Chimeric antigen receptor (CAR)–T cell therapy uses a patient's own genetically modified T cells to seek out and attack cancer cells. By targeting specific tumor antigens, CAR-T cells are increasingly used as an effective immunotherapy in patients with hematologic cancers. However, the cells' cancer-killing efficiency often wanes over time, a result of the cells becoming exhausted from being always "on." A recent study from Stanford published in Science observed that giving cells a brief rest resets their cancer-killing ability. The researchers generated CAR-T cells with a destabilizing domain incorporated into the protein responsible for the cells' cancer-fighting ability. The effect of the destabilizing domain, which disrupts the production of the protein, called a chimeric antigen receptor, or CAR, can be reversed by treatment with a small drug molecule. Therefore, in the absence of the drug the levels of the CAR protein rapidly decrease giving the cell a “rest” and when the drug is reapplied to the cells, the CAR protein is produced turning the cells back “on”. Exhausted cells that were allowed to rest for as few as four days were much better at attacking and killing cancer cells, and animals with tumors that were treated with the rested CAR-T cells lived significantly longer than those that received a control treatment. Turning off all the CAR-T cells in a patient could allow the remaining cancer to grow so future studies will be needed to determine how to selectively turn off a subset of CAR-T cells at a time. This type of fine tuning of cell functioning might prove more effective for cancer patients.
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Dr. Campisi, I found this to be a very interesting approach compared to other therapeutic methods. I was particularly interested in the status of patients after CAR-T treatment. I found some research discussing how/why some of the patient’s that had received this therapy proceeded to develop tumors post-treatment, or gained some type of resistance to CAR-T therapy. CAR-T is effective as it is able to recognize and attack cancerous cells. Thus, one potential issue with CAR-T therapy has to do with antigen loss after treatment. This antigen loss changes or alters the antigens on the surface of the tumor, thereby changing CAR-T ability to recognize it (Huo et al., 2022). While CAR-T is normally efficient in recognizing tumor antigens, this ‘new’ antigen presents a problem and could lead to tumor relapse. In addition to this antigen loss, tumor relapse could be attributed to a tumor cell ability to recruit immunosuppressive cells to suppress T-Cell activity (Huo et al., 2022).
ReplyDeleteCAR-T treatment has been shown to be a very effective therapy to combat cancer cells. The development of screening new tumor antigens could increase the efficacy of this therapy and could decrease potential relapse post treatment. It is thought that by screening new tumor antigens, CAR-T could be designed with multispecificity (Huo et. al, 2022). By being able to recognize more than one antigen, the possibility of antigen loss decreases. In addition, it is thought that CAR-T could be used concurrently with other treatments such as immune checkpoint inhibitors, immune activators, and radiotherapy to improve its overall effect (Huo et al., 2022).
Reference:
Huo, C.-D., Yang, J., Gu, Y.-M., Wang, D.-J., Zhang, X.-X., & Li, Y.-M. (2022). Overcome tumor relapse in CAR T cell therapy. Clinical and Translational Oncology, 1–11. https://doi-org.dml.regis.edu/10.1007/s12094-022-02847-2