Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756, USA.
Center for Synthetic Immunity, The Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA.
Cancer Immunol Immunother. 2018 May;67(5):749-759. doi: 10.1007/s00262-018-2124-1. Epub 2018 Feb 16.
B7H6 is emerging as a promising tumor antigen that is known to be expressed on a wide array of tumors and is reported to stimulate anti-tumor responses from the immune system. As such, B7H6 presents a good target for tumor-specific immunotherapies. B7H6-specific chimeric antigen receptors (CAR) based on a murine antibody showed successful targeting and elimination of tumors expressing B7H6. However, mouse single chain variable fragments (scFvs) have the potential to induce host anti-CAR responses that may limit efficacy, so human scFvs specific for B7H6 were selected by yeast surface display. In this study, we validate the functionality of these human scFvs when formatted into chimeric antigen receptors. The data indicate that T cells expressing these B7H6-specific human scFvs as CARs induced potent anti-tumor activity in vitro and in vivo against tumors expressing high amounts of B7H6. Importantly, these human scFv-based CARs are sensitive to changes in B7H6 expression which may potentially spare non-tumor cells that express B7H6 and provides the foundation for future clinical development.
B7H6 作为一种有前途的肿瘤抗原正在兴起，已知它在广泛的肿瘤上表达，并据报道能刺激免疫系统产生抗肿瘤反应。因此，B7H6 是肿瘤特异性免疫疗法的一个很好的靶点。基于鼠抗体的 B7H6 特异性嵌合抗原受体 (CAR) 显示出成功靶向和消除表达 B7H6 的肿瘤的能力。然而，鼠单链可变片段 (scFv) 有引发宿主抗 CAR 反应的潜力，这可能会限制疗效，因此通过酵母表面展示选择了针对 B7H6 的人源 scFv。在这项研究中，我们验证了这些人源 scFv 形成嵌合抗原受体时的功能。数据表明，表达这些 B7H6 特异性人源 scFv 的 CAR 在体外和体内对表达大量 B7H6 的肿瘤表现出强大的抗肿瘤活性。重要的是，这些基于人源 scFv 的 CAR 对 B7H6 表达的变化敏感，这可能潜在地保护表达 B7H6 的非肿瘤细胞，并为未来的临床开发提供了基础。
