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使用基于 Quantum pBac 的 CAR-T 工程系统制造靶向 CD20/CD19 的 iCasp9 可调节性 CAR-TSCM 细胞。

Manufacturing CD20/CD19-targeted iCasp9 regulatable CAR-TSCM cells using a Quantum pBac-based CAR-T engineering system.

机构信息

GenomeFrontier Therapeutics TW Co., Ltd., Taipei City, Taiwan (R.O.C.).

Division of Hematology, Chang Gung Medical Foundation, Linkou Branch, Taipei City, Taiwan (R.O.C.).

出版信息

PLoS One. 2024 Aug 27;19(8):e0309245. doi: 10.1371/journal.pone.0309245. eCollection 2024.

DOI:10.1371/journal.pone.0309245
PMID:39190688
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11349195/
Abstract

CD19-targeted chimeric antigen receptor (CAR) T cell therapies have driven a paradigm shift in the treatment of relapsed/refractory B-cell malignancies. However, >50% of CD19-CAR-T-treated patients experience progressive disease mainly due to antigen escape and low persistence. Clinical prognosis is heavily influenced by CAR-T cell function and systemic cytokine toxicities. Furthermore, it remains a challenge to efficiently, cost-effectively, and consistently manufacture clinically relevant numbers of virally engineered CAR-T cells. Using a highly efficient piggyBac transposon-based vector, Quantum pBac™ (qPB), we developed a virus-free cell-engineering system for development and production of multiplex CAR-T therapies. Here, we demonstrate in vitro and in vivo that consistent, robust and functional CD20/CD19 dual-targeted CAR-T stem cell memory (CAR-TSCM) cells can be efficiently produced for clinical application using qPB™. In particular, we showed that qPB™-manufactured CAR-T cells from cancer patients expanded efficiently, rapidly eradicated tumors, and can be safely controlled via an iCasp9 suicide gene-inducing drug. Therefore, the simplicity of manufacturing multiplex CAR-T cells using the qPB™ system has the potential to improve efficacy and broaden the accessibility of CAR-T therapies.

摘要

CD19 靶向嵌合抗原受体 (CAR) T 细胞疗法在复发/难治性 B 细胞恶性肿瘤的治疗中带来了范式转变。然而，超过 50%的 CD19-CAR-T 治疗患者出现疾病进展，主要是由于抗原逃逸和低持久性。临床预后受 CAR-T 细胞功能和全身细胞因子毒性的严重影响。此外，高效、具有成本效益且一致地制造大量具有临床相关性的病毒工程化 CAR-T 细胞仍然是一个挑战。我们使用高效的基于 piggyBac 转座子的载体 Quantum pBac™ (qPB)，开发了一种无病毒细胞工程系统，用于开发和生产多种 CAR-T 疗法。在这里，我们证明了体外和体内使用 qPB™ 可以有效地生产用于临床应用的一致、强大和功能的 CD20/CD19 双靶向 CAR-T 干细胞记忆 (CAR-TSCM) 细胞。特别是，我们表明，qPB™ 制造的来自癌症患者的 CAR-T 细胞可以高效扩增，迅速消除肿瘤，并且可以通过 iCasp9 自杀基因诱导药物安全控制。因此，使用 qPB™ 系统制造多种 CAR-T 细胞的简单性有可能提高疗效并拓宽 CAR-T 疗法的可及性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/901dc463099b/pone.0309245.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/43527d7c385d/pone.0309245.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/2818ebd7684a/pone.0309245.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/2afa4cb2e434/pone.0309245.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/7caf89c256fc/pone.0309245.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/719bc71aa2be/pone.0309245.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/901dc463099b/pone.0309245.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/43527d7c385d/pone.0309245.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/2818ebd7684a/pone.0309245.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/2afa4cb2e434/pone.0309245.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/7caf89c256fc/pone.0309245.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/719bc71aa2be/pone.0309245.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1673/11349195/901dc463099b/pone.0309245.g006.jpg

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