Automated manufacture of ΔNPM1 TCR-engineered T cells for AML therapy

IF 4.6 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-02-27 DOI:10.1016/j.omtm.2024.101224

Isabella Elias Yonezawa Ogusuku, Vera Herbel, Simon Lennartz, Caroline Brandes, Eva Argiro, Caroline Fabian, Carola Hauck, Conny Hoogstraten, Sabrina Veld, Lois Hageman, Karin Teppert, Georgia Koutsoumpli, Marieke Griffioen, Nadine Mockel-Tenbrinck, Thomas Schaser, Rosa de Groot, Ian C.D. Johnston, Dominik Lock

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引用次数: 0

Abstract

Acute myeloid leukemia (AML) is a heterogeneous malignancy that requires further therapeutic improvement, especially for the elderly and for subgroups with poor prognosis. A recently discovered T cell receptor (TCR) targeting mutant nucleophosmin 1 (ΔNPM1) presents an attractive option for the development of a cancer antigen-targeted cellular therapy. Manufacturing of TCR-modified T cells, however, is still limited by a complex, time-consuming, and laborious procedure. Therefore, this study specifically addressed the requirements for a scaled manufacture of ΔNPM1-specific T cells in an automated, closed, and good manufacturing practice-compliant process. Starting from cryopreserved leukapheresis, 2E8 CD8-positive T cells were enriched, activated, lentivirally transduced, expanded, and finally formulated. By adjusting and optimizing culture conditions, we additionally reduced the manufacturing time from 12 to 8 days while still achieving a clinically relevant yield of up to 5.5E9 ΔNPM1 TCR-engineered T cells. The cellular product mainly consisted of highly viable CD8-positive T cells with an early memory phenotype. ΔNPM1-TCR CD8 T cells manufactured with the optimized process showed specific killing of AML and . The process has been implemented in an upcoming phase 1/2 clinical trial for the treatment of NPM1-mutated AML.

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自动制造用于急性髓细胞性白血病治疗的 ΔNPM1 TCR 工程 T 细胞

急性髓性白血病（AML）是一种异质性恶性肿瘤，需要进一步改进治疗方法，尤其是针对老年人和预后不良的亚群。最近发现的一种靶向突变型核嗜磷蛋白 1（ΔNPM1）的 T 细胞受体（TCR）为开发癌症抗原靶向细胞疗法提供了一种极具吸引力的选择。然而，TCR修饰T细胞的制造仍然受到复杂、耗时和费力的程序的限制。因此，本研究特别针对ΔNPM1特异性T细胞的规模化生产要求，采用了自动化、封闭式和符合良好生产规范的流程。从低温保存的白细胞开始，对 2E8 CD8 阳性 T 细胞进行富集、激活、慢病毒转导、扩增，最后进行配制。通过调整和优化培养条件，我们还将制造时间从 12 天缩短到了 8 天，同时还获得了高达 5.5E9 ΔNPM1 TCR 工程 T 细胞的临床相关产量。细胞产品主要由具有早期记忆表型的高活性 CD8 阳性 T 细胞组成。用优化工艺制造的ΔNPM1-TCR CD8 T细胞对急性髓细胞白血病和白血病有特异性杀伤作用。该工艺已用于即将开展的治疗 NPM1 突变 AML 的 1/2 期临床试验。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.90

自引率

4.30%

发文量

163

审稿时长

12 weeks

期刊介绍： The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.