Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Cancer Immunol Res. 2020 Apr;8(4):518-529. doi: 10.1158/2326-6066.CIR-19-0734. Epub 2020 Feb 4.
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.
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。