'Synthetic gene circuit' may improve effectiveness of cancer immunotherapy

Synthetic gene circuits that only trigger powerful, tumor-specific immune responses when they detect certain disease markers may help immunotherapies to fight cancer more effectively, according to a new study.

Researchers from the Massachusetts Institute of Technology (MIT) in Cambridge suggest that their artificial DNA-encoded circuits may help to overcome some of the problems that have dogged the translation of cancer immunotherapy from the laboratory to the clinic. They report their work in a paper that was recently published in the journal Cell.

Immunotherapy is a promising, albeit relatively new, type of treatment that enlists the patient's own immune system to fight the cancer.

There are several ways that it can do this. For instance, it can slow or stop the growth and spread of tumor cells, or it can help the immune system to destroy them more effectively.

Some immunotherapies have already been approved and are in clinical use. In 2011, for instance, the Food and Drug Administration (FDA) approved ipilimumab (Yervoy) for the treatment of advanced melanoma that cannot be removed through surgery. 

Overcoming limitations of immunotherapy

However, in their study paper, the MIT researchers explain how, "despite its success in several clinical trials, cancer immunotherapy remains limited" by several factors. These include: the "rarity" of markers that help to selectively target tumor cells; the fact that the tumor itself can suppress the immune system; and the toxic, "off-target" side effects that can arise when agents that stimulate the immune system are delivered to the whole body.

Despite the fact that some of these hurdles have been overcome and tests have been successful, the treatments only work for some patients. In some therapies, only 30 to 40 percent of patients respond, notes senior author Timothy Lu, an associate professor of biological engineering at MIT.

He and his colleagues have devised and tested an approach based on a synthetic gene circuit that can be inserted into cells in the affected part of the body using a virus.

When activated, the circuit triggers the production of proteins that promote several anti-cancer immune responses.

One response is the production of "surface T cell engagers" that instruct the T cells of the immune system to kill cancer cells. Another response produces an antibody called a "checkpoint inhibitor" that stops tumors suppressing the immune system.

The activated circuit also promotes the trafficking of immune system T cells to tumor sites and enhances the power of T cells to attack cancer cells.

Cancer-specific promoters

Perhaps the most interesting feature of the circuit is that, because it is an "AND gate," it only works in the presence of two cancer-specific markers, or "promoters." If only one marker is present, the circuit remains inactive; it requires the presence of both to produce the anti-cancer immune "outputs."

"Only when two of these cancer promoters are activated, does the circuit itself switch on," Prof. Lu explains.

The promoters can be markers that are naturally present in the cancer cells, but the team also tested synthetic promoters that appeared to boost the desired response even more strongly.

When they tested the circuit on cells in the laboratory, the team found that it could differentiate ovarian cancer cells from other types of cell, including noncancerous ovarian cells.

Also, when they tested the synthetic gene circuit in mice implanted with ovarian cancer cells, the team found that it triggered T cells to find and kill the cancer cells without harming surrounding noncancerous cells.

'Single package' of immunotherapies

Prof. Lu suggests that the future of immunotherapy is likely to lie in combining different therapy types. For example, one could knock out a signal that the cancer sends to suppress attack by the immune system, and if the tumor responds by increasing another signal, then that therapy could be combined with another that targets the second signal.

"Our belief is that there is a need to develop much more specific, targeted immunotherapies that work locally at the tumor site, rather than trying to treat the entire body systemically," he explains.

He notes that they also want to be able to combine several immunotherapies in a "single package, and therefore be able to stimulate the immune system in multiple different ways."

The researchers also found that they could readily adapt the circuit for targeting other types of tumor. 

"We identified other promoters that were selective for breast cancer, and when these were encoded into the circuit, it would target breast cancer cells over other types of cell."

Prof. Timothy Lu

The team now plans to test its synthetic gene circuit in other cancer models and to develop a method of insertion that is flexible and straightforward to produce and use.

They also hope to develop the circuit for use with other diseases, including inflammatory bowel disease, rheumatoid arthritis, and other autoimmune disorders.