肿瘤细胞治疗研究
英文原题：Chimeric PD‑1 receptor redirects primary T cells against childhood solid tumors but not to PD‑1 ligand‑positive CD80‑coexpressing cells.
Chimeric PD‑1 receptor redirects primary T cells against childhood solid tumors but not to PD‑1 ligand‑positive CD80‑coexpressing cells.
PD 1 配体是儿科实体瘤有希望的治疗靶点。
用嵌合抗原受体（CAR）工程化的 T 细胞治疗实体瘤的临床应用具有挑战性。其主要原因涉及肿瘤免疫逃避机制，包括免疫检查点分子的高表达，例如程序性死亡1（PD 1）配体PD L1和PD L2。 CAR T 细胞输注后，即使在天然不表达 PD L1 的肿瘤中，也观察到了肿瘤中 PD L1 的诱导表达。此外，许多类型的儿科癌症没有合适的 CAR T 细胞治疗靶点。因此，本研究旨在开发针对PD L1和PD L2的新型CAR T细胞，并评估其对儿童实体瘤的疗效。在不使用单链可变片段的情况下，开发了一种新型 CAR，其包含人 PD 1 受体的免疫球蛋白 V 组结构域作为抗原结合位点（PD 1 CAR T）。通过在离体扩增培养物中添加抗PD 1抗体nivolumab，成功制造了PD 1 CAR T细胞，以防止在制造过程中由于激活的人T细胞中PD L1的诱导表达而导致自相残杀。研究表明，在体外暴露于干扰素和/或肿瘤坏死因子（肿瘤浸润性 T 细胞分泌的细胞因子）时，各种儿科实体瘤细胞中的 PD L1（以及较小程度的 PD L2）表达高度上调，这些细胞最初没有表现出或表现出非常低的表达。此外，PD 1 CAR-T 细胞对表达 PD L1 和 PD L2 的儿科实体瘤细胞表现出强大的细胞毒活性。相反，PD 1 CAR T细胞对共表达CD80的PD L1阳性细胞的作用显着减弱，这表明PD 1 CAR T细胞对正常免疫细胞（包括抗原呈递细胞）的毒性可以最小化。总之，PD 1 配体是儿科实体瘤有希望的治疗靶点。 PD 1 CAR T 细胞，无论是单独使用还是与其他靶点的 CAR T 细胞联合使用，都是实体瘤的潜在治疗选择。
The clinical application of T cells engineered with chimeric antigen receptors (CARs) for solid tumors is challenging. A major reason for this involves tumor immune evasion mechanisms, including the high expression of immune checkpoint molecules, such as the programmed death 1 (PD 1) ligands PD L1 and PD L2. The inducible expression of PD L1 in tumors has been observed after CAR T cell infusion, even in tumors natively not expressing PD L1. Furthermore, numerous types of pediatric cancer do not have suitable targets for CAR T cell therapy. Therefore, the present study aimed to develop novel CAR T cells that target PD L1 and PD L2, and to evaluate their efficacy against pediatric solid tumors. A novel CAR harboring the immunoglobulin V set domain of the human PD 1 receptor as an antigen binding site (PD 1 CAR T) was developed without using a single chain variable fragment. PD 1 CAR T cells were successfully manufactured by adding an anti PD 1 antibody, nivolumab, to the ex vivo expansion culture to prevent fratricide during the manufacturing process due to the inducible expression of PD L1 in activated human T cells. The expression of PD L1 (and PD L2 to a lesser extent) was revealed to be highly upregulated in various pediatric solid tumor cells, which displayed no or very low expression initially, on in vitro exposure to interferon and/or tumor necrosis factor , which are cytokines secreted by tumor infiltrating T cells. Furthermore, PD 1 CAR-T cells exhibited strong cytotoxic activity against pediatric solid tumor cells expressing PD L1 and PD L2. Conversely, the effect of PD 1 CAR T cells was significantly attenuated against PD L1 positive cells coexpressing CD80, suggesting that the toxicity of PD 1 CAR T cells to normal immune cells, including antigen presenting cells, can be minimized. In conclusion, PD 1 ligands are promising therapeutic targets for pediatric solid tumors. PD 1 CAR T cells, either alone or in combination with CAR T cells with other targets, represent a potential treatment option for solid tumors.
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