Chimeric antigen receptor (CAR) T-cell therapy is effective in the treatment of cancers of hematopoietic origin. In the immunosuppressive solid tumor environment, CAR T cells encounter obstacles that compromise their efficacy. We developed a strategy to address these barriers by having CAR T cells secrete single-domain antibody fragments [variable heavy domain of heavy chain antibodies (VHH) or nanobodies] that can modify the intratumoral immune landscape and thus support CAR T-cell function in immunocompetent animals. VHHs are small in size and able to avoid domain swapping when multiple nanobodies are expressed simultaneously-features that can endow CAR T cells with desirable properties. The secretion of an anti-CD47 VHH by CAR T cells improves engagement of the innate immune system, enables epitope spreading, and can enhance the antitumor response. CAR T cells that secrete anti-PD-L1 or anti-CTLA-4 nanobodies show improved persistence and demonstrate the versatility of this approach. Furthermore, local delivery of secreted anti-CD47 VHH-Fc fusions by CAR T cells at the tumor site limits their systemic toxicity. CAR T cells can be further engineered to simultaneously secrete multiple modalities, allowing for even greater tailoring of the antitumor immune response.

中文翻译：

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提高分泌单域抗体片段的嵌合抗原受体 T 细胞的抗肿瘤功效。


嵌合抗原受体 (CAR) T 细胞疗法可有效治疗造血源性癌症。在免疫抑制实体瘤环境中，CAR T 细胞会遇到影响其功效的障碍。我们开发了一种策略来解决这些障碍，方法是让 CAR T 细胞分泌单域抗体片段（重链抗体的可变重域 (VHH) 或纳米抗体），该片段可以改变瘤内免疫景观，从而支持 CAR T 细胞在免疫功能正常的情况下发挥功能。动物。 VHH 尺寸较小，并且能够在同时表达多个纳米抗体时避免结构域交换，这些特征可以赋予 CAR T 细胞理想的特性。 CAR T 细胞分泌抗 CD47 VHH 可改善先天免疫系统的参与，实现表位扩散，并增强抗肿瘤反应。分泌抗 PD-L1 或抗 CTLA-4 纳米抗体的 CAR T 细胞表现出更好的持久性，并证明了这种方法的多功能性。此外，CAR T细胞在肿瘤部位局部递送分泌的抗CD47 VHH-Fc融合体限制了它们的全身毒性。 CAR T 细胞可以进一步设计为同时分泌多种模式，从而可以更好地定制抗肿瘤免疫反应。