CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
AKT 抑制产生强效多功能的临床级 AUTO1 CAR-T 细胞并增强功能与存活
英文原题：AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival.
查看英文原题
AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival.
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研究概要
最终，以 VIII 制备的 AUTO1 可能开始克服导致 CD19+ 复发的产品特异性因素。
中文摘要
背景
AUTO1是一种解离速率较快的CD19靶向嵌合抗原受体（CAR），已在成人淋巴细胞白血病中成功开展临床研究。富含干细胞样记忆T细胞（Tscm）和中央记忆T细胞（Tcm）的CAR-T 细胞群扩增和持续性最佳，但经多线治疗的成人患者中这类细胞数量较少。为改善这一问题，研究评估加入AKT抑制剂VIII，旨在使T细胞扩增与分化过程解耦，从而富集Tscm/Tcm亚群。
方法
在基于半自动化CliniMACS Prodigy平台的AUTO1制造流程中加入VIII，并分别在小规模和cGMP规模下开展生产。
结果
加入VIII制备的AUTO1富集Tscm/Tcm，在体外扩增和细胞毒性更强，体内抗肿瘤活性也更优。此外，VIII使AUTO1向Th1/Th17表型偏移，提高多功能性，并赋予其独特代谢特征及新的自噬特征，从而支持增强扩增和细胞毒性。ALLCAR19研究中B-ALL患者的VIII培养AUTO1产品较平行对照产品具有更优表型、代谢和功能；基于VIII的生产方法可扩展至cGMP规模。
结论
VIII制备的AUTO1有望克服导致CD19阳性疾病复发的部分产品相关因素。
展开英文摘要原文
BACKGROUND
AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm numbers are poor in heavily pretreated adult patients. To improve this, we evaluate the use of AKT inhibitor (VIII) with the aim of uncoupling T-cell expansion from differentiation, to enrich Tscm/Tcm subsets.
METHODS
VIII was incorporated into the AUTO1 manufacturing process based on the semiautomated the CliniMACS Prodigy platform at both small and cGMP scale.
RESULTS
AUTO1 manufactured with VIII showed Tscm/Tcm enrichment, improved expansion and cytotoxicity in vitro and superior antitumor activity in vivo. Further, VIII induced AUTO1 Th1/Th17 skewing, increased polyfunctionality, and conferred a unique metabolic profile and a novel signature for autophagy to support enhanced expansion and cytotoxicity. We show that VIII-cultured AUTO1 products from B-ALL patients on the ALLCAR19 study possess superior phenotype, metabolism, and function than parallel control products and that VIII-based manufacture is scalable to cGMP.
CONCLUSION
Ultimately, AUTO1 generated with VIII may begin to overcome the product specific factors contributing to CD19+relapse.
论文信息
- 作者
- Mehra V、Agliardi G、Dias Alves Pinto J、Shafat MS、Garai AC、Green L、Hotblack A、Arce Vargas F
- 第一作者单位
- Research Department of Haematology, University College London, London, UK.United Kingdom
- 通讯作者单位
- Research Department of Haematology, University College London, London, UK c.roddie@ucl.ac.uk.United Kingdom
- 文献类型
- 非美国政府资助研究
- 期刊
- Journal for immunotherapy of cancer2023 Sep
- 原文标识
- PubMed 37709295 · DOI 10.1136/jitc-2023-007002
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