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.
B7-H3 是一种在许多实体瘤中过表达的细胞表面蛋白，也是嵌合抗原受体（CAR）T 细胞治疗一个有吸引力的靶点。
B7-H3是一种在许多实体瘤中过表达的细胞表面蛋白，是嵌合抗原受体（CAR）T细胞疗法颇具吸引力的靶点。目前临床开发最先进的B7-H3 CAR源自小鼠单克隆抗体（mAb）376.96和MGA271，现已进入I/II期试验。然而，非人源抗体序列可能诱发免疫反应，导致CAR-T细胞被排斥、治疗失败。尽管对单链可变片段（scFv）进行人源化可降低这一风险，其可变区内仍可能残留外源氨基酸。为克服这一局限，我们采用体外噬菌体展示筛选获得完全人源的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，含有候选人源结合分子Y111的CAR-T细胞耐受性良好，且抗肿瘤活性优于基于376.96或MGA271的CAR。Y111 CAR治疗可诱导完全缓解、肿瘤排斥，并显著改善生存，提示Y111是用于实体瘤的有前景的完全人源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 are derived from murine monoclonal antibodies (mAbs) 376.96 and MGA271, which are now in phase I/II trials. However, non-human mAb sequences can provoke immune responses, leading to CAR T-cell rejection and therapeutic failure. Although scFv humanization reduces this risk, residual foreign residues within the variable domains remain. To overcome this limitation, we used 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 were well tolerated and demonstrated superior antitumor activity compared with 376.96- and MGA271-based CARs. Y111 CAR treatment induced 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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