Bacteria producing checkpoint inhibitors shrink tumors in mice

A team of scientists has engineered bacteria to deliver cancer treatments that rev up immune cells directly to tumors.

In studies in mice, the team, led by Tal Danino and Nicholas Arpaia of Columbia University, found that the bacterial shuttles can shrink tumors with just one injection and that treating one tumor stimulates the immune system to kill distant tumors (Sci. Trans. Med. 2020, DOI: 10.1126/scitranslmed.aax0876).

“The beauty of this approach is that the mechanism by which these agents work is not necessarily by directly killing the tumor,” says Dmitriy Zamarin, a Memorial Sloan Kettering Cancer Center oncologist who studies viruses as cancer therapeutics but was not involved in the new study. “It’s really through the activation of the tumor-specific immune response.” He thinks the systemic immune response makes the work promising.

To create the new anticancer system, the research team engineered probiotic Escherichia coli Nissle 1917 to produce nanobodies—segments of antibodies—that block a molecule on cancer cells called PD-L1 or CTLA-4 on immune cells. These are checkpoint molecules, and blocking them overrides a signal produced by cancer cells to tamp down the immune response. By blocking PD-L1 and CTLA-4, the nanobodies make immune cells better cancer killers.

To release the nanobodies, graduate student Candice Gurbatri says they integrated a genetic circuit that prompts the bacteria to self-destruct when they reach a critical concentration inside a tumor. Gurbatri, who led the development of the system, says surviving cells can grow and self-destruct again, continuing the treatment.

The team injected bacteria with the PD-L1 blocker or the CTLA-4 blocker into mice with lymphoma. The tumors shrank, and the bacteria stayed within the tumor site. In mice with colorectal cancer, considered more resistant to immunotherapies, adding bacteria that released an immune stimulator called GM-CSF helped reduce tumor size.

Arpaia says the team needs to better characterize the self-destruct mechanism in the bacteria and determine whether individual bacteria can deliver more than one drug. Tumors naturally carry bacteria, he says, and bacterial therapies have been tried unsuccessfully in the past. He says the team is hopeful that some tweaks will make bacterial cargo ships a successful way to trigger the immune system to attack cancer.