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Some tumours thrive and spread because their cells send out a “don’t eat me” signal that makes the immune system leave them alone. Tumour cells that don’t send the signal are vulnerable to macrophages and other immune cells that can engulf and digest them.
Now, scientists from Columbia University in the city of New York have shown that it is possible to program bacteria to switch off the don’t eat me the signal and induce an anti-tumour immune response. The approach is an example of synthetic biology, an emerging field in which medical treatments promise to be more effective and specific than many molecular methods.
The payload itself was in the form of “an encoded nanobody,” and the bacterium that they used was a “non-pathogenic Escherichia coli strain.”
In a recent Nature Medicine paper, the researchers describe how they programmed bacteria and used them to shrink tumours and increase survival in a mouse model of lymphoma. They saw that the treatment not only shrank the tumours that they injected, but that distant, secondary tumours, or metastases, also responded.
“Seeing untreated tumours respond alongside treatment of primary lesions was an unexpected discovery,” says co-senior author Tal Danino, an assistant professor of biomedical engineering at Columbia University.
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Example of the abscopal effect
Danino states that what they witnessed was the first demonstration of an “abscopal effect” in cancer treatment that uses bacteria. “This means,” he adds, “that we’ll be able to engineer bacteria to prime tumours locally, and then stimulate the immune system to seek out tumours and metastases that are too small to be detected with imaging or other approaches.”
The approach is an example of synthetic biology, an emerging field in which medical treatments promise to be more effective and specific than many molecular methods.
In cancer therapy, the abscopal effect is the ability to provoke an anti-tumour response that destroys cancer cells far away from the primary target. Cells that send don’t eat me signals are common not only in tumours but also in healthy tissue. This presents a challenge to developers of immunotherapies that target the signal.
Danino and colleagues met this challenge by programming the bacteria so that they only released their signal-silencing payload when they could sense that they were within the “tumor microenvironment.”
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E. Coli with encoded nanobodies
The payload itself was in the form of “an encoded nanobody,” and the bacterium that they used was a “non-pathogenic Escherichia coli strain.”
In tumors, E. coli bacteria proliferate in necrotic cores, or pockets of dying cells. The team programmed the bacteria to be quorum-sensing, meaning that when they reached a certain population size, they died and released their payload of encoded nanobodies.
Danino states that what they witnessed was the first demonstration of an “abscopal effect” in cancer treatment that uses bacteria.
This strategy stopped the bacteria from penetrating other tissues and silencing the don’t eat me signals in their cells. However, it also left enough bacterial cells to start a new population, setting up repeating cycles of drug delivery in the tumor.
The team had already demonstrated such a drug delivery strategy in earlier work. In the new study, they showed that it can also selectively switch off don’t eat me signals in cancer cells by targeting CD47, the protein that sends the signal.
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Priming tumour-infiltrating T cells
The team suggests that the treatment works because it does two things. First, the presence of live bacteria induces local inflammation in the tumour. This summons the immune system.
The second thing that the treatment does is trigger immune cells, such as macrophages, to ingest the tumour cells because it switches off their CD47 don’t eat me a signal. In turn, this immune response primes “tumour-infiltrating T cells” that then migrate to distant metastases.
How Long Should You Wash Your Hands To Kill Germs? #bacteria https://t.co/FntW6fRc3r pic.twitter.com/jUg3le8XJF
— Sarah (@mtmamaco) July 4, 2019
The researchers suggest that the findings are “proof-of-concept for an abscopal effect induced by engineered bacterial immunotherapy,” and conclude: “Thus, engineered bacteria may be used for safe and local delivery of immunotherapeutic payloads leading to systemic anti-tumour immunity.”
They are already testing the safety and effectiveness of the method with other types of cancer in mice. After that, they hope to proceed to clinical trials in humans.