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.

我们从诱导性多能干细胞 (iPSC) 中生成双抗原受体 (DR) T 细胞，以减轻肿瘤抗原逃逸。这些细胞被设计为表达抗原细胞表面潜伏膜蛋白 1（LMP1；LMP1-CAR）的嵌合抗原受体（CAR）和针对细胞表面潜伏膜蛋白 2（LMP2）的 T 细胞受体，与人类相关白细胞抗原 A24，用于治疗难治性 Epstein-Barr 病毒相关淋巴瘤。我们将 LMP1-CAR 引入到源自 LMP2 特异性细胞毒性 T 淋巴细胞 (CTL) 的 iPSC 中，以生成对 LMP1 和 LMP2 或 DRrejT 具有活性的再生 CTL (rejT)。所有 DRrejT 处理的小鼠均存活 > 100 天。此外，DRrejTs 拒绝了淋巴瘤细胞的后续接种，表明 DRrejTs 长期存在。我们还证明靶向 CD19 和 LMP2 抗原的 DRrejTs 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。