嵌合抗原受体
白血病
细胞因子
T细胞
癌症研究
过继性细胞移植
CD19
免疫疗法
细胞因子释放综合征
细胞毒性T细胞
白细胞介素2
生物
免疫学
抗原
免疫系统
体外
生物化学
作者
Qian Zhang,Morgan Hresko,Lora K. Picton,Leon Su,Michael J. Hollander,Selene Nuñez-Cruz,Zheng Zhang,Charles-Antoine Assenmacher,Jonathan T. Sockolosky,K. Christopher García,Michael C. Milone
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2021-12-22
卷期号:13 (625)
被引量:69
标识
DOI:10.1126/scitranslmed.abg6986
摘要
Interleukin-2 (IL-2) is a central T cell cytokine that promotes T cell proliferation and effector function; however, toxicity due to its pluripotency limits its application to enhance CAR T cell immunotherapy. Previously, mouse IL-2 and its cognate receptor were engineered to create an orthogonal (ortho) cytokine-cytokine receptor pair capable of delivering an IL-2 signal without toxicity. Here, we engineered a human orthogonal IL-2 (ortho-hIL-2) and human orthogonal IL-2Rβ (ortho-hIL-2Rβ) pair, containing human-specific mutations. Ortho-hIL-2 is selective toward ortho-hIL-2Rβ–expressing cells with no appreciable signaling on wild-type T cells. Ortho-hIL-2 induces IL-2 receptor signaling and supports proliferation of both an IL-2–dependent cell line and primary T cells transduced to express the ortho-hIL-2Rβ. Using CD19-specific chimeric antigen receptor (CAR) T cells, we show that ortho-hIL-2 induces a dose-dependent increase in ortho-hIL-2Rβ+ CAR T cell expansion in vivo by as much as 1000-fold at 2 weeks after adoptive transfer into immunodeficient mice bearing CD19+ Nalm6 leukemia xenografts. Ortho-hIL-2 can rescue the antileukemic effect of an otherwise suboptimal CAR T cell dose. In addition, ortho-hIL-2 administration initiated at the time of leukemic relapse after CAR T cell therapy can rescue an otherwise failed antileukemic response. These data highlight the potential of combining an orthogonal cytokine approach with T cell–based immunotherapies to augment the antitumor efficacy of engineered T cells.
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