Breaking down the microbiology world one bite at a time
Cancer therapies continue to be an ever-evolving area of research. To date, chemotherapy remains one of the most prominent treatment options. While effective against many types of cancer, chemotherapy often induces deleterious side effects. This is because chemotherapy not only kills cancer cells but also healthy cells. During treatment, cells in the hair follicles and the stomach lining are routinely damaged, causing common side effects of baldness and nausea.
In a recent report in Nature Communications, researchers in the lab of Mikhail Shapiro at Caltech have begun to address this issue by harnessing the power of tumor-fighting bacteria. These bacteria act as vehicles, driving cancer-killing machinery directly to cancerous tumors in the body. Importantly, these vehicles can be remote controlled to precisely dictate when and where the bacteria unload their cargo (Figure 1). This strategy has the potential to deliver effective cancer therapies directly to a patient’s tumor, with minimal impact on surrounding healthy cells.
To begin designing their vehicle, the researchers turned to a strain of E. Coli bacteria known as Nissle 1917. This bacteria is approved for probiotic use in humans, and when injected into the bloodstream, is able to find and inhabit tumors, where it thrives in the unique immunosuppressive environment. Throughout the rest of the body, the bacteria is fought off by the immune system. E. Coli Nissle 1917 was hence an ideal vehicle for their system, providing a one-way route directly to tumors, without any extraneous pit-stops along the way.
To equip the bacteria with cancer-fighting abilities, the scientists used genetic engineering to install cancer-killing cargo, called immune checkpoint inhibitors. These drugs are a prominent class of cancer therapy, and work by blocking checkpoint proteins on cancer cells from binding with their partners. This blockade turns on an immune response, the T cell response, enabling T cell killing of cancer cells (Figure 2). These immune checkpoint inhibitors have been used as stand-alone cancer treatments, but commonly induce off-target effects on surrounding tissues when administered to patients. By utilizing bacteria as a vehicle, the researchers aimed to achieve direct transport of these drugs to the cancer tissue, thereby reducing the risk of any off-target effects on surrounding cells.
The Remote Control
With the vehicle loaded and ready to fight cancer, the last item of business was to develop a remote system that could control exactly when and where the cancer drugs are released in the body. This would help to ensure that the drugs are only acting on cancer cells, and not other healthy cells nearby. To accomplish this feat, the researchers genetically installed a temperature-sensing unit onto the vehicle (the bacteria). This temperature-sensing unit ensured that the drug was released only when the bacteria reached 43 degrees celsius. Since the human body operates at 37 degrees Celsius, the drug remains inactive until it infiltrates the tumor and is activated with a “pulse” that briefly increases the temperature. For the source of the pulse, the researchers turned to ultrasound. Ultrasound is a well-known technology used to look inside the human body. It is widely used to check up on growing fetuses, detect heart problems, or look at other internal organs. When the ultrasound energy is focused, it can be used to send a high-intensity signal to very specific locations inside the human body, known as focused ultrasound (FUS). Here, the researchers leveraged FUS to send direct pulses to the tumor microenvironment. These pulses of energy can be fine-tuned to heat up tissue in the immediate area to very specific temperatures. Once the trigger temperature is reached (in this case, 43 degrees celsius), the bacteria release their cancer weaponry to start fighting cancer cells from directly inside the tumor.
Testing the remote-controlled vehicles on real tumors
The research team next tested how well their engineered system fought cancer in tumor-bearing mice. They first injected the engineered bacteria into the mice, allowing it to infiltrate the tumors over 2 days. They then pulsed the tumors with FUS to trigger the release of the anti-cancer drugs directly at the tumor sites. Excitingly, the researchers observed a major reduction in tumor growth in the mice that were treated with the engineered bacteria and FUS pulses. These studies showcased the potential for tumor-fighting bacteria to one day be employed as an effective cancer treatment in humans.
The future of tumor-fighting bacteria
This work combines the power of tumor-inhabiting bacteria, established cancer drugs, and ultrasound pulses to enable precise and effective delivery of cancer treatments directly to cancerous tumors. This technology has the potential to reduce the killing of healthy cells, a major side effect of current cancer treatments. Overall, tumor-fighting bacteria represent a promising strategy for the future of cancer therapy. Similar to this work, other research labs have developed bacterial magnets to target and fight cancer. In addition to treating cancer, these powerful bacteria-driven vehicles have the potential for many other biomedical applications down the road.
Link to original post: Abedi, M. H.; Yao, M. S.; Mittelstein, D. R.; Bar-Zion, A.; Swift, M. B.; Lee-Gosselin, A.; Barturen-Larrea, P.; Buss, M. T.; Shapiro, M. G. Ultrasound-Controllable Engineered Bacteria for Cancer Immunotherapy. Nat. Commun. 2022, 13, 1585. https://doi.org/10.1038/s41467-022-29065-2.
Featured image: Image made in BioRender by the author