CD28 and neoplasm: The risk of developing high-grade ICANS can be attributed to factors such as the pre-treatment tumor immune microenvironment, elevated levels of inflammatory cytokines (e.g., IL-6), C-reactive protein (CRP), ferritin, and D-dimer, as well as the infused product (e.g., CAR-T cells with CD28 as a costimulatory domain) and pre-existing central nervous system (CNS) disorders (31).