-effectiveness of the therapy, and with the cost of healthcare and these emerging technologies being a common concern, this is good to hear. The ability to mass produce such a flexible system at an affordable price is exactly what is needed to ensure that everyone has access to life-saving therapies.

Literature

[1] SynLior Nissim9, Ming-Ru Wu9, Erez Pery, Adina Binder-Nissim, Hiroshi I. Suzuki, Doron Stupp, Claudia Wehrspaun, Yuval Tabach, Phillip A. Sharp, Timothy K. Lu10,’Correspondence information about the author Timothy K. Lu (2017). Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy. Cell DOI:10.1016/j.cell.2017.09.049