Synthetic gene Therapy for Cancer

A new synthetic gene circuit developed by researchers from the Massachusetts Institute of Technology (MIT) in Cambridge, MA, may improve the effectiveness of cancer immunotherapy.

Tumor-specific immune responses are actuated when synthetic gene circuits sense specific disease markers. This team believes they’ve discovered a way to make those responses more effective, by using artificial DNA-encoded circuits to overcome some of the problems that have impaired cancer immunotherapy.

Although relatively new, immunotherapy holds great promise by boosting one’s own immune system to fight cancer more effectively, by slowing or stopping the growth altogether. Since the FDA approved ipilimumab (Yervoy) immunotherapy in 2011 for advanced non-surgical melanoma, more approvals are on the way. The MIT scientists say that while there has been success in many clinical trails immunotherapy is still new and limited. Just some of the hurdle yet to be solved are: finding the markers needed to target tumor cells, tumor immune system suppression, and toxic side-effects to the rest of the body.

Professor Timothy Lu and his team created a virus based “synthetic gene circuit” that can be placed into the cancer cells at a specific location where they stimulate production of proteins that activate several anti-cancer immune responses. Lu has only been able to solve some of the problems above. However, the treatments do work on 30-40% of the patients, which is an enormous step in the right direction.

One major positive response is of "surface T cell engagers" production; they tell the immune system T- cells when and where to kill cancer cells. They also create production of checkpoint inhibitor antibodies which prohibit tumors from depressing the immune system. Activation of this advanced circuit aids in direction of specific T cells to the correct tumor site, thereby enhancing their ability to attack cancer cells.

Prof. Lu says that one of the most interesting feature of these circuits is that it only works when there are two cancer-specific markers, or "promoters" present. If there’s only one marker, the circuit remains closed. The markers can be present naturally or the synthetic they developed; both boosted the desired response.

In fact, the team was able to differentiate ovarian cancer cells from noncancerous cells. When they tested implanted ovarian cancer cells in mice with the synthetic gene circuit, they discovered it triggered T cells kill cancer cells without harming noncancerous cells.

Prof. Lu and his team hope that the future of immunotherapy will be in combining different therapy types. They believe that there’s a great need for more specific targeted immunotherapies that work with the tumor locally as opposed to treating the whole body. They would also like to combine several immunotherapies into one package, in order to boost the immune system in multiple different ways. Along those lines, they were able to identify specific promotors for breast cancer, that when introduced into the circuit, they only targeted breast cancer cells. Now the plan is to experiment with other type of cancer to develop easy to use gene circuits for them.