CD28 and neoplasm: In CAR strategies, an scFV targeting differentiation antigens can be expected to also recognize non-malignant cells that express the same antigens, resulting in adverse effects.35, 36 On-target but off-tumor toxicities can be immediately life threatening.37, 38 It is thought that the fatal toxicity was a result of the high potency of the CAR construct that contained CD28 and 4-1BB, and the use of prior non-myeloablative chemotherapy that further enhanced the treatment effect.