Engineered Gut Bacteria Boost Immunotherapy Efficacy in Mouse Models
核心洞察
Dana-Farber (搜索) researchers engineered harmless gut bacteria to deliver immune-stimulating payloads directly to tumors, enhancing anti-tumor activity.
In mouse models, bacteria carrying modified IL-18 (搜索) exhibited potent tumor-killing effects, leading to tumor-free status in 30-60% of treated animals.
The bacterial therapy outperformed PD-1 (搜索) inhibitors in some experiments and synergized with both PD-1 inhibitors and CAR NK-cells, improving cure rates.
Researchers at Dana-Farber (搜索) Cancer Institute have developed a novel cancer immunotherapy approach by engineering gut bacteria to stimulate the immune system within the tumor microenvironment. This innovative strategy, tested in mice, involves modifying harmless bacteria to carry immune-boosting proteins directly to tumors, potentially overcoming the immunosuppressive effects that often limit the effectiveness of conventional immunotherapies.
Hijacking Gut Bacteria for Targeted Immunotherapy
The study, led by Rizwan Romee, MD, and published in Nature Biotechnology, explores the ability of gut bacteria to infiltrate tumors. Researchers engineered a non-pathogenic strain of E. coli to display immune-stimulating proteins, such as a modified version of IL-18 (搜索), on their cell surfaces. These modified bacteria act as Trojan horses, delivering their immune-boosting cargo directly within the tumor microenvironment.
"This is an example of how out-of-the-box thinking can help spark a fundamental advance," said Romee. "Obviously, much more work is needed before this approach can be tested in patients, but we are very excited about the results we’ve seen so far."
Preclinical Efficacy in Mouse Models
When the engineered bacteria carrying modified IL-18 (搜索) were injected directly into melanoma (搜索) and colorectal tumors (搜索) in mice, the researchers observed significant tumor-killing effects. Between 30% and 60% of the mice became tumor-free months after treatment. Moreover, these mice remained cancer-free even when researchers attempted to re-establish tumors by injecting new cancer cells.
In systemic injection experiments, the bacterial therapy outperformed PD-1 (搜索) checkpoint inhibitors, resulting in a 60% cure rate. Combining the bacterial therapy with a PD-1 inhibitor led to a synergistic effect, curing 90% of the mice of their tumors.
Synergistic Effects with CAR NK-Cells
The research team also investigated the combination of their IL-18 (搜索)-carrying bacteria with CAR NK-cell therapy in a mouse model of mesothelioma (搜索), a cancer known to be resistant to CAR NK-cell treatment. The combination therapy demonstrated superior results compared to the standard, FDA-approved treatment for mesothelioma. The engineered bacteria also appeared to enhance the CAR NK-cells' ability to target tumor sites.
Future Directions
"We’ve developed a remarkable new platform that becomes like a new playground for designing novel cancer therapies because we can express a variety of different agents on the bacterial cell surfaces," said Romee. The team is now focused on expanding their preclinical studies and planning a clinical trial to evaluate the bacteria-based immunotherapy in human cancer patients. This innovative approach represents a promising avenue for enhancing the efficacy of cancer immunotherapies by modulating the tumor microenvironment.