Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Science. 2018 Mar 2;359(6379):1037-1042. doi: 10.1126/science.aar3246.
Interleukin-2 (IL-2) is a cytokine required for effector T cell expansion, survival, and function, especially for engineered T cells in adoptive cell immunotherapy, but its pleiotropy leads to simultaneous stimulation and suppression of immune responses as well as systemic toxicity, limiting its therapeutic use. We engineered IL-2 cytokine-receptor orthogonal () pairs that interact with one another, transmitting native IL-2 signals, but do not interact with their natural cytokine and receptor counterparts. Introduction of IL-2Rβ into T cells enabled the selective cellular targeting of IL-2 to engineered CD4 and CD8 T cells in vitro and in vivo, with limited off-target effects and negligible toxicity. IL-2 pairs were efficacious in a preclinical mouse cancer model of adoptive cell therapy and may therefore represent a synthetic approach to achieving selective potentiation of engineered cells.
白细胞介素-2 (IL-2) 是效应 T 细胞扩增、存活和功能所必需的细胞因子，特别是在过继细胞免疫疗法中的工程 T 细胞中，但它的多效性导致免疫反应的同时刺激和抑制以及全身毒性，限制了其治疗用途。我们设计了白细胞介素-2 细胞因子受体正交 () 对，它们相互作用，传递天然的白细胞介素-2 信号，但不与它们的天然细胞因子和受体对应物相互作用。将 IL-2Rβ 引入 T 细胞中，使得能够在体外和体内选择性地将白细胞介素-2 靶向到工程化的 CD4 和 CD8 T 细胞，同时具有有限的脱靶效应和可忽略的毒性。IL-2 对在过继细胞治疗的临床前小鼠癌症模型中是有效的，因此可能代表了实现工程细胞选择性增强的一种合成方法。
