Department of Respiratory Medicine, Kawasaki Medical School, Okayama, Japan.
Department of Thoracic Surgery, The University of Tokyo, Tokyo, Japan.
J Thorac Oncol. 2019 Dec;14(12):2071-2083. doi: 10.1016/j.jtho.2019.08.008. Epub 2019 Aug 23.
Programmed cell death-1 (PD-1) inhibitors effectively treat NSCLC and prolong survival. Robust biomarkers for predicting clinical benefits of good response and long survival with anti-PD-1 therapy have yet to be identified; therefore, predictive biomarkers are needed to select patients with benefits.
We conducted a prospective study to explore whether serum antibody against NY-ESO-1 and/or XAGE1 cancer-testis antigens predicted primarily good clinical response and secondarily long survival with anti-PD-1 therapy for NSCLC. The serum antibody was detected by enzyme-linked immunosorbent assay, and tumor immune microenvironment and mutation burden were analyzed by immunohistochemistry and next-generation sequencing.
In the discovery cohort (n = 13), six antibody-positive NSCLC cases responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC cases did not. Antibody positivity was associated with good response and survival, regardless of tumor programmed death ligand 1 (PD-L1) expression, mutation burden, and CD8 T-cell infiltration. In the validation cohort (n = 75), 17 antibody-positive NSCLC cases responded well to anti-PD-1 therapy as compared with 58 negative NSCLC cases (objective response rate 65% versus 19%, p = 0.0006) and showed significantly prolonged progression-free survival and overall survival. Antibody titers highly correlated with tumor reduction rates. In the multivariate analysis, response biomarkers were tumor programmed death ligand 1 expression and antibody positivity, and only antibody positivity was a significantly better predictive biomarker of progression-free survival (hazard ratio = 0.4, p = 0.01) and overall survival (hazard ratio = 0.2, p = 0.004).
Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits in anti-PD-1 therapy for NSCLC and probably for other cancers.
程序性死亡受体 1（PD-1）抑制剂可有效治疗非小细胞肺癌（NSCLC）并延长患者生存期。目前尚未发现用于预测抗 PD-1 治疗反应良好和生存时间延长的强大生物标志物；因此，需要预测性生物标志物来选择获益的患者。
我们进行了一项前瞻性研究，以探讨针对 NY-ESO-1 和/或 XAGE1 癌症睾丸抗原的血清抗体是否可预测 NSCLC 患者接受抗 PD-1 治疗后的主要临床反应和次要的生存时间。通过酶联免疫吸附试验检测血清抗体，通过免疫组化和下一代测序分析肿瘤免疫微环境和突变负担。
在发现队列（n=13）中，6 例血清抗体阳性的 NSCLC 患者对 PD-1 治疗有反应（2 例完全缓解和 4 例部分缓解），而 7 例血清抗体阴性的 NSCLC 患者没有反应。抗体阳性与良好的反应和生存相关，无论肿瘤程序性死亡配体 1（PD-L1）表达、突变负担和 CD8 T 细胞浸润情况如何。在验证队列（n=75）中，与 58 例血清抗体阴性的 NSCLC 患者相比，17 例血清抗体阳性的 NSCLC 患者对 PD-1 治疗的反应良好（客观缓解率为 65%比 19%，p=0.0006），且无进展生存期和总生存期显著延长。抗体滴度与肿瘤缓解率高度相关。在多变量分析中，反应生物标志物为肿瘤 PD-L1 表达和抗体阳性，只有抗体阳性是无进展生存期（危险比=0.4，p=0.01）和总生存期（危险比=0.2，p=0.004）的更好预测生物标志物。
我们的研究结果表明，NY-ESO-1 和/或 XAGE1 血清抗体是预测 NSCLC 患者抗 PD-1 治疗临床获益的有用生物标志物，可能也可预测其他癌症。
