Oxford University Clinical Academic Graduate School, University of Oxford, Oxford, UK.
The Clatterbridge Cancer Centre, Wirral, UK.
Br J Cancer. 2021 May;124(10):1661-1669. doi: 10.1038/s41416-021-01310-3. Epub 2021 Mar 15.
Immune checkpoint blockers (ICBs) activate CD8 T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.
Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination (nivolumab and ipilimumab-cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8 T cells was sequenced and differential gene expression according to irAE development assessed.
58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9-33.4) versus not-reached (P = 2.8 × 10). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8 T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.
Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.
免疫检查点抑制剂（ICB）激活 CD8 T 细胞，引发抗癌活性和免疫相关不良事件（irAEs）。irAEs 与基线参数和临床结局的关系尚不清楚。
对接受单药（pembrolizumab/nivolumab-sICB）或联合（nivolumab 和 ipilimumab-cICB）检查点阻断的转移性黑色素瘤患者的两个独立队列（原发性队列 N=144 和继发性队列 N=211）进行了 irAEs 对生存影响的回顾性评估。对治疗前和治疗后 CD8 T 细胞进行 RNA 测序，并根据 irAE 发展评估差异基因表达。
58.3%的患者出现早期 irAEs，这与两个队列的无进展生存期（PFS）和总生存期（OS）延长相关（log-rank 检验，OS：P<0.0001）。无 irAEs 的患者中位生存期为 16.6 个月（95%CI：10.9-33.4），而未达到（P=2.8×10）。治疗前单核细胞和中性粒细胞计数，而不是 BMI，是临床结局的额外预测因素。根据 irAE 的发展，观察到 CD8 T 细胞中许多基因途径成员的差异表达，未发生 irAEs 的患者在治疗前和治疗后表现出 CXCR1 的上调。
ICB 后早期 irAE 发展与 MM 患者的生存获益相关。irAEs 的发生与许多基因途径的表达有关，这表明 irAE 的发生在一定程度上反映了基线免疫激活。
