Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA
START Midwest, Grand Rapids, Michigan, USA.
J Immunother Cancer. 2024 Aug 13;12(8):e009475. doi: 10.1136/jitc-2024-009475.
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).
程序性死亡受体-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 信号转导。虽然免疫检查点抑制剂（ICIs）可以缓解这种抑制，但它们不能驱动 CD28 共刺激，而这种共刺激可能在机制上有助于 ICI 耐药。因此，在检查点抑制的情况下，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）是一种 CD80 变体免疫球蛋白结构域（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。Davoceticept 的 CD28 共刺激活性受 PD-L1 限制，可能会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 抑制期间用 davoceticept 治疗可能通过上调 PD-L1 来增强抗肿瘤活性，这可能与 davoceticept 的 PD-L1 依赖性共刺激机制协同作用。本报告详细介绍了在 NEON-2 期研究中，davoceticept 与 pembrolizumab（抗 PD-1）联合使用后发生的两例致命性心脏事件。这两例事件均发生在 60 多岁的女性中；一例患有脉络膜黑色素瘤和既往免疫治疗，另一例患有 ICI 初治微卫星稳定结直肠癌。临床过程迅猛，症状在 2 周内出现，随后迅速恶化。一名患者的心脏尸检证实为免疫相关性心肌炎，免疫测序显示单一 T 细胞克隆扩张，而该克隆在预处理肿瘤中不存在。这些病例强调了在检查点抑制的背景下靶向 CD28 激动剂时，了解可能导致免疫相关性心肌炎和其他严重免疫相关不良事件的危险因素的重要性。NEON-2（NCT04920383）。
