Genetic Engineering Creates an Immune System Cloak to Extend Bacterial Drug Circulation

Cancerous tumors are masters of disguise that fly under the radar of the human immune system, hiding to evade capture while growing and wreaking havoc on their host's health. However, when oncolytic (cancer-killing) bacteria are injected into a tumor, the immune system is alerted to the invader and destroys it, simultaneously attacking the tumor.

While previous research from Johns Hopkins University is successfully completing clinical trials, University of Rhode Island College of Pharmacy Assistant Professor Kaitlin Dailey is expanding on that work to more specifically target tumors that are difficult or impossible to access, especially those associated with pancreatic cancer-one of the deadliest types.

Dailey's lab is working with the microorganism Clostridium novyi-NonToxic, reengineering the already non-toxic bacteria through a first-of-its-kind synthetic and engineering biology platform for targeted gene editing. Those edits allow the bacteria to be injected into the bloodstream without causing sepsis, giving it a chance to access hard-to-reach tumors, and even metastatic cancer, regardless of where the tumor is in the body.

"By using a bacteria as our therapeutic mechanism, we can re-prime the immune system so that not only are we able to directly target the tumor, but we've effectively vaccinated against reoccurrence," said Dailey, who is also an affiliate with the Legorreta Cancer Center at Brown University.

And if we can target and dose a tumor through intravenous inoculation, the opportunity is then on the table to target not only a primary tumor, but also metastasis. Even if we can't get our therapeutic into a metastasis, or if there's a tumor that is very early in development, we've retrained the immune system to recognize it as a tumor and can elicit destruction of that tumor at very early stages."

Kaitlin Dailey, Assistant Professor, College of Pharmacy, University of Rhode Island

Dailey has seen success in targeting pancreatic cancer in mice trials. The next step is to help the bacteria circulate through the blood without the immune system recognizing and killing it before it reaches the targeted tumor. She and her team of graduate and undergraduate students are working on a genetic engineering platform to modify the bacteria to cloak it from the immune system until it reaches its target.

"It's a really common pharmacy concept: How do we increase the amount of time that our therapeutic is in circulation," Dailey said. "We want to safely increase the circulation time and subsequently the amount of bacteria that gets to the tumor site. That's where we are focusing our efforts right now because that's the most direct way to increase therapeutic efficacy."

Dailey's innovative work on the development and clinical translation of Clostridium novyi-NonToxic as an oncolytic bacterium represents a transformative approach to treating metastatic cancers, including pancreatic cancer and other solid tumors, and exemplifies the potential of translational synthetic biology in oncology. After showing she can modify the bacteria and still maintain its anti-cancer capacities, she hopes to one day advance to human clinical trials.

"It might sound ridiculous, but I genuinely am trying to cure cancer. There are a lot of steps along the way, but they're all under the umbrella of patient impact," Dailey said, noting that in the past she assisted in autopsies on patients who died of cancer. "You know cancer is bad, but then you see that patients have no diaphragm left because the tumor has taken over their entire abdomen, that they have no liver left and it's made them cirrhotic. Nothing prepares you for those experiences. And that's my guiding light: It's for those people. I couldn't help them, but I might be able to help the next. Our lab's goal and our mission is to get therapeutics to patients in an effort to cure cancer."