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分泌单域抗体片段的嵌合抗原受体 T 细胞的抗肿瘤疗效增强。

Improved Antitumor Efficacy of Chimeric Antigen Receptor T Cells that Secrete Single-Domain Antibody Fragments.

机构信息

Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts.

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.

出版信息

Cancer Immunol Res. 2020 Apr;8(4):518-529. doi: 10.1158/2326-6066.CIR-19-0734. Epub 2020 Feb 4.

Abstract

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.

摘要

嵌合抗原受体 (CAR) T 细胞疗法在治疗血液来源的癌症方面非常有效。在免疫抑制的实体肿瘤环境中,CAR T 细胞遇到了影响其疗效的障碍。我们开发了一种策略,通过让 CAR T 细胞分泌单域抗体片段(重链抗体的可变重域 [VHH] 或纳米体)来解决这些障碍,这些抗体片段可以修饰肿瘤内的免疫景观,从而支持免疫活性动物中 CAR T 细胞的功能。VHH 体积小,能够避免在同时表达多个纳米体时发生结构域交换——这些特性可以赋予 CAR T 细胞所需的特性。CAR T 细胞分泌抗 CD47 VHH 可改善固有免疫系统的结合,实现表位扩展,并增强抗肿瘤反应。分泌抗 PD-L1 或抗 CTLA-4 纳米体的 CAR T 细胞具有更好的持久性,并展示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 融合物可限制其全身毒性。CAR T 细胞可以进一步工程化以同时分泌多种模式,从而可以更精确地调节抗肿瘤免疫反应。

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