肿瘤细胞治疗研究
英文原题：Engineering functionality-optimized fully human B7-H3 CAR T cells for enhanced solid tumor therapy.
Engineering functionality-optimized fully human B7-H3 CAR T cells for enhanced solid tumor therapy.
临床上最先进的B7-H3 CAR源自鼠单克隆抗体(mAb) 376.96和MGA271，目前正在进行1/2期试验。
B7-H3是一种在多种实体瘤中过表达的细胞表面蛋白，是嵌合抗原受体（CAR）T细胞治疗的一个有吸引力的靶点。临床上进展最快的B7-H3 CAR源自鼠单克隆抗体（mAb）376.96和MGA271，目前正在进行1/2期试验。然而，非人源mAb序列可引发免疫反应，导致CAR T细胞排斥和治疗失败。尽管单链可变片段（scFv）人源化可降低这一风险，但可变结构域内残留的外源残基仍然存在。为克服这一局限性，本研究利用体外噬菌体展示技术生成全人源B7-H3特异性scFv用于CAR设计。在胰腺癌、神经母细胞瘤和胶质母细胞瘤异种移植模型中， incorporating先导人源结合物Y111的CAR T细胞耐受性良好，并显示出优于基于376.96和MGA271的CAR的抗肿瘤活性。Y111 CAR治疗诱导完全缓解、肿瘤排斥和显著的生存获益，表明Y111是一种有前景的用于实体瘤的全人源B7-H3 CAR。
B7-H3 is a cell surface protein overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR) T cell therapy. The most clinically advanced B7-H3 CARs derive from murine monoclonal antibodies (mAbs) 376.96 and MGA271 and are now in phase 1/2 trials. However, non-human mAb sequences can provoke immune responses, leading to CAR T cell rejection and therapeutic failure. Although single-chain variable fragment (scFv) humanization reduces this risk, residual foreign residues within variable domains remain. To overcome this limitation, here we use in vitro phage display to generate fully human B7-H3-specific scFvs for CAR design. In pancreatic cancer, neuroblastoma, and glioblastoma xenograft models, CAR T cells incorporating the lead human binder Y111 are well tolerated and demonstrate superior antitumor activity compared with 376.96- and MGA271-based CARs. Y111 CAR treatment induces complete responses, tumor rejection, and significant survival benefits, identifying Y111 as a promising fully human B7-H3 CAR for solid tumors.
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