11 January 2021

A commonly used cancer drug could be used to create a molecular on-off switch to regulate the activity of CAR-T cells, US researchers have reported.

CAR-T cells effectively target blood cancers but they can grow rapidly over weeks and months, in some cases causing life-threatening inflammatory reactions that are difficult to control.

Scientists at Dana-Farber Cancer Institute and Massachusetts General Cancer Center, USA, say they hope the introduction of switchable cell therapies will enable patients to tune the amount of CAR-T cell activity from day to day, reducing toxic side effects. Writing in Science Translational Medicine, they describe using the cancer drug lenalidomide to create an on-off switch for CAR-T cells.

The research team created the off-switch using a new approach called targeted protein degradation, which exploits a mechanism that cells use to dispose of unwanted or abnormal proteins.

They engineered small protein tags that are sent to the cellular “garbage disposal” by lenalidomide. When the degradation tag was affixed to the CAR, it allowed the tagged CAR to be degraded during lenalidomide treatment .

When lenalidomide treatment is stopped, the CAR-T cells are switched back on and recover their anti-tumour activity.

First author Dr Max Jan said: “From the start, our goal was to build cancer therapies that are less hard on people. Having built these switches using human genetic sequences and an FDA-approved drug, we are excited for the potential to translate this research to clinical use.”

The scientists also built an on-switch CAR by further engineering the CAR-T cells so that they only work in the presence of both their tumor target molecule and interact with lenalidomide. This, they say, has the potential to be especially safe, because the T cells only recognise and attack tumour cells during lenolidamide treatment.

Senior author Dr Benjamin Ebert, chair of medical oncology at Dana-Farber, said the long-term goal is to have multiple different drugs that control different on and off switches so that scientists can develop ever-more complex cellular therapies.

Jan M, Scarfò I, Larson RC, Walker A, Schmidts A, Guirguis AA, Gasser JA, Słabicki M, Bouffard AA, Castano AP, Kann MC, Cabral ML, Tepper A, Grinshpun DE, Sperling AS, Kyung T, Sievers QL, Birnbaum ME, Maus MV, Ebert BL. (2021) “Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide.” Science Translational Medicine doi: 10.1126/scitranslmed.abb6295

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