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Feb 04, 2016
 |  BC Innovations  |  Tools & Techniques

Calibrating CARs

Switchable CAR T cells could target solid tumors safely

Instead of focusing on how to turn chimeric antigen receptor (CAR) T cells off when things go wrong, a group at the California Institute for Biomedical Research (Calibr) has engineered a universal CAR T cell that is only switched on when it's wanted. By designing the system to dial out side effects and dial in tissue specificity, the researchers believe the new type of CAR T cells will be both powerful and safe enough to use against solid tumors.

That's been one of the main limitations of CAR T cells, whose dramatic impact has so far been limited to blood cancers. The most advanced CAR T cells in development - from Juno Therapeutics Inc., partners Novartis AG and the University of Pennsylvania - target CD19 to treat acute lymphoblastic leukemia (ALL), and other disclosed CAR T cell therapies in the clinic are for leukemias, lymphomas and hematologic malignancies.

However, while patients can live with the B cell depletion that sometimes comes with targeting CD19, most other tumor antigens are also expressed on healthy tissues that would lead to much more severe toxicities if targeted. CAR T cell therapies can also cause cytokine release syndrome, an inflammatory reaction caused by release of cytokines that can be severe or fatal if not quickly reversed.

Conventional CAR T cells target tumors directly via an antibody fragment against a tumor antigen, joined to an intracellular domain that triggers T cell activation. Several companies are developing strategies to prevent adverse events that involve shutting down the T cell activity in the presence of danger signals. (See Table: CAR dashboards)

The problem with those methods, said Alexandre Juillerat, senior scientist at Cellectis S.A., is that once the cells are shut down, they can't be turned back on to restore therapeutic activity.

Other approaches to limiting CAR T cell activity require additional antigenic signals to raise the threshold for activation. But those depend on having the right antigen expression patterns in vivo, and can't be controlled in the clinic.

The Calibr group, led by the institute's founding director Peter Schultz, took a strategy that involved a two-component system containing a CAR T cell engineered to target a foreign inert peptide, and an antibody "switch" composed of the relevant peptide conjugated to a tumor-targeting antibody. (See Figure: Switch it up)

Schultz is also CEO and professor of chemistry at The Scripps Research Institute.

The idea is that the CAR T cells will be directed to the tumor by the switch and will not have any activity by themselves because the peptide is not present in humans. As a result, the strength and duration of the CAR T cells' activity can be controlled by modifying the dosing and design of the switch.

Using mouse models of leukemia, the team showed a single CAR T cell design could work in tandem with switches against different tumor antigens, with less risk than conventional CAR T cells of triggering cytokine release syndrome. Now the group is planning...

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