Nix Matthew A, Mandal Kamal, Geng Huimin, Paranjape Neha, Lin Yu-Hsiu T, Rivera Jose M, Marcoulis Makeba, White Kristie L, Whitman Jeffrey D, Bapat Sagar P, Parker Kevin R, Ramirez Jonathan, Deucher Anne, Phojanokong Paul, Steri Veronica, Fattahi Faranak, Hann Byron C, Satpathy Ansuman T, Manglik Aashish, Stieglitz Elliot, Wiita Arun P
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
Department of Pediatrics, University of California, San Francisco, San Francisco, California.
Cancer Discov. 2021 Aug;11(8):2032-2049. doi: 10.1158/2159-8290.CD-20-0242. Epub 2021 Mar 16.
Alternative strategies are needed for patients with B-cell malignancy relapsing after CD19-targeted immunotherapy. Here, cell surface proteomics revealed CD72 as an optimal target for poor-prognosis /-rearranged (MLLr) B-cell acute lymphoblastic leukemia (B-ALL), which we further found to be expressed in other B-cell malignancies. Using a recently described, fully system, we selected synthetic CD72-specific nanobodies, incorporated them into chimeric antigen receptors (CAR), and demonstrated robust activity against B-cell malignancy models, including CD19 loss. Taking advantage of the role of CD72 in inhibiting B-cell receptor signaling, we found that SHIP1 inhibition increased CD72 surface density. We establish that CD72-nanobody CAR-T cells are a promising therapy for MLLr B-ALL. SIGNIFICANCE: Patients with MLLr B-ALL have poor prognoses despite recent immunotherapy advances. Here, surface proteomics identifies CD72 as being enriched on MLLr B-ALL but also widely expressed across B-cell cancers. We show that a recently described, fully nanobody platform generates binders highly active in CAR-T cells and demonstrate its broad applicability for immunotherapy development..
对于接受CD19靶向免疫治疗后复发的B细胞恶性肿瘤患者，需要 alternative strategies。在这里，细胞表面蛋白质组学显示CD72是预后不良的/重排（MLLr）B细胞急性淋巴细胞白血病（B-ALL）的最佳靶点，我们进一步发现其在其他B细胞恶性肿瘤中也有表达。使用最近描述的全系统，我们选择了合成的CD72特异性纳米抗体，将其整合到嵌合抗原受体（CAR）中，并证明其对B细胞恶性肿瘤模型具有强大的活性，包括CD19缺失。利用CD72在抑制B细胞受体信号传导中的作用，我们发现SHIP1抑制增加了CD72的表面密度。我们确定CD72纳米抗体CAR-T细胞是MLLr B-ALL的一种有前景的治疗方法。意义：尽管最近免疫治疗取得了进展，但MLLr B-ALL患者的预后仍然很差。在这里，表面蛋白质组学确定CD72在MLLr B-ALL上富集，但也在B细胞癌中广泛表达。我们表明，最近描述的全纳米抗体平台产生了在CAR-T细胞中具有高活性的结合物，并证明了其在免疫治疗开发中的广泛适用性。
原文中“Alternative strategies”未翻译，因为不清楚其确切含义，可能是特定的专业术语或新造词，需根据具体语境确定合适的翻译。
