程序性死亡 1 (PD-1) 和细胞毒性 T 淋巴细胞相关抗原 4 (CTLA-4) 的结合可以干扰 T 细胞激活所需的 CD28 信号传导。虽然免疫检查点抑制剂 (ICIs) 可以缓解这种抑制，但它们无法驱动 CD28 共刺激，而 CD28 共刺激可能在机制上导致 ICI 耐药。因此，检查点抑制背景下的 CD28 共刺激可能会激活肿瘤微环境中免疫抑制的 T 细胞。 Davoceticept (ALPN-202) 是 CD80 变异免疫球蛋白结构域 (vIgD) 的 Fc 融合物，旨在介导 PD-L1 依赖性 CD28 共刺激，同时抑制 PD-L1 和 CTLA-4 检查点。 PD-L1 限制 davoceticept 的 CD28 共刺激活性可以最大限度地减少全身 T 细胞激活并避免不良的全身毒性。同时，临床前研究表明，在PD-1抑制期间使用达沃西普治疗可能通过上调PD-L1来增强抗肿瘤活性，可能与达沃西普的PD-L1依赖性共刺激机制产生协同作用。本报告详细介绍了 1 期研究 NEON-2 中达沃西普联合派姆单抗（抗 PD-1）治疗后发生的两例致命心脏事件。这两起事件都发生在 60 多岁的女性身上；一名患有脉络膜黑色素瘤并接受过免疫治疗，另一名患有 ICI 初治微卫星稳定结直肠癌。临床病程为暴发性，症状在 2 周内出现，随后迅速下降。一名患者的心脏尸检证实了免疫相关性心肌炎，免疫测序显示治疗前肿瘤中不存在的单个 T 细胞克隆的扩增。这些病例强调了了解当在检查点抑制背景下以 CD28 激动为目标时可能导致免疫相关心肌炎和其他严重免疫相关不良事件的风险因素的重要性。NEON-2 (NCT04920383)。© 作者 (或其雇主）2024。根据 CC BY-NC 允许重复使用。不得商业再利用。请参阅权利和权限。英国医学杂志出版。

Engagement of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) can interfere with the CD28 signaling requisite for T-cell activation. While immune checkpoint inhibitors (ICIs) can relieve this suppression, they are unable to drive CD28 costimulation that may mechanistically contribute to ICI resistance. Thus, CD28 costimulation in the context of checkpoint inhibition may activate immunosuppressed T-cells in the tumor microenvironment. Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain (vIgD) designed to mediate PD-L1-dependent CD28 costimulation while inhibiting the PD-L1 and CTLA-4 checkpoints. PD-L1-restriction of davoceticept's CD28 costimulatory activity may minimize systemic T-cell activation and avoid untoward systemic toxicities. At the same time, preclinical studies have suggested that treatment with davoceticept during PD-1 inhibition may enhance antitumor activity by upregulating PD-L1, potentially synergizing with davoceticept's PD-L1-dependent costimulatory mechanism. This report details two cases of fatal cardiac events following treatment with davoceticept in combination with pembrolizumab (anti-PD-1) in the phase 1 study, NEON-2. Both events occurred in females in their 60s; one with choroidal melanoma and prior immunotherapy, the other with ICI-naïve microsatellite stable colorectal cancer. The clinical courses were fulminant with symptom onset at 2 weeks, followed by rapid decline. Cardiac autopsy from one patient confirmed immune-related myocarditis, and immunosequencing revealed expansion of a single T-cell clone that was not present in the pretreatment tumor. These cases highlight the importance of understanding risk factors that may contribute to immune-related myocarditis and other severe immune-related adverse events when CD28 agonism is targeted in the context of checkpoint inhibition.NEON-2 (NCT04920383).© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.