A groundbreaking cancer therapy that enlists bacteria and viruses as allies has been engineered by researchers at Columbia Engineering. The Synthetic Biological Systems Lab detailed in a recent study in Nature Biomedical Engineering how their innovative system conceals a virus within a bacterium that actively seeks out tumors,allowing it to evade the immune system and specifically target cancerous growths.

This novel approach leverages the natural ability of bacteria to locate and attack tumors, combined with the inherent capacity of viruses to infect and destroy cancer cells. Tal Danino, an associate professor of biomedical engineering at Columbia Engineering, spearheaded the team’s creation of the CAPPSID system (Coordinated activity of Prokaryote and Picornavirus for Safe Intracellular Delivery).Charles M.Rice, a virology expert at The rockefeller University, collaborated with the Columbia team.

“We aimed to enhance bacterial cancer therapy by enabling the bacteria to deliver and activate a therapeutic virus directly inside tumor cells, while engineering safeguards to limit viral spread outside the tumor,” says co-lead author Jonathan Pabón, an MD/PhD candidate at Columbia.

Researchers suggest that this technology, which has been validated in mice, represents the first instance of directly engineered cooperation between bacteria and viruses to target cancer.

The method combines the bacteria’s natural inclination to target tumors with the virus’s ability to infect and kill cancer cells. “By bridging bacterial engineering with synthetic virology, our goal is to open a path toward multi-organism therapies that can accomplish far more than any single microbe coudl achieve alone,” says zakary S.Singer, a co-lead author and former postdoctoral researcher in Tal Danino’s lab.

“This is probably our most technically advanced and novel platform to date,” says Danino, who is also affiliated with the Herbert Irving Comprehensive Cancer Center at Columbia University Irving medical Center and Columbia’s Data Science Institute.

Evading the Immune System

One of the primary obstacles in oncolytic virus therapy is the body’s immune response. Pre-existing antibodies against the virus, whether from prior infection or vaccination, can neutralize it before it reaches the tumor. The Columbia team circumvented this issue by encapsulating the virus within tumor-seeking bacteria.

“The bacteria act as an invisibility cloak, hiding the virus from circulating antibodies, and ferrying the virus to where it is needed,” Singer says.

“The bacteria act as an invisibility cloak, hiding the virus from circulating antibodies, and ferrying the virus to where it is needed,” Singer says.

Pabón emphasizes that this strategy is particularly relevant for viruses commonly encountered in daily life.

“Our system demonstrates that bacteria can potentially be used to launch an oncolytic virus to treat solid tumors in patients who have developed immunity to these viruses,” he says.

Targeting Tumors with Precision

The bacterial component of the system utilizes Salmonella typhimurium, a species known to naturally migrate to the oxygen-deprived, nutrient-rich environment inside tumors. Once inside the tumor, the bacteria invade cancer cells and release the virus directly into the tumor’s core.

“We programmed the bacteria to act as a Trojan horse by shuttling the viral RNA into tumors and then lyse themselves directly inside of cancer cells to release the viral genome, which could then spread between cancer cells,” Singer says.

By harnessing the bacteria’s tumor-homing capabilities and the virus’s ability to replicate within cancer cells, the researchers have developed a delivery system capable of penetrating and spreading throughout the tumor, overcoming limitations previously encountered with bacteria-only or virus-only approaches.

ensuring Safety Against Uncontrolled Infections

A significant concern with live virus therapies is preventing the virus from spreading beyond the tumor. The team addressed this by ensuring the virus requires a molecule only available from the bacteria to spread. Since the bacteria remain within the tumor, this essential component (a protease) is not accessible elsewhere in the body.

“Spreadable viral particles could only form in the vicinity of bacteria, which are needed to provide special machinery essential for viral maturation in the engineered virus, providing a synthetic dependence between microbes,” Singer says. This safety mechanism provides an additional layer of control, preventing the virus from spreading in healthy tissue even if it escapes the tumor.

“it is systems like these — specifically oriented towards enhancing the safety of these living therapies — that will be essential for translating these advances into the clinic,” Singer says.

Future research and Clinical Applications

This publication represents a significant advancement toward making this bacteria-virus system available for clinical use.

“As a physician-scientist, my goal is to bring living medicines into the clinic,” Pabón says. “Efforts toward clinical translation are currently underway to translate our technology out of the lab.”

Danino, Rice, Singer, and Pabón have filed a patent application (WO2024254419A2) with the U.S. Patent and Trademark Office related to this work.

The team plans to test this approach on a broader spectrum of cancers, utilizing diffrent tumor types, mouse models, viruses, and payloads, with the goal of creating a “toolkit” of viral therapies capable of sensing and responding to specific conditions within a cell. They are also assessing the potential of combining this system with bacterial strains that have already demonstrated safety in clinical trials.