PDF(Pubmed)
Abstract：
Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.
摘要：
Relatlimab（rela;抗LAG-3）加nivolumab（nivo;抗PD-1）可安全有效地治疗晚期黑色素瘤。我们设计了一项试验（NCT03743766），其中晚期黑色素瘤患者接受rela，尼沃,或rela+nivo询问rela+nivo的免疫机制。这项正在进行的试验的生物标本分析表明，rela+nivo导致CD8+T细胞受体信号传导能力增强，CD8+T细胞分化改变，尽管保留了耗尽曲线，但仍导致细胞毒性升高。细胞毒性和耗竭特征的共表达是由PRDM1、BATF、ETV7和TOX。在rela+nivo后出现的克隆扩增的CD8+T细胞中，效应子功能上调。rela+nivo肿瘤内CD8+T细胞特征与良好的预后相关。这种肿瘤内rela+nivo特征在外周血中被验证为CD38+TIM3+CD8+T细胞的频率升高。总的来说,我们证明，尽管保留了耗尽特征，但细胞毒性可以增强，这将为未来的治疗策略提供信息。
