CD33-CD123 条件性门控可降低毒性，同时增强靶向急性髓系白血病的嵌合抗原受体 T 细胞的特异性和记忆表型。
CD33-CD123 IF-THEN Gating Reduces Toxicity while Enhancing the Specificity and Memory Phenotype of AML-Targeting CAR-T Cells.
作者信息
Jambon Samy, Sun Jianping, Barman Shawn, Muthugounder Sakunthala, Bito Xue Rachel, Shadfar Armita, Kovach Alexandra E, Wood Brent L, Thoppey Manoharan Varsha, Morrissy A Sorana, Bhojwani Deepa, Wayne Alan S, Pulsipher Michael A, Kim Yong-Mi, Asgharzadeh Shahab, Parekh Chintan, Moghimi Babak
机构信息
Division of Hematology and Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
出版信息
Blood Cancer Discov. 2025 Jan 8;6(1):55-72. doi: 10.1158/2643-3230.BCD-23-0258.
Abstract
Our study demonstrates the use of "IF-THEN" SynNotch-gated CAR-T cells targeting CD33 and CD123 in AML reduces off-tumor toxicity. This strategy enhances T-cell phenotype, improves expansion, preserves HSPCs, and mitigates cytokine release syndrome-addressing critical limitations of existing AML CAR-T therapies.
摘要
我们的研究表明，在急性髓系白血病（AML）中使用靶向CD33和CD123的“如果-那么”（IF-THEN）合成Notch受体门控嵌合抗原受体（CAR）T细胞可降低肿瘤外毒性。该策略增强了T细胞表型，改善了细胞扩增，保护了造血干细胞，并减轻了细胞因子释放综合征，解决了现有AML CAR-T疗法的关键局限性。
相似文献
1
CD33-CD123 IF-THEN Gating Reduces Toxicity while Enhancing the Specificity and Memory Phenotype of AML-Targeting CAR-T Cells.CD33-CD123 条件性门控可降低毒性，同时增强靶向急性髓系白血病的嵌合抗原受体 T 细胞的特异性和记忆表型。
Blood Cancer Discov. 2025 Jan 8;6(1):55-72. doi: 10.1158/2643-3230.BCD-23-0258.
2
Loop33 × 123 CAR-T targeting CD33 and CD123 against immune escape in acute myeloid leukemia.针对急性髓系白血病免疫逃逸的靶向 CD33 和 CD123 的 Loop33 × 123 CAR-T。
Cancer Immunol Immunother. 2024 Nov 13;74(1):20. doi: 10.1007/s00262-024-03847-7.
3
CD70 CAR T cells secreting an anti-CD33/anti-CD3 dual-targeting antibody overcome antigen heterogeneity in AML.分泌抗CD33/抗CD3双靶向抗体的CD70嵌合抗原受体T细胞克服了急性髓系白血病中的抗原异质性。
Blood. 2025 Feb 13;145(7):720-731. doi: 10.1182/blood.2023023210.
4
Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design.CD33 导向嵌合抗原受体 T 细胞免疫疗法治疗急性髓系白血病的系统临床前评价确定了优化的构建设计。
J Immunother Cancer. 2021 Sep;9(9). doi: 10.1136/jitc-2021-003149.
5
A dual-targeting approach with anti-IL10R CAR-T cells engineered to release anti-CD33 bispecific antibody in enhancing killing effect on acute myeloid leukemia cells.采用双靶点策略，用抗 IL10R CAR-T 细胞工程改造，使其释放抗 CD33 双特异性抗体，增强对急性髓细胞白血病细胞的杀伤作用。
Cell Oncol (Dordr). 2024 Oct;47(5):1879-1895. doi: 10.1007/s13402-024-00971-5. Epub 2024 Jul 15.
6
Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts.开启和关闭嵌合抗原受体T细胞：一种将T细胞重新靶向急性髓系白血病母细胞的新型模块化平台。
Blood Cancer J. 2016 Aug 12;6(8):e458. doi: 10.1038/bcj.2016.61.
7
Finding new lanes: Chimeric antigen receptor (CAR) T-cells for myeloid leukemia.寻找新途径：嵌合抗原受体（CAR）T 细胞治疗髓系白血病。
Cancer Rep (Hoboken). 2020 Apr;3(2):e1222. doi: 10.1002/cnr2.1222. Epub 2020 Jan 8.
8
CD33-Specific Chimeric Antigen Receptor T Cells with Different Co-Stimulators Showed Potent Anti-Leukemia Efficacy and Different Phenotype.不同共刺激分子的 CD33 特异性嵌合抗原受体 T 细胞表现出强大的抗白血病疗效和不同的表型。
Hum Gene Ther. 2018 May;29(5):626-639. doi: 10.1089/hum.2017.241. Epub 2018 Mar 19.
