Injecting mice with engineered, live bacteria has been shown to shrink cancer tumors. With trials underway to bring this immunotherapy solution to the clinic, Synlogic is paving the way for synthetic biology and living medicines to transform the landscape of healthcare and medicine.
In 1890, William Coley, a young cancer surgeon, was distraught. One of his first patients had just died of widespread cancer, despite Coley amputating his forearm. Determined to do something about it, Coley came across an intriguing solution.
The medical literature of the day hinted that dozens of cancer patients had a regression of their disease while they were also carrying a separate infection. Could the body, in fighting against a pathogen, also be battling a tumor? After injecting bacteria into a patient who showed tumor shrinkage, Coley’s toxin, as it came to be known, was tried out on nearly a thousand patients to varying degrees of success.
Controversial at the time, and almost forgotten in the age of chemotherapy and radiotherapy, cancer immunotherapy (also known as immuno-oncology) has been rediscovered by modern-day researchers, who are leveraging the incredible power of our own human immune system to bring new cancer treatments to the mainstream.
“William Coley is the grandfather of immunotherapy,” says Aoife Brennan, CEO of Synlogic, a synthetic biology company on the cusp of using live, engineered bacteria as a cancer drug in humans. A new study from the Synlogic team shows that injecting cancerous mice with live, engineered bacteria can cause long-term remission of certain cancer types.
“Many of the observations [Coley] had we are now rediscovering when we look at predictors of response to immunotherapy,” Brennan told me. “We’ve really started to understand that stimulating an immune response can be an appropriate way to treat cancer.”
Cancer immunotherapy, then and now
Cancer immunotherapy has come a long way since Coley’s day. Treatment options are now available that use antibodies to target specific proteins of cancer. These antibodies come as drugs, vaccines or immune cell infusions, and they work to enable the body’s natural defenses to fight cancer normally.
We also now know that tumors come in a wide range of forms. Some are ‘hot’ and some are ‘cold’, but we’re not talking about temperature here.
A hot tumor shows signs of inflammation, meaning that the immune system is alert to the tumor and has dispatched T-cells to attack it. But they can get war-weary due to the presence of the body’s checkpoint system, which is there for a good reason: to stop immune cells from going too strong on the offensive. Tumors can trick this checkpoint system into ignoring cancer. Drugs known as checkpoint inhibitors can block these proteins, letting T-cells proceed with their attack.
The problem is that few tumors are hot. Cold tumors are more common and more deadly, including breast cancer, prostate cancer, and pancreatic cancer. How can we get the body to attack cold tumors, too? Here’s where a living therapeutic system comes in.
“We have this great platform to stimulate an immune response,” Brennan says of the method Synlogic is pioneering to treat multiple forms of cancer. “Our immune systems evolved to recognize pathogens and have a number of pathways to deal with them. We had this concept: what if we could engineer bacteria to stimulate the right immune responses and multiple different pathways in the same way an infection would?”
The Synlogic live therapeutic solution
To take advantage of both biotechnology and the human body’s amazing immune capabilities, companies like Synlogic work at the intersection of biology and engineering—a field we call synthetic biology—to make useful biological applications. Using tools like gene editing and machine learning, synthetic biology researchers can, for example, develop a strain of bacteria that is stripped down to its bare essentials—you can think of it as a chassis, like the basic framework of a car. They can then engineer that chassis to include specific, desirable components, and ultimately fine-tune its behavior and functions.
In Synlogic’s case, they are using these techniques to design living therapeutics programmed to treat disease in new ways. To develop a cancer therapy, Synlogic’s solution is to inject living bacteria directly into a tumor to stimulate the body’s defenses to act right where they’re needed, not unlike Willam Coley did all those years ago. The best part? Synthetic biology can be used to engineer bacteria that elicit an immune response but pose no danger of causing disease themselves, reducing a danger Coley first recognized in 1891.
“Instead of using an attenuated [weakened] pathogen,” Brennan continues, “we are taking non-pathogenic bacteria and engineering in certain pathways and effectors that are important in the immune response. The first strain we’ve taken forward, to prove the pathway is viable, is called SYNB1891, in honor of William Coley and the year he injected live bacteria into a patient’s tumor.”
To make their SYNB1891 strain, Synlogic started with a non-pathogenic version of E. coli known as the Nissle chassis. To it, they introduced a STING agonist from a different microorganism, Listeria. The STING agonist boosts the body’s defense pathways and is a potent inhibitor of pancreatic cancer. It is further engineered so that it only works in the specific anaerobic environment of the tumor it’s been injected into.
Once inside the tumor, these therapeutic bacteria can live for up to 10 days, acting like a flare that alerts the body’s immune cells to come and investigate what’s going on. When they arrive, they engulf the bacteria with the STING agonist, which then triggers the person’s immune system to target and attack the tumor itself.
An effective treatment in mice
The publication in Nature Communications highlights the effectiveness of Synlogic’s technique in mice and points to its potential for human therapeutics.
“We’ve looked in animals and shown that we can cause tumor regressions, even in cold tumors,” says Brennan of the treatment. “We can stimulate an immune response in mice that is tumor-specific and that causes complete remission.”
In fact, the study shows that around one-third of mice with melanoma showed complete tumor rejection after tumors were injected with SYNB1891. The combined effect of the STING agonist and the bacterial chassis was crucial. Injection of the STING agonist alone led to 10% long-term survival of mice, but SYNB1891 injection increased that to 40%. With lymphoma, the effects were as high as 80% tumor rejection depending on the dose.
The treatment also appeared to provide mice with long-term protection in the form of immune memory. When cured mice were reexposed to the same tumor at least 60 days after the treatment, they remained tumor-free.
Promisingly, treatment of human cells with SYNB1891 led to a similar stimulation of the immune response as seen in mouse models, providing a positive indication that success in mouse models can be translated to treatments in people.
SYNB1891 is now in phase one clinical trials. The first patients that Synlogic is working with are those with cancers that can be accessed close to the skin surface, including breast cancer, melanoma, and lymphoma. The phase one study will slowly increase the dose of the live therapeutic, ensuring safety, primarily, as well as clinical effectiveness.
“We’ve worked with the FDA to carve a path for this kind of approach and are now treating patients who have tumors with the engineered bacteria,” Brennan said.
An exciting prospect is the potential for treating a broad spectrum of tumors, regardless of the type, providing a more off-the-shelf solution that does not require the complexities of personalized treatments.
“If you have the right immune cells in the vicinity and overcome some of the cloaking mechanisms that tumors use to evade the immune response,” Brennan says, “we can essentially take the brake off the immune system and allow it to do its thing with the cancer.”
The outlook for live therapeutics
Where William Coley’s pioneering experiments were met with skepticism in the late nineteenth century, Synlogic has picked up the mantle and is paving the way for the acceptance of live therapeutics as not just a viable option, but an effective one that can broaden and enhance the landscape of medicine.
“The challenge,” according to Brennan, “is to show that this is a drug development approach that has legs.”
With promising preclinical evidence and clinical trials underway for this synthetic biology approach, we hope it’s just a matter of time before this proof of concept becomes a life-saving treatment.
Follow me on Twitter at @johncumbers and @synbiobeta. Subscribe to my weekly newsletters in synthetic biology. Thank you to Peter Bickerton for additional research and reporting in this article. I’m the founder of SynBioBeta, and some of the companies that I write about—including Synlogic—are sponsors of the SynBioBeta conference and weekly digest. Here’s the full list of SynBioBeta sponsors.2