Brain Tumor Immunotherapy and Biology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Cancer Immunotherapy, Department of Biomedicine, University of Basel, Basel, Switzerland.
Nat Commun. 2024 Nov 9;15(1):9718. doi: 10.1038/s41467-024-54129-w.
A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive microenvironment, which is densely populated by protumoral glioma-associated microglia and macrophages (GAMs). Myeloid immune checkpoint therapy targeting the CD47-signal regulatory protein alpha (SIRPα) axis induces GAM phagocytic function, but CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. In this work, we engineer a CAR T cell against epidermal growth factor receptor variant III (EGFRvIII), constitutively secreting a signal regulatory protein gamma-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eradicate orthotopic EGFRvIII-mosaic GBM in vivo, promoting GAM-mediated tumor cell phagocytosis. In a subcutaneous CD19 lymphoma mouse model, anti-CD19-SGRP CAR T cell therapy is superior to conventional anti-CD19 CAR T. Thus, combination of CAR and SGRP eliminates bystander tumor cells in a manner that could overcome main mechanisms of CAR T cell therapy resistance, including immune suppression and antigen escape.
嵌合抗原受体 (CAR) T 细胞疗法治疗胶质母细胞瘤 (GBM) 的一个重大挑战是其免疫抑制微环境，该微环境中充斥着促肿瘤性胶质母细胞瘤相关的小胶质细胞和巨噬细胞 (GAMs)。针对 CD47-信号调节蛋白α (SIRPα) 轴的髓样免疫检查点疗法可诱导 GAM 的吞噬功能，但 CD47 阻断单药治疗与实体瘤中的毒性和低生物利用度相关。在这项工作中，我们构建了一种针对表皮生长因子受体变异体 III (EGFRvIII) 的 CAR T 细胞，该细胞持续分泌与 CD47 具有高亲和力的信号调节蛋白γ相关蛋白 (SGRP)。抗 EGFRvIII-SGRP CAR T 细胞在体内根除了 EGFRvIII 镶嵌性 GBM，促进了 GAM 介导的肿瘤细胞吞噬作用。在皮下 CD19 淋巴瘤小鼠模型中，抗 CD19-SGRP CAR T 细胞疗法优于传统的抗 CD19 CAR T。因此，CAR 和 SGRP 的联合以一种可以克服 CAR T 细胞疗法耐药的主要机制的方式消除了旁观者肿瘤细胞，包括免疫抑制和抗原逃逸。
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