Stanford Touts Remote-Controllable CAR-T Cell Therapy

Scientists from Stanford University designed a regulatable SNIP CAR-T platform that could circumvent toxicities associated with conventional CAR-T therapy. 

Chimeric antigen receptor (CAR) T cell therapy is T-cell modified to fit a patient’s cancer profile, then infused back into the patient’s body to fight cancer. It showed remarkable therapeutic activity in leukemia, and adults with lymphoma, while frequently tested on other cancers. Despite these promising results, severe and adverse events such as cytokine release syndrome (CRS) and neurotoxicity are common and can be fatal, causing the therapy to be reserved until other therapies fail. 

This research published on Cell presents SNIP CARs, a protease-based platform for regulating chimeric antigen receptor activity using a small molecule drug (grazoprevir) already approved by the FDA for hepatitis C treatment. “Previous efforts to create drug-regulatable CAR-T cells have yielded systems that are very finicky, or leaky,” Lead author Louai Labanieh said. “This is the first time we’ve been able to tune their activity so precisely.” 

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Controlling CAR-T Cells Activity to Increase Effectiveness

By incorporating a molecular switch that turns on only when an oral medicine is supplied, the team hopes to address CAR-T therapy’s limited window to modulate cell dosage and activity when toxicity occurs. 

In an induced lethal toxicity mouse model, mice that were treated with the SNIP CAR-T cells recovered after the grazoprevir treatment stopped, showing the system’s potential to act as a safer alternative for patients than conventional CAR-T therapy. SNIP CAR-T cells also have improved efficacy in numerous models associated with more functional, less exhausted, and higher levels of memory CAR-T cells, which proved valuable in preserving healthy tissues.

Surprisingly, they also found that modulating grazoprevir dose made CAR-T cells attack cancer cells better, while avoiding normal tissues which express lower levels of the target molecule. The ability to design these cells to recognize target molecules co-occurring on healthy cells could transform the ability to tackle human solid tumors, reducing the previous “on-target off-tumor” toxicity effect.

However, determining the appropriate oral drug dose for a patient could be challenging due to variables caused by different T cell activity, tumor antigen expression, etc. Clinical studies will be the next step to establish the system’s possibilities in humans, particularly grazoprevir’s longer half-life in humans compared with mice.

Author

Fujie Tham