Written by: Dana-Farber Editorial Team
Tumors are experts at dodging the immune system. This evasion not only helps to ensure their survival, but also has important implications for treatment. That’s because cancer therapies that harness the immune system, such as CAR T-cells or other engineered immune cells, are often rendered ineffective by the milieu that surrounds a tumor — known as the tumor microenvironment, or TME, which works to suppress the tumor-killing activities of patients’ own immune cells as well as immunotherapies.
Now, a new study in Nature Biotechnology led by Dana-Farber’s Rizwan Romee, MD, describes a novel strategy for overcoming the immunosuppressive effects of the TME. The approach — so far tested only in mice — involves co-opting harmless bacteria that normally live in the human gut and engineering them to carry immune-stimulating payloads on their outer surface. Like a Trojan horse, these bacteria can home to tumors and unleash their immune-boosting power, paving the way for the immune system and cancer immunotherapies to be more effective cancer killers.
A new study in Nature Biotechnology led by Dana-Farber’s Rizwan Romee, MD, describes a novel strategy for overcoming the immunosuppressive effects of the the tumor microenvironment, or TME.
“This is an example of how out-of-the-box thinking can help spark a fundamental advance,” said Romee, a co-senior author of the study together with Jiahe Li, PhD, of the University of Michigan. “Obviously, much more work is needed before this approach can be tested in patients, but we are very excited about the results we’ve seen so far.”
For the last several years, researchers have noticed that bacteria reside within the tumors of cancer patients. At first, they believed the microbes were simply contaminants, carried over on the surgical equipment used to excise the cancer cells. But that turned out not to be the case. Bacteria from the gut make their way into tumors and the surrounding TME, and even live and thrive there. What they are doing, however, is not yet understood.
“We decided to hijack this pathway,” said Romee. “This is one of those voilà moments in which we had an idea we thought was good, but it took us three years to prove it.”
Romee and his colleagues, led by first author and graduate student Shaobo Yang, set out to design their Trojan horse. They selected a harmless, non-pathogenic form of E. coli that has been deeply characterized in the laboratory and lacks the genetic capabilities of other, more wily bacteria that can develop antibiotic resistance. The researchers then engineered these bacteria, drawing on approaches developed by environmental scientists, and modified the microbes using scaffolding proteins that display different immune-boosting proteins on the bacterial cell surfaces. Once Romee, Yang and their colleagues were satisfied with the properties of these microscopic Trojan Horses, they tested them in a handful of mouse cancer models.
Notably, when bacteria carrying a modified version of IL-18 were injected directly into tumors, including melanomas and colorectal tumors, the researchers observed potent tumor-killing effects. Months after treatment, roughly 30-60% of mice were tumor free, and when the researchers sought to establish new tumors in these animals by injecting cancer cells, all of them continued to remain cancer-free.
In a second set of experiments, the research team treated two groups of tumor-bearing mice — one with the IL-18-carrying bacteria and another with a PD-1 checkpoint inhibitor (known in humans as pembrolizumab); this time, both groups were treated using systemic injections. Remarkably, the bacterial therapy outperformed the PD-1 inhibitor, with a 60% cure rate. And when they two treatments were combined, they appeared to work synergistically, with 90% of mice cured of their tumors.
The researchers also tested their IL-18 carrying bacteria together with a form of immune cell therapy, called CAR NK cells. In a mouse model of mesothelioma, which is refractory to CAR NK-cell treatment, the combination yielded better results than the standard, FDA-approved therapy for this form of cancer. Moreover, the engineered bacteria appeared to work like a GPS, helping the CAR NK-cells navigate to tumor sites.
“We’ve developed a remarkable new platform that becomes like a new playground for designing novel cancer therapies because we can express a variety of different agents on the bacterial cell surfaces,” said Romee.
Now, the team is working to expand their preclinical studies and hopes to launch a clinical trial to test the bacteria-based immunotherapy in human cancer patients.
