抗IL10R CAR-T细胞释放抗CD33双特异性抗体的双靶向方法可增强对急性髓性白血病细胞的杀伤效果。

IF 6.6 2区 医学 Q1 Medicine
Cellular Oncology Pub Date : 2024-10-01 Epub Date: 2024-07-15 DOI:10.1007/s13402-024-00971-5
Zhifeng Yan, Runxia Gu, Haotian Ma, Nianci Chen, Ting Zhang, Yingxi Xu, Shaowei Qiu, Haiyan Xing, Kejing Tang, Zheng Tian, Qing Rao, Min Wang, Jianxiang Wang
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引用次数: 0

摘要

背景:免疫疗法,包括嵌合抗原受体(CAR)T细胞和双特异性抗体(BsAbs),在急性髓性白血病(AML)的治疗中遇到了一些挑战,包括这些疗法的持久性有限、抗原丢失和白血病干细胞(LSCs)对治疗的耐药性。方法:在这里,我们提出了一种新的双靶向方法,利用工程化的抗IL10R CAR-T细胞分泌靶向CD33的双特异性抗体。这一创新策略源于我们之前的研究,该研究建立了IL-10与急性髓性白血病细胞干性之间的联系,旨在提高靶向效率,同时消灭LSCs和急性髓性白血病囊胚:我们首先证明了这种协同方法在消灭表达不同水平靶抗原的急性髓细胞白血病细胞系和原代细胞方面的卓越疗效,即使是在 CD33 或 IL10R 低表达的情况下也是如此。此外,分泌抗 CD33 bsAbs 的 IL10R CAR-T 细胞(CAR.BsAb-T)不仅能增强 IL10R CAR-T 细胞的激活和诱导细胞毒性,还能增强旁观者 T 细胞的激活和诱导细胞毒性,从而更有效地靶向 CD33 阳性的肿瘤细胞。我们的体内实验进一步证明,CAR.BsAb-T 细胞可以有效地重新定向 T 细胞,减少肿瘤负荷,并且没有明显的毒性。此外,通过这种策略将 bsAbs 运送到肿瘤局部,有助于减轻与原型 bsAbs 快速清除相关的药代动力学挑战:总之,单载体靶向 IL10R CAR(随后分泌 CD33 靶向 bsAb)的工程设计解决了 IL10R 和 CD33 异质性表达导致的免疫逃逸问题,代表了旨在改善治疗效果的急性髓细胞性白血病疗法的一个有希望的进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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.

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.

Background: Immunotherapies, including chimeric antigen receptor (CAR) T cells and bispecific antibodies (BsAbs), encounter several challenges in the management of acute myeloid leukemia (AML), including limited persistence of these treatments, antigen loss and resistance of leukemia stem cells (LSCs) to therapy.

Methods: Here, we proposed a novel dual-targeting approach utilizing engineered anti-IL10R CAR-T cells to secrete bispecific antibodies targeting CD33. This innovative strategy, rooted in our previous research which established a connection between IL-10 and the stemness of AML cells, designed to improve targeting efficiency and eradicate both LSCs and AML blasts.

Results: We first demonstrated the superior efficacy of this synergistic approach in eliminating AML cell lines and primary cells expressing different levels of the target antigens, even in cases of low CD33 or IL10R expression. Furthermore, the IL10R CAR-T cells that secret anti-CD33 bsAbs (CAR.BsAb-T), exhibited an enhanced activation and induction of cytotoxicity not only in IL10R CAR-T cells but also in bystander T cells, thereby more effectively targeting CD33-positive tumor cells. Our in vivo experiments provided additional evidence that CAR.BsAb-T cells could efficiently redirect T cells, reduce tumor burden, and demonstrate no significant toxicity. Additionally, delivering bsAbs locally to the tumor sites through this strategy helps mitigate the pharmacokinetic challenges typically associated with the rapid clearance of prototypical bsAbs.

Conclusions: Overall, the engineering of a single-vector targeting IL10R CAR, which subsequently secretes CD33-targeted bsAb, addresses the issue of immune escape due to the heterogeneous expression of IL10R and CD33, and represents a promising progress in AML therapy aimed at improving treatment outcomes.

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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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