肿瘤细胞治疗研究
英文原题：Automated manufacture of ΔNPM1 TCR-engineered T cells for AML therapy.
急性髓系白血病（AML）是一种异质性恶性肿瘤，需要进一步的治疗改进，尤其是对老年人和预后不良的亚组。
急性髓系白血病（AML）是一种异质性恶性肿瘤，需要进一步的治疗改进，尤其是对老年患者和预后不良亚组。最近发现的一种靶向突变型核磷蛋白1（ΔNPM1）的T细胞受体（TCR）为开发靶向肿瘤抗原的细胞疗法提供了一个有吸引力的选择。然而，TCR修饰T细胞的制造仍然受限于复杂、耗时且繁琐的程序。因此，本研究专门针对以自动化、封闭且符合药品生产质量管理规范的方式规模化制造ΔNPM1特异性T细胞的要求进行了探讨。从冷冻保存的白细胞单采术开始，富集2E8 CD8阳性T细胞，进行激活、慢病毒转导、扩增，最后进行制剂化。通过调整和优化培养条件，我们还额外将制造时间从12天缩短至8天，同时仍实现了高达5.5E9 ΔNPM1 TCR工程化T细胞的临床相关产量。细胞产品主要由高活性的CD8阳性T细胞组成，具有早期记忆表型。使用优化工艺制造的ΔNPM1 TCR CD8 T细胞在体外和体内均显示出对AML的特异性杀伤。该工艺已应用于即将开展的用于治疗NPM1突变型AML的1/2期临床试验。
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 in vitro and in vivo . The process has been implemented in an upcoming phase 1/2 clinical trial for the treatment of NPM1-mutated AML.
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