CD28 and cancer: Although mitogens and anti-CD3/CD28 have been widely used to activate and expand immune cells ex vivo in cancer immunotherapies, our findings suggest that Pan T-cell activators do not model normal allorecognition-based stimulation and a reliance of these agents may lead to artifactual conclusion regarding immune responses, and could underlie the cytokine release syndrome commonly seen in overly robust T-cell responses to “non-self” (Han and Takita 1972; Maciel et al. 1976; Suntharalingam et al. 2006).