John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138.
Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2213222120. doi: 10.1073/pnas.2213222120. Epub 2022 Dec 28.
Adoptive T cell transfer (ACT) therapies suffer from a number of limitations (e.g., poor control of solid tumors), and while combining ACT with cytokine therapy can enhance effectiveness, this also results in significant side effects. Here, we describe a nanotechnology approach to improve the efficacy of ACT therapies by metabolically labeling T cells with unnatural sugar nanoparticles, allowing direct conjugation of antitumor cytokines onto the T cell surface during the manufacturing process. This allows local, concentrated activity of otherwise toxic cytokines. This approach increases T cell infiltration into solid tumors, activates the host immune system toward a Type 1 response, encourages antigen spreading, and improves control of aggressive solid tumors and achieves complete blood cancer regression with otherwise noncurative doses of CAR-T cells. Overall, this method provides an effective and easily integrated approach to the current ACT manufacturing process to increase efficacy in various settings.
过继性 T 细胞转移(ACT)疗法存在许多局限性(例如,对实体瘤的控制效果不佳),而将 ACT 与细胞因子疗法相结合可以提高疗效,但也会导致严重的副作用。在这里,我们描述了一种纳米技术方法,通过用非天然糖纳米颗粒对 T 细胞进行代谢标记,来提高 ACT 疗法的疗效,允许在制造过程中将抗肿瘤细胞因子直接共轭到 T 细胞表面。这允许局部、集中地发挥 otherwise toxic cytokines 的活性。这种方法增加了 T 细胞向实体瘤的浸润,激活了宿主免疫系统向 1 型反应,鼓励抗原扩散,并改善了侵袭性实体瘤的控制,并在使用否则非治愈剂量的 CAR-T 细胞时实现完全血液癌消退。总的来说,这种方法为当前的 ACT 制造过程提供了一种有效且易于集成的方法,以提高各种情况下的疗效。