Researchers have developed a bacterial delivery platform that uses engineered Salmonella to transport viral genetic material directly into tumors, producing near-complete tumor eradication in mouse models of pancreatic and liver cancer while generating durable antitumor immunity.
The approach, published in Cell Reports Medicine, combines two areas of cancer research that have largely advanced independently: bacterial cancer therapies and oncolytic viruses. By using tumor-targeting bacteria to protect and deliver viral genetic material, the investigators hope to overcome one of the major limitations facing systemic viral therapies for solid tumors.
“We put these two together,” said Neil Forbes, PhD, professor of chemical engineering at the University of Massachusetts Amherst and senior author of the study. “Our Salmonella protects the viral genetic material and delivers it specifically inside tumor cells.”
Combining bacterial and viral cancer therapies
Oncolytic viruses have attracted considerable attention as potential cancer therapies because they can selectively infect tumor cells, destroy them, and stimulate antitumor immune responses. However, delivering viruses to internal solid tumors has proven challenging. “If you inject the virus into the blood, it gets cleared by the immune system,” Forbes said. “You get a few to the tumor, but not enough that it either makes an effect, or you put in so many that it’s toxic.” As a result, many oncolytic virus clinical trials for solid tumors rely on direct injection into accessible tumors, limiting their use in cancers located deep within the body.
Forbes and colleagues sought to address that challenge using engineered Salmonella, which naturally accumulates within tumors after intravenous administration. The researchers modified the bacteria to invade cancer cells and then release their cargo intracellularly specifically into tumors.
Rather than administering intact viral particles, the team loaded the bacteria with plasmids containing the complete genome of an oncolytic virus. After entering tumor cells, the bacteria release the viral genetic material, which then migrates to the nucleus and begins the viral replication process.
“The Salmonella get inside the cancer cell, they release the genomic material that then traffics to the nucleus of the cancer cell, where the virus starts to work like it naturally does,” Forbes said. The virus subsequently replicates, forms infectious viral particles, destroys the host cancer cell, and spreads throughout the tumor microenvironment.
Strong responses in pancreatic and liver tumors
The researchers evaluated the platform in mouse models of pancreatic and liver cancer, using animals with fully functional immune systems. “We use mice with full immune systems because that’s the whole idea here—we’re going to trigger an immune response,” Forbes said.
The results were striking. According to Forbes, treatment produced near-complete tumor eradication in most animals. The study also demonstrated that intravenous administration was sufficient to achieve therapeutic activity. Tumor responses following systemic delivery were comparable to those observed with direct tumor injection.
“We showed that we can get the same tumor reduction from an IV injection as we do from an intratumoral injection,” Forbes said. The finding suggests that the bacterial carrier successfully protected the viral payload in circulation and delivered it to tumor sites after systemic administration.
Evidence of durable antitumor immunity
Beyond direct tumor destruction, the investigators found evidence that the therapy generated a robust adaptive immune response against cancer cells.
To test whether immune memory had developed, the researchers harvested splenocytes from treated mice and transferred them into naïve animals that had never been exposed to tumors, Salmonella, or the virus. The recipient animals were subsequently challenged with tumor cells. “In 100% of the cases they did not take any tumors,” Forbes said. “We’ve generated this antitumor immunity against the tumor.” Importantly, the protection appeared to be directed against the cancer itself rather than against the bacterial or viral components of the therapy.
According to Forbes, the findings suggest the treatment could potentially help prevent metastatic disease or tumor recurrence after elimination of the primary tumor.
Addressing safety concerns
The use of live bacteria as a cancer therapy has historically raised concerns about toxicity and safety. To address those issues, the researchers engineered additional modifications into the Salmonella strain.
During development of the platform, the team removed bacterial antiviral genes that would otherwise interfere with viral production. Unexpectedly, those modifications also appeared to improve safety. “We found that those Salmonella we made with those deletions end up being much safer,” Forbes said.
The modified bacteria were cleared more efficiently from normal tissues and were more susceptible to elimination by macrophages, reducing the likelihood of persistent infection.
While treatment was not entirely free of side effects, Forbes described the observed toxicities as relatively mild. “The side effects from any delivery of bacteria are going to be like standard flu-like symptoms,” he said. “We’re talking about late-stage cancer patients where the prognosis is usually really poor.”
Expanding the therapeutic toolbox
Although the current work remains preclinical, Forbes believes the study highlights the broader potential of engineered bacterial therapies as programmable platforms for cancer treatment. “I think that bacteria have massive potential to treat disease, specifically cancer, in ways that we can’t do with small molecules,” he said.
Unlike conventional drugs, bacteria can be engineered to carry multiple therapeutic payloads, control where treatment occurs and coordinate several biological mechanisms simultaneously.” It is very plastic, highly modifiable, very flexible,” Forbes said. “We can control timing, we can control localization, so we have a lot of power.”
Forbes hopes the findings encourage more researchers to explore bacterial approaches alongside other forms of immunotherapy and targeted therapy. “I want people to see the massive ways that we could treat cancer,” he said. “There are a lot of possibilities that I think are untapped.”
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