A Ludwig Cancer Research study has devised a new type of chimeric antigen-receptor (CAR) T cell-;a family of promising immunotherapies for cancer- that can be switched on and off on demand. The study, led by Melita Irving of the Lausanne Branch of the Ludwig Institute for Cancer Research, George Coukos, director of the Branch, and their colleague Bruno Correia of the École Polytechnique Fédérale de Lausanne (EPFL), addresses a central conundrum of CAR-T therapies: their tendency to provoke potentially deadly runaway immune responses against healthy tissues in patients. Their report appears in the current issue of Nature Biotechnology .
"We wanted to develop a way to dampen CAR-T cell therapy as a safety mechanism in the event of an adverse reaction in a patient," says Coukos. "To do that we designed CAR-T cells that can be reversibly inactivated with small molecules that can be given systemically and act rapidly."
CAR-T cells are designed to detect specific molecular markers, or antigens, and destroy the cancer cells that bear them. To that end, researchers engineer a chimeric molecule, expressed on a T cell, that is stitched together from the functional units-;or "domains"-;of a few key proteins. The external part of the CAR protein does the antigen detecting. The inner part has two other key components. One is the signaling domain of a protein named CD3-zeta that is absolutely required to activate the T cell. The other is the signaling part of another protein, usually CD28, that supports the proliferation and survival of the activated T cell.
These cellular immunotherapies have been approved for the treatment of some blood cancers, and researchers are working on targeting them at solid tumors. But the treatment has significant risks. CAR-T cells can inadvertently elicit cascading, systemic immune reactions known as cytokine release syndrome, which can cause serious side effects.
Researchers have sought to blunt these risks by, for example, engineering CAR-T cells to commit suicide on demand or require a drug to become activated.
The former approach leads, however, to the waste of a very expensive immunotherapy, while the latter has been challenged by the short half-lives of the drugs. Our approach offers novel and unique solutions to this difficult molecular engineering problem." Melita Irving, Lausanne Branch of the Ludwig Institute for Cancer Research
To build their "STOP-CAR-T" system, the researchers stuck the CD3-zeta activation domain on one molecule and the antigen-detecting portion on the another. To link the two chains together, so that they'd function as a single unit, they added to each chain the interacting domains of two unrelated proteins that spontaneously pair up inside the cell. The researchers also ensured that the binding could be disrupted by existing small molecules administered systemically. Elegant computational modeling and protein engineering done in Correia's laboratory identified ideal molecular partners for these binding domains and ensured that these newly added binding domains would not interfere with the complex protein interactions within the cell required for the signaling that activates T cells. Related Stories
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