9
Tandem bispecific CD123/CLL-1 CAR-T cells exhibit specific cytolytic effector functions against human acute myeloid leukaemia.双特异性 CD123/CLL-1 CAR-T 细胞对人急性髓系白血病表现出特异性细胞溶解效应功能。
Eur J Haematol. 2024 Jan;112(1):83-93. doi: 10.1111/ejh.14104. Epub 2023 Sep 15.
10
Developing a membrane-proximal CD33-targeting CAR T cell.开发一种靶向膜近端 CD33 的嵌合抗原受体 T 细胞。
J Immunother Cancer. 2024 May 20;12(5):e009013. doi: 10.1136/jitc-2024-009013.
引用本文的文献
1
Insights into next-generation immunotherapy designs and tools: molecular mechanisms and therapeutic prospects.下一代免疫疗法设计与工具的见解：分子机制与治疗前景。
J Hematol Oncol. 2025 Jun 7;18(1):62. doi: 10.1186/s13045-025-01701-6.
2
Mechanisms of antigen-dependent resistance to chimeric antigen receptor (CAR)-T cell therapies.嵌合抗原受体（CAR）-T细胞疗法抗原依赖性耐药机制。
Cancer Cell Int. 2025 Feb 24;25(1):64. doi: 10.1186/s12935-025-03697-y.
本文引用的文献
1
Structural surfaceomics reveals an AML-specific conformation of integrin β as a CAR T cellular therapy target.结构表面组学揭示了整合素β作为 CAR T 细胞治疗靶点的 AML 特异性构象。
Nat Cancer. 2023 Nov;4(11):1592-1609. doi: 10.1038/s43018-023-00652-6. Epub 2023 Oct 30.
2
Cooperative CAR targeting to selectively eliminate AML and minimize escape.协同 CAR 靶向治疗以选择性消除 AML 并最小化逃逸。
Cancer Cell. 2023 Nov 13;41(11):1871-1891.e6. doi: 10.1016/j.ccell.2023.09.010. Epub 2023 Oct 5.
3
Co-opting signalling molecules enables logic-gated control of CAR T cells.信号分子的协同作用使 CAR T 细胞的逻辑门控控制成为可能。
Nature. 2023 Mar;615(7952):507-516. doi: 10.1038/s41586-023-05778-2. Epub 2023 Mar 8.
4
The proteogenomic subtypes of acute myeloid leukemia.急性髓系白血病的蛋白质基因组亚型
Cancer Cell. 2022 Mar 14;40(3):301-317.e12. doi: 10.1016/j.ccell.2022.02.006. Epub 2022 Mar 3.
5
NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity.非门控 CD93 CAR T 细胞可有效靶向 AML，同时最小化内皮细胞交叉反应性。
Blood Cancer Discov. 2021 Sep 16;2(6):648-665. doi: 10.1158/2643-3230.BCD-20-0208. eCollection 2021 Nov.
6
CD33-directed immunotherapy with third-generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33-edited acute myeloid leukemia and hematopoietic stem and progenitor cells.第三代嵌合抗原受体 T 细胞和吉妥珠单抗奥佐米星联合针对未修饰和 CD33 编辑的急性髓系白血病及造血干细胞和祖细胞的 CD33 导向免疫治疗。
Int J Cancer. 2022 Apr 1;150(7):1141-1155. doi: 10.1002/ijc.33865. Epub 2021 Nov 23.
7
SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models.SynNotch CAR 电路增强实体瘤识别并促进小鼠模型中的持续抗肿瘤活性。
Sci Transl Med. 2021 Apr 28;13(591). doi: 10.1126/scitranslmed.abd8836.
8
SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma.SynNotch-CAR T 细胞在治疗脑胶质瘤中克服了特异性、异质性和持久性方面的挑战。
Sci Transl Med. 2021 Apr 28;13(591). doi: 10.1126/scitranslmed.abe7378.
9
Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling.短暂休息通过表观遗传重塑恢复衰竭的 CAR-T 细胞的功能。
Science. 2021 Apr 2;372(6537). doi: 10.1126/science.aba1786.
10
Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma.GD2-B7H3 SynNotch CAR-T 在转移性神经母细胞瘤中的疗效和特异性的临床前评估。
Nat Commun. 2021 Jan 21;12(1):511. doi: 10.1038/s41467-020-20785-x.
Zotero 插件