Researchers at Columbia Engineering have developed a groundbreaking cancer therapy that harnesses the coordinated action of engineered bacteria and oncolytic viruses to target solid tumors. The system, called CAPPSID (Coordinated Activity of Prokaryote and Picornavirus for Safe Intracellular Delivery), was described in Nature Biomedical Engineering and represents the first example of directly engineered cooperation between bacteria and cancer-targeting viruses.
The platform was developed by Tal Danino's Synthetic Biological Systems Lab at Columbia Engineering in collaboration with virologist Charles M. Rice at The Rockefeller University. "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.
Overcoming Immune Barriers Through Bacterial Cloaking
One of the most significant challenges in oncolytic virus therapy is the body's immune response. When patients have pre-existing antibodies against therapeutic viruses from prior infections or vaccinations, these antibodies can neutralize the virus before it reaches tumors. The Columbia team addressed this limitation by concealing the virus inside 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," explains co-lead author Zakary S. Singer, a former postdoctoral researcher in Danino's lab. This bacterial cloaking mechanism allows the viral genome to bypass circulating antiviral antibodies and reach tumors even in immune mice.
The system uses Salmonella typhimurium, a bacterium that naturally migrates to the hypoxic, nutrient-rich environment found within tumors. Once the bacteria reach the tumor site, they invade cancer cells and release viral RNA directly into them, launching a potent oncolytic viral infection.
Engineered Safety Through Viral Dependence
To ensure the therapeutic virus remains confined to tumor tissue, the researchers engineered a sophisticated control mechanism. The modified virus requires a specific protease that can only be produced by the bacteria. Since the bacteria are localized to the tumor, the protease—and consequently the virus's ability to mature and spread—is also limited to that site.
"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 notes. This safeguard creates a second layer of control, ensuring that even if the virus escapes the tumor, it cannot spread in healthy tissue.
Co-lead author Jonathan Pabón, an MD/PhD candidate at Columbia, emphasizes the therapeutic goal: "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."
Dual Mechanism of Action
The CAPPSID system exploits complementary strengths of both microorganisms. The bacteria leverage their natural tumor-homing instincts to penetrate solid tumors, while the virus utilizes its ability to selectively replicate in and kill cancer cells. The researchers programmed the bacteria to act as a Trojan horse, shuttling viral RNA into tumors and then lysing themselves directly inside cancer cells to release the viral genome.
"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 could achieve alone," Singer explains. This approach addresses limitations that have historically constrained both bacteria-only and virus-only therapeutic strategies.
Clinical Translation Efforts
The technology has been validated in mouse models and shows promise for clinical applications. "As a physician-scientist, my goal is to bring living medicines into the clinic," says Pabón. "Efforts toward clinical translation are currently underway to translate our technology out of the lab."
The research team has filed a patent application (WO2024254419A2) with the U.S. Patent and Trademark Office related to this work. Looking ahead, they are testing the approach across a wider range of cancers, exploring different tumor types, mouse models, viruses, and therapeutic payloads.
The researchers are also evaluating how CAPPSID can be combined with bacterial strains that have already demonstrated safety in clinical trials, potentially accelerating the path to human testing. Their goal is to develop a comprehensive toolkit of viral therapies that can sense and respond to specific conditions inside cancer cells.
"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 concludes.
