Sayak Banerjee, Amity University Kolkata
CAR T cells are genetically modified immune cells that have been engineered to recognize and invade tumor cells. The immune T cells are collected and modified in the laboratory to generate finely-tuned chimeric antigen receptor, which identifies a distinctive protein on the surface of the patient’s cancer cells. The modified CAR T cells are then re-introduced to the patient, where they flow through the body and reside on the cancer cells by binding to the specific surface protein that they have been engineered to distinguish. As a result, immune attacks, the desolation of cancer cells, and the proliferation of CAR T cells are triggered. It was found that once administered to the patient, these “living drugs” not only multiply and kill tumor cells within some months, but they can also cause serious inflammatory reactions that are almost uncontrollable.
The cytokine release syndrome (CRS) might be stimulated due to this uncontrolled proliferation of the CAR T cells which cause toxicities varying from mild fever to critical organ failure. It is hoped that in the future, switchable cell therapies may permit patients to take a pill that will adjust the quantity of CAR T cell activity to lessen the toxic side effects.
The scientists used a comparatively new method, targeted protein degradation, to create the ON and OFF switch systems for CAR T cells, which involves the utilization of cells’ mechanism of disposal of undesirable protein. The cell structure responsible for garbage disposal marks the proteins for destruction. Lenalidomide, a commonly used cancer drug, when employed, use this pathway by targeting distinctive proteins for degradation. Using this technique they engineered small protein tags that were to be sent for disposal which enabled the tagged CAR to be degraded during the therapy. This prevented the T cells from identifying the cancer cells, but after the drug treatment, the new CAR proteins can accumulate and reinstate the anti-tumor function since the T cells repeatedly produce CAR proteins. The researchers suggested that this OFF-switch system hereafter may permit patients to have their CAR T cell treatment paused for a short period to prevent transient toxicity, but still show long-term therapeutic effects against their cancer. An ON switch CAR was made by additionally modifying the proteins physically associated with lenalidomide. This allowed the T cells to identify and attack the tumor cells during the drug treatment. In the course of the treatment of lenalidomide sensitive cancers like multiple myeloma, ON-switch CAR T cells enable a coordinated attack by the immune cells and the drug that monitors them.
In vivo, ON-switch split CARs exhibits a lenalidomide-dependent antitumor mechanism, and OFF-switch degradable CARs were diminished by drug treatment to prevent inflammatory cytokine release while maintaining antitumor potency. The long-term objective is to have numerous different drugs that control different on and off switches. Thus, it was concluded that these lenalidomide-gated switches are reversible, swift, and appropriately efficient systems to regulate transgene function in various gene and cell-based therapies.
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Source: Jan, Max et al. “Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide.” Science translational medicine vol. 13,575 (2021): eabb6295. doi:http://10.1126/scitranslmed.abb6295
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