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Engineered Bacteria Deliver Cancer Immunotherapy

E. coli

Escherichia coli, or E. coli, bacteria (National Institute of Allergy and Infectious Diseases)

13 Feb. 2020. A biomedical engineering team designed probiotic bacteria, which in lab mice are shown to deliver and enhance cancer immunotherapy drugs. Researchers at Columbia University in New York describe their engineered bacteria and findings in yesterday’s issue of the journal Science Translational Medicine (paid subscription required).

Treatments that invoke the immune system to attack tumor cells are a major advance in cancer therapy. Checkpoint inhibitors are a key mechanism in these immunotherapy treatments, which block proteins standing in the way of T-cells in the immune system from attacking cancer cells. Among the blocking proteins often targeted by checkpoint inhibitors are programmed cell death–ligand 1, or PDL1, and cytotoxic T lymphocyte–associated protein-4, or CTLA-4.

While cancer immunotherapies with checkpoint inhibitors are successful in attacking some tumors, they have drawbacks. One particular problem, say the authors, is their high rate of adverse side effects found in up to 70 percent of patients, including fatigue, skin rashes, endocrine disorders, and liver toxicity, usually linked to immune-related causes. In addition, immunotherapies can be more effective when given as combinations of treatments, which only increases the risks for adverse effects.

A team from the lab of Columbia biomedical engineering professor Tal Danino is seeking solutions with synthetic biology to make immunotherapies safer for cancer patients, as well as boost their effectiveness. Danino and colleagues alter the genetics of benign bacteria, making it possible to program microbial behavior much like integrated circuits. In the case of cancer treatments, some bacteria are found in tumor tissue, but do not cause infections, thus providing a potential mechanism for cancer drug delivery.

“We wanted to engineer a safe probiotic vehicle capable of delivering immune checkpoint therapies locally to minimize side effects,” says Danino in a university statement. “We also wanted to broaden the versatility of the system by producing a range of immunotherapeutic combinations, including cytokines that could further elicit anti-tumor immunity, but are otherwise difficult to systemically deliver because of toxicity concerns.”

The team led by doctoral candidate and first author Candice Gurbatri took advantage of earlier work with synthetic bacteria designed to lyse, or break down cell membranes, under specified conditions. The previous study, with many of the same authors, found bacteria could be programmed to carry drug molecules, then break apart releasing their cargoes. In this case, the Columbia team started with a benign, probiotic form of E. coli bacteria known as Nissle 1917 that grows inside tumors, to design a drug delivery vehicle.

Using computational models, the researchers altered the Nissle 1917 genome to design a synchronized lysing integrated circuit, or SLIC, strain to carry their drug cargoes. Those cargoes consisted of nanoscale fragments of anti-PDL1 and CTLA-4 checkpoint inhibitors. Tests in lab mice induced with lymphoma and colorectal cancer show a single injection of SLIC bacteria with nanoscale drug fragments into the tumors blocked PDL1 and CTLA-4 proteins, enabling T-cells in the mice to attack the tumors, to a greater extent than antibody injections alone.

The findings show the engineered SLIC bacteria activated more T-cells and caused more tumor shrinkage in the test mice. And as noted by Gurbatri, the treatments spared healthy tissue in mice. “We have demonstrated,” says Gurbatri, “that the engineered bacteria remain functional and localized within the tumor as the bacteria grow in mice for at least two weeks after treatment, preventing the microbes from affecting healthy tissue.”

In 2017, Danino and bioengineering professor Jeff Hasty at University of California in San Diego, founded the company GenCirq Inc. in Santa Barbara, California to commercialize their research in synthetic biology.  The company is developing synthetic lysis circuits for drug delivery.

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