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
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DOI：
10.1016/j.ymthe.2021.10.006
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发表时间：
2022-02-02
影响因子：
12.4
通讯作者：
Komatsu, Norio
中科院分区：
文献类型：
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作者：
Harada, Sakiko;Ando, Miki;Komatsu, Norio
我们从诱导多能干细胞（iPSC）产生双抗原受体（DR）T细胞以减轻肿瘤抗原逃逸。这些细胞被工程化以表达抗原细胞表面潜伏膜蛋白1（LMP 1; LMP 1-CAR）的嵌合抗原受体（CAR）和针对细胞表面潜伏膜蛋白2（LMP 2）的T细胞受体，与人白细胞抗原A24联合，以治疗难治性EB病毒相关淋巴瘤。我们将LMP 1-CAR引入来源于LMP 2特异性细胞毒性T淋巴细胞（CTL）的iPSC中，以产生对LMP 1和LMP 2有活性的再生CTL（rejT）或DRrejT。所有DRrejT治疗的小鼠均存活>100天。此外，DRrejTs拒绝淋巴瘤细胞的后续接种，表明DRrejTs长期持续。我们还证明了靶向CD 19和LMP 2抗原的DRrejT表现出强大的肿瘤抑制作用，并赋予明显的生存优势。协同抗肿瘤作用和体内持久性，以及DRrejT疗法的无限可用性，将提供强大且可持续的T细胞免疫疗法。
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.