Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Cell Design Institute and Center for Synthetic Immunology, University of California, San Francisco, San Francisco, CA, USA.
Nat Nanotechnol. 2021 Feb;16(2):214-223. doi: 10.1038/s41565-020-00813-z. Epub 2020 Dec 14.
Biomaterials can improve the safety and presentation of therapeutic agents for effective immunotherapy, and a high level of control over surface functionalization is essential for immune cell modulation. Here, we developed biocompatible immune cell-engaging particles (ICEp) that use synthetic short DNA as scaffolds for efficient and tunable protein loading. To improve the safety of chimeric antigen receptor (CAR) T cell therapies, micrometre-sized ICEp were injected intratumorally to present a priming signal for systemically administered AND-gate CAR-T cells. Locally retained ICEp presenting a high density of priming antigens activated CAR T cells, driving local tumour clearance while sparing uninjected tumours in immunodeficient mice. The ratiometric control of costimulatory ligands (anti-CD3 and anti-CD28 antibodies) and the surface presentation of a cytokine (IL-2) on ICEp were shown to substantially impact human primary T cell activation phenotypes. This modular and versatile biomaterial functionalization platform can provide new opportunities for immunotherapies.
生物材料可以提高治疗药物的安全性和呈现效果，从而实现有效的免疫治疗，而对表面功能化的高度控制对于免疫细胞的调节至关重要。在这里，我们开发了具有生物相容性的免疫细胞结合颗粒（ICEp），它使用合成短 DNA 作为支架，实现高效且可调的蛋白质加载。为了提高嵌合抗原受体（CAR）T 细胞疗法的安全性，将微米级大小的 ICEp 瘤内注射，为系统给予的 AND 门控 CAR-T 细胞提供启动信号。局部保留的 ICEp 呈现高浓度的启动抗原，激活 CAR T 细胞，从而在免疫缺陷小鼠中清除局部肿瘤，而不影响未注射的肿瘤。证明了 ICEp 上共刺激配体（抗 CD3 和抗 CD28 抗体）和细胞因子（IL-2）的比率控制和表面呈现对人原代 T 细胞激活表型有重大影响。这种模块化和多功能的生物材料功能化平台可为免疫疗法提供新的机会。
