Scientists harness nature to engineer stronger CAR-T cells by switching CAR signalling and receptor shedding

Good news! Cancer is history (soon)!

"In brief

• Stanford Medicine researchers developed a CAR-T cell design, called the AIR platform, that uses a natural protein-shedding process to reduce unwanted signaling.
• In cell and mouse studies, AIR-equipped CAR-T cells showed less exhaustion and stronger antitumor activity.
• By mimicking natural immune regulation, the approach could help advance future CAR-T treatment options for patients with solid tumors.

...

While impressively fatal against blood and lymphatic cancers, CAR-T cells hit barricades in the harsher solid-tumor environment, inhibiting their success. A chief obstacle is tonic signaling, which occurs when the CAR is continuously alert and the cell is trigger-ready, even if its antigen is nowhere nearby. ... CAR-T cells become exhausted and dysfunctional, dehydrating their ability to track and kill their targets. ..."

From the highlights and abstract:

"Highlights

• A 15-aa AIR motif endows activation-induced receptor shedding in human T cells

• AIR tunes tonic signaling CARs, reducing exhaustion and improving anti-tumor potency

• AIR improves CAR activity by selectively dampening NFAT signaling and limiting AICD

• AIR enables logic-gated CARs and activation-shed FAS/TGFBR2 to enhance tumor control

Summary

We sought to endow T cell autonomous regulation of cell surface protein expression by exploiting the conditional proteolytic activity of ADAM17 following T cell activation.

Screening of canonical ADAM17 substrates yielded a minimal 15-aa CD62L-derived motif that confers rapid and reversible cleavage of a receptor following T cell activation—termed activation-induced release (AIR).

Embedding AIR into tonic-signaling CARs reduced basal CAR expression proportional to the degree of tonic signaling induced, curtailing exhaustion and improving antitumor potency.

In non-tonic signaling CARs, AIR decreased activation-induced cell death and enhanced T cell expansion after stimulation.

AIR’s modularity supports higher-order logic-gating;

AIR-regulated peptide masks enable antigen-dependent unmasking of an EGFR-targeting CAR.

Finally, CRISPR knockin of AIR into endogenous FAS or TGFBR2 endowed them with activation-induced shedding, which enhanced tumor clearance while preserving signaling in non-activating conditions.

AIR is a compact switch that provides fast, autonomous regulation of surface proteins for next-generation cell therapies."

Scientists harness nature to engineer stronger CAR-T cells | Stanford Report "Taking inspiration from biology, Stanford researchers developed a CAR-T cell design that improved tumor control in mice."

Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis

Graphical abstract

Figure 1. Characterization of the T cell surfaceome identifies proteins with activation-dependent surface expression, and analysis of the minimal regions required for surface downregulation