Theralizumab (TGN1412), a monoclonal agonist of CD28, served as a cautionary first attempt to manipulate co-stimulatory molecules to enhance tumor response, leading to severe cytokine release syndrome with multi-organ dysfunction in several participants.36 The severity of toxicity and poor understanding of its underlying mechanism dampened enthusiasm for additional co-stimulatory strategies, but recent breakthroughs have reinvigorated this field. The gene discussed is CD28; the disease is neoplasm.