Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, Massachusetts 02155, United States.
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, United States.
ACS Biomater Sci Eng. 2022 Feb 14;8(2):722-733. doi: 10.1021/acsbiomaterials.1c01532. Epub 2022 Feb 1.
Chimeric antigen receptor (CAR)-engineered adoptive cell therapy marks a revolution in cancer treatment based on the highly successful responses to CAR T cell therapy in the treatment of blood cancers. Due to the versatile structure of CARs, this technology can be easily adapted to other immune cell types, including macrophages and NKs, and applied in the treatment of many other cancers. However, high costs and fatal adverse effects represent significant concerns for future development. In vitro transcribed (IVT) mRNA therapeutics, which possess a high safety profile and straightforward production methods, could provide a useful alternative for CAR cell construction. However, the low stability and transfection efficiency of IVT-mRNA in immune cells limit further applications. In this work, we successfully engineered CAR macrophages (CAR-Ms) and CAR T cells with CAR mRNA using lipid nanoparticles (LNPs). Both the LNP formulations and mRNA modifications were optimized for in vitro mRNA transfection. More importantly, the CAR macrophages and CAR T cells both demonstrated significant cytotoxic effects on B lymphoma in vitro, underscoring the great potential of mRNA-engineered adoptive cell therapy.
嵌合抗原受体 (CAR)-修饰过的过继细胞疗法标志着癌症治疗的一场革命，其基于在血液癌症的 CAR T 细胞疗法中取得的高度成功应答。由于 CAR 具有多功能结构，该技术可以轻松应用于其他免疫细胞类型，包括巨噬细胞和 NK 细胞，并应用于治疗许多其他癌症。然而，高成本和致命的副作用是未来发展的重大关注点。体外转录 (IVT) mRNA 疗法具有高安全性和简单的生产方法，可为 CAR 细胞构建提供一种有用的替代方法。然而，免疫细胞中 IVT-mRNA 的低稳定性和转染效率限制了其进一步的应用。在这项工作中，我们使用脂质纳米颗粒 (LNP) 成功地用 CAR mRNA 对 CAR 巨噬细胞 (CAR-Ms) 和 CAR T 细胞进行了工程化修饰。我们对 LNP 配方和 mRNA 修饰都进行了优化，以实现体外 mRNA 转染。更重要的是，CAR 巨噬细胞和 CAR T 细胞在体外均对 B 淋巴瘤表现出显著的细胞毒性作用，这突显了 mRNA 修饰过继细胞疗法的巨大潜力。
