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Redesigned CAR T Cells

synthetic molecules which allow them to recognize and attach to specific proteins on tumor cells when reintroduced into the patients’ bodies. Axicabtagene ciloleucel emerged as an important and novel CAR T-cell treatment for adults with lymphoma, providing long-lasting remission for some with advanced cancer. However, the therapy has been known to have a dark side, too—profound side effects. In 2017, National Cancer Institute (NCI) researchers tweaked their original CAR T-cell design in hopes of creating a less toxic therapy with improved effectiveness. Results of their first clinical trial offer cause for optimism. “We’re changing the structure of the actual chimeric antigen receptor in hopes of doing one of two things, or both: decrease toxicity and increase efficacy,” explained Jennifer Brudno, MD, Assistant Research Physician of NCI’s Center for Cancer Research, and first author of findings published in Nature Medicine (2020;26(2):270-280). One such severe response is the cytokine release syndrome (CRS), “... caused when CAR T cells are infused into the body. Both the T cells and other immune cells respond to the CAR T cells and make inflammatory chemicals, including cytokines. As a result, the body reacts and patients can develop high temperatures, fast heart rates, low blood pressures, and low oxygen levels, which in some instances can be life-threatening,” Brudno explained. CRS can in some instances be relieved by the administration of medications to suppress the immune system, such as tocilizumab and corticosteroids. However, Brudnoe also explained that higher dose steroids may actually inhibit CAR T-cell function, which is an additional problem in managing CAR T-cell toxicity. Neurologic toxicity is the other category of potentially severe toxicities. “Patients can become excessively somnolent to the point of being comatose and needing to be on a ventilator,” Brudno explained. “I tell patients their brain is not telling their lungs to breathe properly. Patients can have seizures and swelling, called cerebral edema, when extra fluid accumulates in the brain tissue. Not every patient experiences severe neurologic toxicities, but in the patients that do, they can be life-threatening.”