دورية أكاديمية
A rational approach to assess off-target reactivity of a dual-signal integrator for T cell therapy.
| العنوان: | A rational approach to assess off-target reactivity of a dual-signal integrator for T cell therapy. |
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| المؤلفون: | Wang X; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA., Wong LM; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA., McElvain ME; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA., Martire S; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA., Lee WH; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA., Li CZ; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA., Fisher FA; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA., Maheshwari RL; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA., Wu ML; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA., Imun MC; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA., Murad R; Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA., Toledo Warshaviak D; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA., Yin J; Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA., Kamb A; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA. Electronic address: akamb@a2bio.com., Xu H; A2 Biotherapeutics, 30301 Agoura Rd., Agoura Hills, CA 91301, USA. Electronic address: hxu@a2bio.com. |
| المصدر: | Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2022 Feb 15; Vol. 437, pp. 115894. Date of Electronic Publication: 2022 Jan 25. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Academic Press Country of Publication: United States NLM ID: 0416575 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0333 (Electronic) Linking ISSN: 0041008X NLM ISO Abbreviation: Toxicol Appl Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: New York, NY : Academic Press Original Publication: New York. |
| مواضيع طبية MeSH: | Cell- and Tissue-Based Therapy*, Receptors, Antigen, T-Cell/*metabolism , T-Lymphocytes/*physiology, Antigens, CD19/genetics ; Antigens, CD19/metabolism ; Cell Line, Tumor ; Computational Biology ; Gene Deletion ; Gene Expression Regulation ; Humans ; RNA, Messenger/genetics ; RNA, Messenger/metabolism |
| مستخلص: | Cell therapy is an emerging therapeutic modality with the power to exploit new cancer targets and potentially achieve positive outcomes for patients with few other options. Like all synthetic treatments, cell therapy has the risk of toxicity via unpredicted off-target behavior. We describe an empirical method to model off-tumor, off-target reactivity of receptors used for investigational T cell therapies. This approach utilizes an optimal panel of diverse human cell-lines to capture the large majority of protein-coding gene expression in adult human tissues. We apply this cell-line set to test Jurkat and primary T cells engineered with a dual-signal integrator, called Tmod TM , that contains an activating receptor (activator) and a separate inhibitory receptor (blocker). In proof-of-concept experiments, we use CD19 as the activating antigen and HLA-A*02 as the blocker antigen. This specific Tmod system, which employs a blocker targeting a ubiquitously expressed HLA class I antigen to inhibit CAR activation, has an inherent mechanism for selectivity/safety, designed to activate only when a specific HLA class I antigen is lost. Nonetheless, it is important to test off-target reactivity in functional assays, especially given the disconnect between ligand-binding and function among T cell receptors (TCRs) and chimeric antigen receptors (CARs). We show these cell-based assays yield consistent results with high sensitivity and specificity. The general strategy is likely applicable to more traditional single-receptor CAR- and TCR-T therapeutics. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Cell-based; Cross-reactivity; Functional assay; Genome; Safety; T cell therapy; Tmod |
| المشرفين على المادة: | 0 (Antigens, CD19) 0 (CD19 molecule, human) 0 (RNA, Messenger) 0 (Receptors, Antigen, T-Cell) |
| تواريخ الأحداث: | Date Created: 20220127 Date Completed: 20220303 Latest Revision: 20220303 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1016/j.taap.2022.115894 |
| PMID: | 35085592 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1096-0333 |
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| DOI: | 10.1016/j.taap.2022.115894 |