Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Division of Medical Oncology and Hematology, University Health Network, Canada, Toronto, ON, Canada.
F1000Res. 2020 May 7;9:337. doi: 10.12688/f1000research.22715.1. eCollection 2020.
Validated biomarkers are needed to identify patients at increased risk of immune-related adverse events (irAEs) to immune checkpoint blockade (ICB). Antibodies directed against endogenous antigens can change after exposure to ICB. Patients with different solid tumors stratified into cohorts received pembrolizumab every 3 weeks in a Phase II trial (INSPIRE study). Blood samples were collected prior to first pembrolizumab exposure (baseline) and approximately 7 weeks (pre-cycle 3) into treatment. In a discovery analysis, autoantibody target immuno-mass spectrometry was performed in baseline and pre-cycle 3 pooled sera of 24 INSPIRE patients based on clinical benefit (CBR) and irAEs. Thyroglobulin (Tg) and thyroid peroxidase (TPO) were identified as the candidate autoantibody targets. In the overall cohort of 78 patients, the frequency of CBR and irAEs from pembrolizumab was 31% and 24%, respectively. Patients with an anti-Tg titer increase ≥1.5x from baseline to pre-cycle 3 were more likely to have irAEs relative to patients without this increase in unadjusted, cohort adjusted, and multivariable models (OR=17.4, 95% CI 1.8-173.8, p=0.015). Similarly, patients with an anti-TPO titer ≥ 1.5x from baseline to pre-cycle 3 were more likely to have irAEs relative to patients without the increase in unadjusted and cohort adjusted (OR=6.1, 95% CI 1.1-32.7, p=0.035) models. Further, the cohort adjusted analysis showed patients with anti-Tg titer greater than median (10.0 IU/mL) at pre-cycle 3 were more likely to have irAEs (OR=4.7, 95% CI 1.2-17.8, p=0.024). Patients with pre-cycle 3 anti-TPO titers greater than median (10.0 IU/mL) had a significant difference in overall survival (23.8 vs 11.5 months; HR=1.8, 95% CI 1.0-3.2, p=0.05). Patient increase ≥1.5x of anti-Tg and anti-TPO titers from baseline to pre-cycle 3 were associated with irAEs from pembrolizumab, and patients with elevated pre-cycle 3 anti-TPO titers had an improvement in overall survival.
需要验证的生物标志物来识别免疫检查点阻断（ICB）后发生免疫相关不良事件（irAEs）风险增加的患者。 接触 ICB 后，针对内源性抗原的抗体可能会发生变化。 在一项 II 期试验（INSPIRE 研究）中，将不同的实体瘤患者分层为队列，每 3 周接受一次 pembrolizumab 治疗。 在基线（第一次 pembrolizumab 暴露前）和治疗大约 7 周（前 3 周期）时采集血样。 在一项发现性分析中，根据临床获益（CBR）和 irAEs，对 24 名 INSPIRE 患者的基线和前 3 周期的混合血清进行了自身抗体靶标免疫质谱分析。 甲状腺球蛋白（Tg）和甲状腺过氧化物酶（TPO）被确定为候选自身抗体靶标。 在 78 名患者的总队列中，pembrolizumab 的 CBR 和 irAEs 发生率分别为 31%和 24%。 与基线至前 3 周期无此增加的患者相比，抗 Tg 滴度增加≥1.5x 的患者发生 irAEs 的可能性更高，未经调整、队列调整和多变量模型（OR=17.4，95%CI 1.8-173.8，p=0.015）。 同样，与基线至前 3 周期无此增加的患者相比，抗 TPO 滴度增加≥1.5x 的患者发生 irAEs 的可能性更高，未经调整和队列调整（OR=6.1，95%CI 1.1-32.7，p=0.035）模型。 此外，队列调整分析表明，前 3 周期抗 Tg 滴度大于中位数（10.0 IU/mL）的患者发生 irAEs 的可能性更大（OR=4.7，95%CI 1.2-17.8，p=0.024）。 前 3 周期抗 TPO 滴度大于中位数（10.0 IU/mL）的患者总生存差异有统计学意义（23.8 与 11.5 个月；HR=1.8，95%CI 1.0-3.2，p=0.05）。 基线至前 3 周期抗 Tg 和抗 TPO 滴度增加≥1.5x 与 pembrolizumab 相关 irAEs 相关，前 3 周期抗 TPO 滴度升高的患者总生存改善。
