肿瘤细胞治疗研究
英文原题：LMP2A-Targeting CAR-T Cells Equipped With Inducible IL-18 to Address EBV-Associated Malignancies.
我们的结果表明，LMP2A_CAR-Ts 和 LMP2A_iIL-18_TRUCKs 可特异性识别由 HLA-A*02:01 呈递的 EBV 来源 CLG 肽。
EB病毒（EBV）感染全球多达95%的人口，并持续存在于B细胞和上皮细胞中。EBV感染细胞不受控制地增殖可导致EBV相关恶性肿瘤，例如移植后淋巴增殖性疾病（PTLD）或鼻咽癌（NPC）。据估计，全球约1.8%的癌症死亡与EBV相关，目前治疗选择有限。作为一种新型治疗方法，研究者开发了靶向EBV来源潜伏膜蛋白2A（LMP2A）的CAR-T 细胞（LMP2A_CAR-T）。为特异性清除被细胞内病原体感染的恶性B细胞，研究者利用类似T细胞受体（TCR）的特异性，构建了针对HLA-A*02:01呈递的LMP2A来源肽CLGGLLTMV（CLG）的CAR。为增强肿瘤微环境中的功能，研究者还使LMP2A_CAR-T可诱导释放IL-12（LMP2A_iIL-12_TRUCK）或IL-18（LMP2A_iIL-18_TRUCK）。LMP2A_CAR-T及LMP2A_iIL-18_TRUCK可特异性识别HLA-A*02:01阳性的EBV转化B淋巴母细胞系，以及负载CLG肽的HLA-A*02:01阳性细胞（A02_CLG+细胞），证明了其靶向特异性；但出乎意料的是，LMP2A_iIL-12_TRUCK呈现不同的效应记忆T细胞和NK样表型，并表现出不依赖A02_CLG的反应性。相较之下，LMP2A_CAR-T和LMP2A_iIL-18_TRUCK可有效诱导T细胞信号传导和活化，释放细胞毒性介质（LMP2A_iIL-18_TRUCK还释放IL-18），并以靶标特异性方式介导细胞毒作用。结果表明，LMP2A_CAR-T及LMP2A_iIL-18_TRUCK可特异性识别HLA-A*02:01呈递的EBV来源CLG肽。尤其是LMP2A_iIL-18_TRUCK，其抗肿瘤应答进一步增强，并可能募集旁观者免疫细胞、克服EBV介导的免疫逃逸机制，有望成为多种EBV相关恶性肿瘤的新型治疗选择。
Epstein-Barr virus (EBV) infects up to 95% of the world's population and persists in B cells and epithelial cells. Uncontrolled proliferation of EBV-infected cells can result in the development of EBV-associated malignancies, for example, post-transplant lymphoproliferative disorder (PTLD) or nasopharyngeal cancer (NPC). It is estimated that 1.8% of deaths due to cancer worldwide are associated with EBV, and the treatment options are limited. As a new therapeutic approach, we developed chimeric antigen receptor T cells targeting EBV-derived latent membrane protein 2A (LMP2A_CAR-Ts). To enable specific elimination of malignant B cells infected with the intracellular pathogen, we utilised T-cell receptor (TCR)-like specificity to generate a CAR against the LMP2A-derived peptide CLGGLLTMV (CLG) presented in the context of HLA-A*02:01. To increase functionality in the tumour microenvironment, LMP2A_CAR-Ts were additionally equipped with inducible release of IL-12 (LMP2A_iIL-12_TRUCKs) or IL-18 (LMP2A_iIL-18_TRUCKs). LMP2A_CAR-Ts and LMP2A_iIL-18_TRUCKs specifically recognised HLA-A*02:01 + EBV-transformed B-lymphoblastoid cell lines and HLA-A*02:01 + cells loaded with CLG peptide (A02_CLG + cells), proving their target specificity, while, unexpectedly, LMP2A_iIL-12_TRUCKs exhibited a disparate T EM and NK-like phenotype and A02_CLG-independent reactivity. In contrast, LMP2A_CAR-Ts and LMP2A_iIL-18_TRUCKs effectively induced T-cell signalling, activation, release of cytotoxic mediators, including IL-18 by LMP2A_iIL-18_TRUCKs and mediated cytotoxicity in a target-specific manner. Our results demonstrate that LMP2A_CAR-Ts and LMP2A_iIL-18_TRUCKs specifically recognise the EBV-derived CLG peptide presented in the context of HLA-A*02:01. Especially, LMP2A_iIL-18_TRUCKs with an even improved anti-tumour response, as well as the potential to recruit bystander immune cells and overcome EBV-mediated immune evasion strategies, might serve as a novel treatment option for various EBV-associated malignancies.
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