Researchers have developed bacteria-based personalized cancer vaccines that trigger the immune system to specifically target and eliminate cancer cells.
Scientists at Columbia University have modified probiotic bacteria to train the immune system to attack cancer cells, paving the way for a new type of cancer vaccine that utilizes the natural ability of bacteria to locate tumors. These vaccines can be tailored to each person’s individual tumors and may also help prevent future occurrences.
In experiments with mouse models of advanced colorectal cancer and melanoma, the bacterial vaccine significantly enhanced the immune response, effectively reducing or even eradicating both primary and metastatic tumors while sparing healthy tissue.
The results were published on October 16 in Nature.
This bacterial approach showed greater effectiveness compared to peptide-based therapeutic cancer vaccines previously tested in various clinical trials.
“A major benefit of our system is its ability to simultaneously activate multiple components of the immune system, leading to a strong antitumor response. This might explain its effectiveness in treating advanced solid tumors, which are usually challenging for other immunotherapies,” states Andrew Redenti, an MD/PhD student at Columbia’s Vagelos College of Physicians and Surgeons, who co-led the study.
“The overall outcome is that the bacterial vaccine manages to control or eliminate the advancement of primary or metastatic tumors and extends survival in mouse models,” adds Jongwon Im, a PhD student involved in the bacterial engineering development of the project.
This bacterial vaccine is customized for each individual tumor. “Each cancer is distinct—tumor cells contain unique genetic mutations that set them apart from healthy cells. By programming bacteria to guide the immune system towards these specific mutations, we can create more effective treatments that boost a patient’s own immune response to identify and destroy cancer cells,” explains Nicholas Arpaia, PhD, Associate Professor of Microbiology & Immunology, who led the research along with Tal Danino, PhD, an Associate Professor of Biomedical Engineering at Columbia.
“As we integrate more safety enhancements through genetic programming, we are nearing the point where we can begin testing this therapy in patients,” he also noted.
Bacteria in Cancer Treatment
The use of bacteria in cancer treatment dates back to the late 1800s when Dr. William Coley, a surgeon at New York Hospital, observed that some patients with inoperable tumors showed signs of tumor regression after being injected with bacteria. Today, bacteria are still utilized therapeutically, particularly for early-stage bladder cancer. Researchers have discovered that certain bacteria can naturally seek out and thrive in tumor environments, often triggering an immune response in the process.
However, this method does not typically allow for precise control over the immune response against cancer cells. “These characteristics alone generally do not provide enough power for bacteria to trigger immune reactions capable of annihilating a tumor, but they serve as a solid foundation for developing new cancer treatments,” notes Nicholas Arpaia, PhD.
Activating Multiple Immune System Components Safely
The new system is based on a modified strain of probiotic E. coli bacteria. The researchers made various genetic alterations to carefully regulate how these bacteria interact with the immune system to promote tumor destruction.
The modified bacteria carry protein targets known as neoantigens that are specific to the cancer being treated. These neoantigens educate the immune system to seek out and attack the cancer cells that display them, while preserving healthy cells that do not have these cancer-associated proteins. Thanks to the design of this bacterial system and the additional genetic adjustments, these bacterial therapies can also counteract the immunosuppressive tactics that tumors use to evade the immune response.
Additionally, these genetic modifications have been made to prevent the bacteria from avoiding immune detection. This safety feature ensures that the engineered bacteria can be readily identified and removed by the immune system if they do not locate the tumor.
In tests conducted on mice, the researchers observed that these precisely designed bacterial cancer vaccines recruited a broad range of immune cells to attack tumor cells while inhibiting responses that would typically suppress tumor-targeted immune reactions.
The bacterial vaccine also inhibited tumor growth in mice prior to tumor formation and stopped the regrowth of tumors in mice that had already been treated successfully, indicating potential for preventing cancer recurrence in patients who have undergone remission.
Customization for Each Patient
To create these microbial vaccines for humans, the first step would involve sequencing a patient’s cancer to identify its specific neoantigens using bioinformatics. Then, the bacteria would be tailored to produce large quantities of the identified neoantigens and other immune-modulating factors. When administered to the patient, the engineered bacteria would locate the tumors, establish themselves, and continuously release their therapeutic “payloads.”
Once activated by the bacterial vaccine, the immune system would be triggered to clear out cancer cells throughout the body and prevent metastasis.
Each immunotherapy is uniquely tailored for the individual, based on the specific neoantigens present in their tumors. “The time taken to initiate treatment will depend on how long it takes to sequence the tumor. After that, creating the bacterial strains is relatively quick. Manufacturing bacteria can be less complex than other vaccine platforms,” Danino points out.
The engineered bacteria are also designed to address cancer’s rapid mutation and evasion of treatment. “Because our platform permits the delivery of multiple neoantigens, it should theoretically be challenging for tumor cells to lose all of those targets simultaneously and escape the immune reaction,” explains Arpaia.
The researchers believe their strategy might be more successful than previous cancer vaccines. Although earlier attempts have induced immune responses against tumor neoantigens, they have failed to sufficiently modify the immunosuppressive tumor environment.
Arpaia concludes, “Bacteria can deliver higher concentrations of therapeutic agents compared to those that can be tolerated when distributed systemically throughout the body. In this case, we can target delivery directly to the tumor and more effectively manage how we engage the immune system.”
Further Information
The study is titled, “Probiotic neoantigen delivery vectors for precision cancer immunotherapy.”
All contributors include Andrew Redenti, Jongwon Im, Benjamin Redenti, Fangda Li, Mathieu Rouanne, Zeren Sheng, William Sun, Candice R. Gurbatri, Shunyu Huang, Meghna Komaranchath, YoungUk Jang, Jaeseung Hahn, Edward R. Ballister, Rosa L. Vincent, Ana Vardoshivilli, Tal Danino, and Nicholas Arpaia (all associated with Columbia University).
The research was backed by grants from the National Institutes of Health (R01CA249160, R01CA259634, U01CA247573, and T32GM145766), the Searle Scholars Program, and a Roy and Diana Vagelos Precision Medicine Pilot Grant.
Andrew Redenti, Jongwon Im, Tal Danino, and Nicholas Arpaia have filed a provisional patent application with the US Patent and Trademark Office related to this innovation.
