A chemically inducible IL-2 receptor signaling complex allows for effective in vitro and in vivo selection of engineered CD4+ T cells

体内 细胞生物学 T细胞受体 FOXP3型 CD19 嵌合抗原受体 癌症研究 体外 T细胞 生物 免疫学 抗原 免疫系统 遗传学
作者
Peter J. Cook,Su Jung Yang,Gene I. Uenishi,Annaiz Grimm,Samuel E. West,Lijie Wang,Chester Jacobs,Andrea Repele,Travis Drow,Ahmad Boukhris,Noelle P. Dahl,Karen Sommer,Andrew M. Scharenberg,David J. Rawlings
出处
期刊:Molecular Therapy [Elsevier]
卷期号:31 (8): 2472-2488 被引量:11
标识
DOI:10.1016/j.ymthe.2023.04.021
摘要

Engineered T cells represent an emerging therapeutic modality. However, complex engineering strategies can present a challenge for enriching and expanding therapeutic cells at clinical scale. In addition, lack of in vivo cytokine support can lead to poor engraftment of transferred T cells, including regulatory T cells (Treg). Here, we establish a cell-intrinsic selection system that leverages the dependency of primary T cells on IL-2 signaling. FRB-IL2RB and FKBP-IL2RG fusion proteins were identified permitting selective expansion of primary CD4+ T cells in rapamycin supplemented medium. This chemically inducible signaling complex (CISC) was subsequently incorporated into HDR donor templates designed to drive expression of the Treg master regulator FOXP3. Following editing of CD4+ T cells, CISC+ engineered Treg (CISC EngTreg) were selectively expanded using rapamycin and maintained Treg activity. Following transfer into immunodeficient mice treated with rapamycin, CISC EngTreg exhibited sustained engraftment in the absence of IL-2. Furthermore, in vivo CISC engagement increased the therapeutic activity of CISC EngTreg. Finally, an editing strategy targeting the TRAC locus permitted generation and selective enrichment of CISC+ functional CD19-CAR-T cells. Together, CISC provides a robust platform to achieve both in vitro enrichment and in vivo engraftment and activation, features likely beneficial across multiple gene-edited T cell applications.
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