Sci Tran Med: CAR-T New Switch - Tonadamine | The latest results in the journal Science

CAR-T cell therapy has achieved a lot in the treatment of blood cancer, and the competition around CAR-T is fierce among pharmaceutical companies and research institutions.
three CAR-T cell therapies have been approved worldwide, while up to 500 CAR-T cell therapies are in the clinical and preclinical stages.
safety has also been a concern behind car-T's high efficacy, including cytokine release syndrome (CRS).
if CAR-T cells proliferate uncontrolled after being injected into a patient, CRS may be triggered, resulting in toxic reactions as mild as fever, severe to organ failure, and life-threatening.
scientists are also working on ways to better control the activity of CAR-T cells.
January 6th Science Translational Medicine published a study of CAR-T cell switches, and researchers at the Dana-Farber Cancer Institute and the Massachusetts General Hospital Cancer Center found that using a commonly used cancer drug, amines, can turn CAR-T cells on or off.
the use of amines can inactivate T cells with OFF switches, while T cells with ON switches need to be activated by using both amines and target antigens to control when T cells are activated.
researchers used targeted protein degradation techniques to create switching systems for CAR-T cells.
in cells, E3 (Ubisin) connective enzymes can mark a small protein called ubibin as defective or damaged by attaching it to the target protein.
, the protein shredder (i.e., protease) in the cell degrades the labeled target protein.
2004, three scientists from Israel and the United States won the Nobel Prize in Chemistry for discovering "the protein degradation process mediated by ubibin."
that the amine works with this mechanism.
these drugs can redirect the E3 ubiganic connective enzyme CRL4CRBN, thereby causing transcription factors IKZF1 and IKZF3 poly ubibination, resulting in IKZF1 and IKZF3 being degraded by protease bodies.
In the OFF switch, the researchers designed degradation labels, and systematic screening identified "super-degradation" labels that increased degradation sensitivity to amine-induced, which, when attached to CAR, induced degradation-labeled CAR ubibinization and protease degradation, preventing T cells from continuing to identify cancer cells.
Because these engineered T-cells continue to make CAR proteins, new CAR proteins accumulate and T-cell anti-tumor function is restored after the amine treatment, and in the ON switch structure, researchers designed a amine-induced djubial system to develop a CAR that needs to be activated at the same time as the amine and target antigen.
In in vivo experiments, the researchers evaluated the anti-tumor effectiveness of ON-switched CAR-T cells in the body using pomamines with similar activity and toxicity and the same degradation-specificity, because pomadamine has a longer half-life in the body than lysamine.
NSG mice were implanted with CD19 plus fluorinase and human sleeve cell lymphoma cells, and during pomadamine therapy, the researchers observed a decrease in overall tumor burden and an increase in T-cell amplification.
the residual tumor burden expanded and the T-cell population shrunk after the treatment of pomadamine stopped. the addition of
super-degradation labels allows the addition of amines to turn off car-T cell effector functions, daily use of amines or pomalidamine therapy temporarily stops CAR expression, CAR abundance is restored after discontinuation, and anti-tumor effectiveness is preserved.
the biodegradable CAR (Source: Science Translational Medicine) in addition, Pomeranide limits the release of cytokines.
When pomedamine was treated 1 or 2 times a day compared to untreated mice, the concentration of IFN-γ was reduced by 4 times and 6 times, respectively, and the daily poomadamine treatment was reduced by 4 times.
: Science Translational Medicine Overall, the reversibleness of this switching system may be used in the future to temporarily discontinue CAR-T cell therapy in patients, reduce short-term toxicity, and preserve long-term therapeutic effects on cancer.
our long-term goal is to have a variety of drugs that control different switches so scientists can develop increasingly complex cell therapies.
Benjamin Ebert, author of the paper, concludes.