Non-toxic bacterial therapy shows promise for targeting tumors

A University of Massachusetts Amherst-Ernest Pharmaceuticals team of scientists has made "exciting," patient-friendly advances in developing a non-toxic bacterial therapy, BacID, to deliver cancer-fighting drugs directly into tumors. This emerging technology holds promise for very safe and more effective treatment of cancers with high mortality rates, including liver, ovarian and metastatic breast cancer.

Clinical trials with participating cancer patients are estimated to begin in 2027. "This is exciting because we now have all the critical pieces for getting an effective bacterial treatment for cancer," says Neil Forbes, senior author of the research published recently in the journal Molecular Therapy and professor of chemical engineering at UMass Amherst.

"What we're trying to do is unlock the potential to treat late-stage cancers," adds lead author Vishnu Raman, who earned his Ph.D. in the Forbes Lab at the UMass Amherst Institute for Applied Life Sciences (IALS). "Bacteria naturally home to tumors and because this treatment is so targeted, it can treat some cancers without the harsh side effects you'd see with other systematically delivered therapies, like chemotherapy."

The new findings are the culmination of more than a decade of research by Raman, chief scientific officer of Ernest Pharmaceuticals, an IALS startup co-founded by Raman, Forbes and co-author Nele Van Dessel, a bioengineer who developed the bacterial delivery system as a post-doctoral researcher in the Forbes Lab.

The team has been finetuning the development of non-toxic, genetically engineered strains of Salmonella to target tumors and then control the release of cancer-fighting drugs inside cancer cells. In addition to sparing healthy tissue from damage, this cancer treatment platform is able to deliver orders of magnitude more therapy than the administered dose because the simple-to-manufacture bacteria grow exponentially in tumors. 

We were focusing on how to make this strain really safe and user friendly. The genetic engineering steps we took made this strain at least 100 times safer than anything that's been tried in the past." 

Vishnu Raman, lead author 

In this third-generation delivery strain, Raman figured out a way to control when the bacteria, after it has been intravenously injected, invades the cancer cells and delivers the therapy. This greatly improved the ability to target the tumors with higher concentrations of the drug therapy, while also making the treatment much safer."In the first-generation strain, we were basically relying on the bacteria's own brain to go find the tumor and deliver the therapy. But we couldn't control exactly when that was happening so there were risks associated with invading healthy cells, as well as pre-mature clearance of the bacteria before they colonize tumors, and we wanted to mitigate both risks," Raman says.

Early on in the research, the scientists discovered that it was the bacterial flagella – part of the cell that aids in movement – that enables the bacteria to invade cancer cells. So they engineered a genetic circuit in the bacteria that turns on the production of flagella with a simple, over-the-counter dose of aspirin. Without the turn-on switch provided by salicylic acid, the active metabolic product in the blood after a person takes an aspirin, the bacteria remain dormant in the tumor. 

"One core part of this technology is the controlled activation of flagella," Raman explains. "And the other core part is once the bacteria go inside cancer cells, we engineered them with a suicide circuit. So they rupture on their own and deliver the therapy inside the cancer cell."

In pre-clinical research with mouse models, the bacteria is injected intravenously. "It goes everywhere, but then the immune system rapidly clears the attenuated bacteria from healthy organ tissue within two days. The bacteria continue to grow exponentially only within tumors during that time. On the third day, we give an over-the-counter dose of aspirin to trigger the bacteria to invade the cancer cells and then deliver the therapy," Raman says. 

"We wanted to make it as simple as possible," he adds. "So the patient could get the infusion and three days later, at home, they just take an oral dose of aspirin."

The team is now focused on setting up the process to receive regulatory approval to begin clinical trials.

"We have seen a lot of growth in the area of microbial-based cancer treatment," Raman says, "and we are proud to be at the forefront of this field."