肿瘤细胞治疗研究
英文原题：Dual-antigen targeted iPSC-derived chimeric antigen receptor-T cell therapy for refractory lymphoma.
Dual-antigen targeted iPSC-derived chimeric antigen receptor-T cell therapy for refractory lymphoma.
我们从诱导多能干细胞（iPSCs）中生成双抗原受体（DR）T细胞，以减轻肿瘤抗原逃逸。
我们利用诱导多能干细胞（iPSCs）生成了双抗原受体（DR）T细胞，以减轻肿瘤抗原逃逸。这些细胞被工程化改造以表达针对抗原细胞表面潜伏膜蛋白1（LMP1）的嵌合抗原受体（CAR；LMP1-CAR）以及针对细胞表面潜伏膜蛋白2（LMP2）的T细胞受体，并与人类白细胞抗原A24相关联，用于治疗难治性Epstein-Barr病毒相关淋巴瘤。我们将LMP1-CAR导入来源于LMP2特异性细胞毒性T淋巴细胞（CTLs）的iPSCs中，以生成对LMP1和LMP2具有活性的 rejuvenated CTLs（rejTs），即DRrejTs。所有接受DRrejT治疗的小鼠存活超过100天。此外，DRrejTs排斥了后续接种的淋巴瘤细胞，表明DRrejTs长期存续。我们还证明，靶向CD19和LMP2抗原的DRrejTs表现出强大的肿瘤抑制效果，并赋予了明显的生存优势。协同抗肿瘤效应和体内持久性，加上DRrejT疗法不受限制的可获得性，将提供强大且可持续的T细胞免疫治疗。
We generated dual-antigen receptor (DR) T cells from induced pluripotent stem cells (iPSCs) to mitigate tumor antigen escape. These cells were engineered to express a chimeric antigen receptor (CAR) for the antigen cell surface latent membrane protein 1 (LMP1; LMP1-CAR) and a T cell receptor directed to cell surface latent membrane protein 2 (LMP2), in association with human leucocyte antigen A24, to treat therapy-refractory Epstein-Barr virus-associated lymphomas. We introduced LMP1-CAR into iPSCs derived from LMP2-specific cytotoxic T lymphocytes (CTLs) to generate rejuvenated CTLs (rejTs) active against LMP1 and LMP2, or DRrejTs. All DRrejT-treated mice survived >100 days. Furthermore, DRrejTs rejected follow-up inocula of lymphoma cells, demonstrating that DRrejTs persisted long-term. We also demonstrated that DRrejTs targeting CD19 and LMP2 antigens exhibited a robust tumor suppressive effect and conferred a clear survival advantage. Co-operative antitumor effect and in vivo persistence, with unlimited availability of DRrejT therapy, will provide powerful and sustainable T cell immunotherapy.
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