肿瘤细胞治疗研究
英文原题：A Checkpoint Reversal Receptor Mediates Bipartite Activation and Enhances CAR T-cell Function.
为了抵消PD-L1抑制信号，我们设计了带有CD28或41BB共刺激内域的PD-1检查点逆转受体（CPR），并使用双顺反子载体将其与第一代或含CD28的第二代HER2特异性CAR（CPR/CART）共表达。
摘要：CAR-T 细胞 (CART) 在实体瘤中的功效受到免疫抑制的限制。在我们的研究中，我们观察到效应细胞因子介导原发性胶质母细胞瘤中 PD-L1 免疫检查点的上调。为了抵消 PD-L1 抑制信号，我们用 CD28 或 41BB 共刺激内域设计了 PD-1 检查点逆转受体 (CPR)，并使用双顺反子载体将它们与第一代或包含 CD28 的第二代 HER2 特异性 CAR (CPR/CART) 共表达。我们发现，通过 CAR 生成的信号 1 和 CPR 共刺激（信号 2），双向 T 细胞激活，微调促炎细胞因子的释放和持续的抗肿瘤活性。尽管 CPR28 和 CPR41BB 都能在体外有效抵消 PD-1 信号，但 CPR41BB 在与第一代 CAR (CAR /CPR41BB) 共表达时，可在重复抗原刺激后促进中枢记忆分化。 CAR /CPR41BB T细胞与肿瘤靶点形成强大的免疫突触，类似于含有41BB的第二代CART，保持与41BB共刺激相关的有利代谢参数，并在成血管细胞瘤和转移性骨肉瘤的异种移植模型中过继转移后表现出优异的抗肿瘤功能。因此，具有 41BB 共刺激的 CPR 分子可以减少 PD-1 抑制并补充 CAR 信号传导以优化 T 细胞激活，可以增强 CART 针对实体瘤的功效。意义：增强 CART 功能和持久性，同时平衡免疫效应器介导的炎症至关重要。利用我们的临床相关 HER2-CAR 平台，我们证明了可以在 CART 设计中利用 PD-1/PD-L1 免疫检查点等肿瘤固有信号来调节免疫突触和代谢参数，从而在不增加细胞因子产生的情况下改善抗肿瘤功能。
ABSTRACT: The efficacy of chimeric antigen receptor T cells (CART) in solid tumors is limited by immune inhibition. In our study, we observed that effector cytokines mediated the upregulation of the PD-L1 immune checkpoint in primary glioblastoma. To offset the PD-L1 inhibitory signal, we engineered PD-1 checkpoint reversal receptors (CPR) with a CD28 or 41BB costimulatory endodomain and coexpressed them with a first-generation or a CD28-containing second-generation HER2-specific CAR (CPR/CART) using bicistronic vectors. We found that bipartite T-cell activation, by CAR-generated signal 1 and CPR costimulation (signal 2), fine-tuned proinflammatory cytokine release and sustained antitumor activity. Whereas both CPR28 and CPR41BB effectively counteracted the PD-1 signal in vitro, CPR41BB, when coexpressed with a first-generation CAR (CAR /CPR41BB), promoted central memory differentiation following repeat antigenic stimulation. CAR /CPR41BB T cells formed a robust immune synapse with tumor targets, similar to a 41BB-containing second-generation CART, maintained the favorable metabolic parameters associated with 41BB costimulation, and demonstrated superior antitumor function after adoptive transfer in xenograft models of gioblastoma and metastatic osteosarcoma. Thus, a CPR molecule with 41BB costimulation that curtails PD-1 inhibition and complements CAR signaling to optimize T-cell activation could enhance CART efficacy against solid tumors. SIGNIFICANCE: Enhancing CART function and persistence while balancing immune effector-mediated inflammation is crucial. Using our clinically relevant HER2-CAR platform, we demonstrate that tumor-intrinsic signals like the PD-1/PD-L1 immune checkpoint can be leveraged in CART design to modulate immune synapse and metabolic parameters, improving antitumor function without increasing cytokine production.
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