Abstract The persistence and reactivity of CAR T cells were enhanced by adding co‐stimulatory domains, which is the basis of currently approved CAR‐T cell therapies. However, this comes at the expense of increasing toxicities from the strong cytokine release effect. This is the first report from anti‐CD19 CAR‐T cell therapy with a single activation domain to show a favourable safety profile and clinical efficacy with two patients who achieved durable responses up to 28 months in a cohort with heavily pretreated B cell malignancies.