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猪源转座酶介导的抗 CD19 CAR-T 细胞经 aAPCs 或磁珠体外扩增后的评估。

Evaluation of piggyBac-mediated anti-CD19 CAR-T cells after ex vivo expansion with aAPCs or magnetic beads.

机构信息

Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.

Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.

出版信息

J Cell Mol Med. 2021 Jan;25(2):686-700. doi: 10.1111/jcmm.16118. Epub 2020 Nov 22.

DOI:10.1111/jcmm.16118
PMID:33225580
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7812273/
Abstract

Adoptive immunotherapy is a new potential method of tumour therapy, among which anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T cell), is a typical treatment agent for haematological malignancies. Previous clinical trials showed that the quality and phenotype of CAR-T cells expanded ex vivo would seriously affect the tumour treatment efficacy. Although magnetic beads are currently widely used to expand CAR-T cells, the optimal expansion steps and methods have not been completely established. In this study, the differences between CAR-T cells expanded with anti-CD3/CD28 mAb-coated beads and those expanded with cell-based aAPCs expressing CD19/CD64/CD86/CD137L/mIL-15 counter-receptors were compared. The results showed that the number of CD19-specific CAR-T cells with a 4-1BB and CD28 co-stimulatory domain was much greater with stimulation by aAPCs than that with beads. In addition, the expression of memory marker CD45RO was higher, whereas expression of exhausted molecules was lower in CAR-T cells expanded with aAPCs comparing with the beads. Both CAR-T cells showed significant targeted tumoricidal effects. The CAR-T cells stimulated with aAPCs secreted apoptosis-related cytokines. Moreover, they also possessed marked anti-tumour effect on NAMALWA xenograft mouse model. The present findings provided evidence on the safety and advantage of two expansion methods for CAR-T cells genetically modified by piggyBac transposon system.

摘要

过继免疫疗法是一种新的肿瘤治疗方法，其中抗 CD19 嵌合抗原受体 T 细胞疗法（CAR-T 细胞）是血液系统恶性肿瘤的典型治疗药物。以前的临床试验表明，体外扩增的 CAR-T 细胞的质量和表型会严重影响肿瘤治疗效果。尽管目前磁珠被广泛用于扩增 CAR-T 细胞，但尚未完全建立最佳的扩增步骤和方法。在这项研究中，比较了用抗 CD3/CD28 mAb 包被珠和表达 CD19/CD64/CD86/CD137L/mIL-15 反向受体的基于细胞的 aAPC 扩增的 CAR-T 细胞之间的差异。结果表明，与珠相比，aAPC 刺激产生的具有 4-1BB 和 CD28 共刺激结构域的 CD19 特异性 CAR-T 细胞数量要多得多。此外，与珠相比，在 aAPC 上扩增的 CAR-T 细胞中记忆标记物 CD45RO 的表达更高，而衰竭分子的表达则更低。两种 CAR-T 细胞均表现出显著的靶向杀伤肿瘤作用。用 aAPC 刺激的 CAR-T 细胞分泌与细胞凋亡相关的细胞因子。此外，它们对 NAMALWA 异种移植小鼠模型也具有明显的抗肿瘤作用。本研究结果为猪内肽酶转座子系统基因修饰的 CAR-T 细胞的两种扩增方法的安全性和优势提供了证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/601dfffee43d/JCMM-25-686-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/f207ac3df9c7/JCMM-25-686-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/a700e68b2490/JCMM-25-686-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/3d8bd74e3662/JCMM-25-686-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/8135a440511c/JCMM-25-686-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/18e7684a875f/JCMM-25-686-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/dc4c513e3352/JCMM-25-686-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/601dfffee43d/JCMM-25-686-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/f207ac3df9c7/JCMM-25-686-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/a700e68b2490/JCMM-25-686-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/3d8bd74e3662/JCMM-25-686-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/8135a440511c/JCMM-25-686-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/18e7684a875f/JCMM-25-686-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/dc4c513e3352/JCMM-25-686-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7616/7812273/601dfffee43d/JCMM-25-686-g007.jpg

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