Yi Zhongzhen, Prinzing Brooke L, Cao Felicia, Gottschalk Stephen, Krenciute Giedre
Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Integrative Molecular and Biomedical Science Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA.
Mol Ther Methods Clin Dev. 2018 Feb 2;9:70-80. doi: 10.1016/j.omtm.2018.01.009. eCollection 2018 Jun 15.
Glioblastoma is the most aggressive primary brain tumor in humans and is virtually incurable with conventional therapies. Chimeric antigen receptor (CAR) T cell therapy targeting the glioblastoma antigen EphA2 is an attractive approach to improve outcomes because EphA2 is expressed highly in glioblastoma but only at low levels in normal brain tissue. Building upon our previous findings in this area, we generated and evaluated a panel of EphA2-specific CARs. We demonstrate here that T cells expressing CD28.ζ and 41BB.ζ CARs with short spacers had similar effector function, resulting in potent antitumor activity. In addition, incorporating the 41BB signaling domain into CD28.ζ CARs did not improve CAR T cell function. While we could not determine functional differences between CD28.ζ, 41BB.ζ, and CD28.41BB.ζ CAR T cells, we selected CD28.ζ CAR T cells for further clinical development based on safety consideration.
胶质母细胞瘤是人类最具侵袭性的原发性脑肿瘤，传统疗法几乎无法治愈。靶向胶质母细胞瘤抗原EphA2的嵌合抗原受体（CAR）T细胞疗法是一种改善治疗结果的有吸引力的方法，因为EphA2在胶质母细胞瘤中高表达，但在正常脑组织中仅低水平表达。基于我们此前在该领域的研究结果，我们构建并评估了一组EphA2特异性CAR。我们在此证明，表达带有短间隔区的CD28.ζ和41BB.ζ CAR的T细胞具有相似的效应功能，从而产生强大的抗肿瘤活性。此外，将41BB信号域整合到CD28.ζ CAR中并未改善CAR T细胞功能。虽然我们无法确定CD28.ζ、41BB.ζ和CD28.41BB.ζ CAR T细胞之间的功能差异，但出于安全性考虑，我们选择了CD28.ζ CAR T细胞进行进一步的临床开发。
