New CAR-T Cell Therapy Can Be Switched On, Off

A new type of chimeric antigen receptor (CAR) T cell can be switched on and off, according to a new study from the Ludwig Institute for Cancer Research.

The study, published in Nature Biotechnology, addresses the tendency of most CAR-T therapies to provoke immune responses against healthy tissues in patients.

“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,” said George Coukos, MD, PhD, director of the Lausanne Branch of the Ludwig Institute, in a press release. “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 antigens and destroy the cancer cells that bear them. Researchers engineer a chimeric molecule expressed on a T cell stitched together from the functional units of key proteins.

The external part of the CAR protein detects antigens and the inner part has 2 other key components. One is the signaling domain of a CD3-zeta protein (CD3-zeta) that is required to activate the T cell and the other is the signaling part of the CD28 protein that supports the proliferation and survival of the activated T cell.

These cellular immunotherapies have been approved for the treatment of certain blood cancers and researchers are working on targeting them at solid tumors; however, the treatment has significant risks. CAR-T cells can inadvertently elicit cascading, systemic immune reactions known as cytokine release syndrome, which can cause serious adverse events.

In the study, researchers combined the CD3-zeta activation domain on 1 molecule and the antigen-detecting protein to the other. They then added the interacting domains of 2 unrelated proteins that pair up inside the cell in order to link the molecules.

The researchers ensured that the binding could be disrupted by existing small molecules administered systemically. Computational modeling and protein engineering identified ideal molecular partners for these binding domains and ensured that they would not interfere with protein interactions within the cell required for the signaling that activates T cells.

The study authors first confirmed in cell cultures that this 2-protein CAR-T system worked as well as similarly targeted, but traditionally designed, CAR-T systems and could be switched off by a drug-like molecule. They then grew tumors expressing that antigen, showing that both types of the CAR-T system’s effects could be abrogated with the administration of the small molecule before or after the initiation of CAR-T therapy.

A “STOP-CAR-T” system is currently being developed that can be controlled by an approved drug and tweaking the system in various ways to determine whether it is possible to lower the amount of drug required to control the cells, according to the press release.

“This work itself, and its potential, is really exciting, but I think it is also illustrative of how well-orchestrated, multidisciplinary collaborations can yield significant scientific breakthroughs,” Coukos said in the press release.

Reference

• Building a safer CAR-T therapy. [news release]. Ludwig Cancer Research website. Published February 3, 2020. https://www.ludwigcancerresearch.org/news-releases/building-a-safer-car-t-therapy/. Accessed February 3, 2020.