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细胞因子缀合以增强 T 细胞疗法。

Cytokine conjugation to enhance T cell therapy.

机构信息

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.

出版信息

Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2213222120. doi: 10.1073/pnas.2213222120. Epub 2022 Dec 28.

Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99da/9910457/8534dc2e8d54/pnas.2213222120fig01.jpg

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