GD2 CAR T cells with inducible IL-18 in refractory solid tumors

We report the first clinical evaluation of IL-18-engineered CAR T-cell therapy in patients with solid tumors. In an academic phase I dose-finding study, 23 patients with advanced solid tumors received GD2IL18CART, a GD2-specific CAR T-cell product with antigen-inducible IL-18 secretion. Treatment at the recommended dose was associated with clinically significant but manageable inflammatory toxicity, whereas dose escalation resulted in fatal hyperinflammation in one patient. GD2IL18CART cells expanded in vivo in all patients, accompanied by increases in serum IL-18, IFN-γ and IL-18BP. Objective responses occurred in four of eleven patients with neuroblastoma, including complete remissions, but not in patients with other tumor types. These findings demonstrate the feasibility of IL-18-engineered CAR T-cell therapy for solid tumors and provide evidence of antitumor activity in neuroblastoma. Exploratory tissue analyses identify features of the tumor microenvironment that may constrain therapeutic activity and provide targets for further improvement.