Columbia Engineering say they have developed a new cancer therapy which pairs an engineered bacteria and an oncolytic virus to deliver a viral load directly into tumors to destroy them, while simultaneously evading the body’s immune defenses. The new therapy, described in Nature Biomedical Engineering, pairs the bacterium Salmonella typhimurium, with Senecavirus A (SVA), a virus that is known to preferentially infect and destroy cancer cells.
“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,” said co-lead author Jonathan Pabón, an MD/PhD candidate at Columbia.
Named the CAPPSIDE system (Coordinated Activity of Prokaryote and Picornavirus for Safe Intracellular Delivery), this new therapy works by pairing S. typhimurium’s ability to navigate to the anaerobic interior of tumors while carrying SVA, which then infects and kills the cancer cells from within. This effectively avoids the limiting effects of traditional viral therapies, immune neutralization. The Columbia team say this is first example of a directly engineered cooperative system between bacteria and oncolytic viruses.
“The bacteria act as an invisibility cloak, hiding the virus from circulating antibodies, and ferrying the virus to where it is needed,” explained Zakary S. Singer, PhD, a co-lead author and former postdoctoral researcher in the lab of Tal Danino, PhD, an associate professor of biomedical engineering at Columbia University who was the project’s leader.
The researchers engineered S. typhimurium to carry and transcribe SVA’s RNA genome inside the host cells. Once inside the tumor, the bacteria self-destruct to release the virus. To add another level of control and safety, the virus was modified to require a protease enzyme supplied only by the engineered bacteria. Without this enzyme, the virus cannot complete its life cycle or spread in healthy tissue.
“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 said.
To test the efficacy of this new construct, the Columbia team treated mouse models with subcutaneous small cell lung cancer (SCLC) tumors. The resulting data showed that CAPPSID cleared the tumors in fully immunocompetent animals and was able to bypass systemic antiviral antibodies. The system was also tested across a variety of mouse and human cell lines, where it also showed effective launch and spread of anti-tumor activity.
This new combination approach has the potential to overcome shortcomings of current bacterial and viral methods of attacking cancer cells. Bacteria can be engineered to deliver therapeutic molecules but often stay trapped within the tumor, and oncolytic viruses can lyse cancer cells but are often cleared by the immune system before reaching their targets.
“Being presumably the first example of direct engineered cooperativity between bacteria and oncolytic viruses, this work demonstrates bespoke interacting communities of programmable medicines,” the researchers wrote.
“This is probably our most technically advanced and novel platform to date,” noted Danino, who is also affiliated with the Herbert Irving Comprehensive Cancer Center at Columbia University Irving Medical Center.
The investigators say their development could also enhance the efficacy of other immunotherapies, including CAR T-cell treatments. By potentially increasing viral persistence and promoting tumor cell destruction even in immune-competent hosts, CAPPSID could enhance the local immune response and prime tumors for better outcomes when used in combination with other therapies.
Despite promising results, the system has limitations. The authors acknowledge that RNA viruses like SVA are prone to mutations and that future efforts may require more robust genetic safeguards. The CAPPSID system also needs to be evaluated across a broader range of cancer types and in clinical settings.
Future work on this therapeutic platform will including adapting it for different tumor models and payloads. In addition, RNA viruses like SVA are prone to mutations which may require developing safeguards against this. The team is also investigating ways to combine CAPPSID with bacterial strains that have already passed safety testing in clinical trials.
“As a physician-scientist, my goal is to bring living medicines into the clinic,” said Pabón. “Efforts toward clinical translation are currently underway to translate our technology out of the lab.”
