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November 14, 2017

Cancer Immunotherapies May Deploy Nonimmune Cells Engineered to a "T"

Cell-based anticancer therapies may include synthetic T cells, nonimmune cells equipped with signal-transduction devices that sense targets and trigger release of prodrug activators. In this image, a synthetic T cell recognizes a tumor cell and docks to it. In the process, antenna proteins bend, triggering a chain reaction that results in the tumor cell’s destruction. [ETH Zurich]

  • Rather than hone the killer instincts of immune cells—and risk unleashing an overzealous horde—cancer immunotherapies may recruit and train nonimmune cells, which have the potential to be more controllable. Alternatively, cancer immunotherapies could assemble antitumor units consisting of both engineered immune cells, such as chimeric antigen receptor T (CAR-T) cells, and engineered nonimmune cells, including cells outfitted with “synthetic T-cell receptor–like signal transduction devices.”

    If given the right kit, even a soft cell—an adipose stem cell, for example—could join the anticancer fight, suggests a team of scientists based at ETH Zurich. This team, led by Martin Fussenegger, Ph.D., a professor of biotechnology and bioengineering, reports that it can equip nonimmune cells with additional components, and muster ranks of synthetic designer cells that mimic T cells.

    Details appeared November 13 in the journal Nature Chemical Biology, in an article entitled, “Nonimmune cells equipped with T-cell-receptor–like signaling for cancer cell ablation.” The nonimmune cells, the article emphasized, could contribute “to the advancement of synthetic biology by extending available design principles to transmit extracellular information to cells.” That is, synthetic T cells could be equipped with different docking sites, in modular fashion, to attack selectively different targets.

    The ETH Zurich scientists developed a sort of sensing and triggering device that can function in human nonimmune cells. The device, a signal-transduction apparatus, can sense when it contacts a target cell and then trigger the release of output molecules.

    “This device employs an interleukin signaling cascade, whose OFF/ON switching is controlled by biophysical segregation of a transmembrane signal-inhibitory protein from the sensor cell–target cell interface,” wrote the authors of the Nature Chemical Biology article. “We further show that designer nonimmune cells equipped with this device driving expression of a membrane-penetrator/prodrug-activating enzyme construct could specifically kill target cells in the presence of the prodrug, indicating its potential usefulness for target-cell-specific, cell-based enzyme-prodrug cancer therapy.”

    Although T cells are being engineered to combat tumors more effectively, their deployment in immune-cell therapies can have significant side-effects. Also, the production of modified T cells poses serious technical difficulties. Human nonimmune cells modified to incorporate custom cell-contact-sensing output devices, however, could extend the applicability of cell-based cancer therapies. In addition, these synthetic T cells might avoid the risks associated with engineered immune cells.

    One of the components of synthetic T cells entails molecular antennae protruding well outside the membrane. Also embedded within the cell membrane are antibodies with specific docking sites, which can sense the target structures of the cancer cell and bind to them. The third component is a gene network that generates a molecule complex.

    This molecule complex constitutes a molecular "warhead" that penetrates the membrane of the target cell. It is linked to a converter molecule that activates an anticancer substance in the tumor cell's interior.

    The precursor of this active substance needs to be added to the system externally. Cancer cells absorb this substance, and the converter module transforms the drug from a prodrug to an active drug state. The cancer cells bursts, and the active substance is released, destroying other tumor cells in the "death zone" around the synthetic T cell.

    “This bystander effect,” observed Dr. Fussenegger, “makes our synthetic T cells even more effective.”

    The mechanism triggering the signal cascade leading to the destruction of the cancer cell is new, and has a physical function: as the synthetic T cell moves closer toward the target cell, the antennae proteins buckle. The antennae's anchorage deep within the cell therefore loses contact with a molecular switch that it had previously blocked. As a response to the ON command, a signal cascade is initiated which actuates the production of the molecule complex.

    The new type of artificial T cell has several advantages over current cancer treatments. Whereas during chemotherapy the body is flooded with active substances in order to kill as many rapidly dividing cells as possible in a very unselective manner, only a few artificial T cells are needed in the new therapy. What's more, these are only deployed locally and in a carefully targeted fashion.

    "Our innovative T cells may detect and kill metastasizing cancer cells at a very early stage, when other treatments are not effective," Dr. Fussenegger asserted. "The artificial T cells operate totally independently from the body's immune system,” he added, “enabling it to continue to function perfectly normally, so that fewer side effects are likely.”

    For the current study, scientists used docking sites that detect only one specific type of mammalian cancer cell. "This technology provides us with an enormous degree of generalization that cannot be achieved with the genuine T cells used in current cancer therapies," Dr. Fussenegger stressed.

    It's still not clear whether—and how—this system will function in the human body. So far, ETH Zurich researchers have only tested their new cells in cell cultures. "At present, our new system is still a long way from a therapeutic application," admitted Dr. Fussenegger. "But I believe we have opened up a new front in the battle against cancer."

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