PROJECT SUMMARY Chimeric antigen receptor T cells, or CAR T, are engineered white blood cells from patients that can destroy cancer. CAR T has the potential to cure several blood cancers, including leukemia and lymphoma. However, side effects of CAR T, called cytokine release syndrome (CRS) and neurotoxicity, can cause life-threatening problems with patients’ blood pressure, breathing, and brain. We developed a system to identify patients at risk of severe CRS and neurotoxicity by measuring two simple blood tests, CRP and ferritin, well before the CAR T are even given. We now propose a new approach to prevent CRS and neurotoxicity among those patients at greatest risk of CRS and neurotoxicity. This entails treating these high-risk patients with two prophylactic medications, dexamethasone and anakinra, before they show any signs of CAR T toxicity. In smaller studies, prophylactic dexamethasone or anakinra have been shown to be safe and offer strong signals of success in preventing CRS or neurotoxicity after CAR T. They have not yet been studied as a combination in this setting. Our proposed trial will be a large study of 182 patients who receive either dexamethasone plus anakinra or a placebo within the first few days of receiving CAR T. We will closely monitor patients for signs of CRS and/or neurotoxicity within the first 30 days of CAR T therapy, when this risk is the greatest. It is important to highlight that Hispanic patients are at 3 times greater risk for severe CRS, compared to White non-Hispanic patients. We will specifically investigate whether preventative dexamethasone and anakinra reduces the risk of such severe toxicity among Hispanic patients, and improve CAR T health equity. Work in the lab also suggests that preventing CRS and neurotoxicity will not only help to make CAR T therapy safer, but possibly more effective against cancer too. Research from our group shows that preventing CRS and neurotoxicity prevents the patient’s immune system from impairing CAR T function via a metabolite called arginine. We expect that successful completion of this project will facilitate safe CAR T therapy and possibly improve curative outcomes for treated cancer patients.