Derbala M H, Hajjar J, Stephen B, Gurses S A, Kwiatkowski E, Budde P, Zucht H-D, Bräutigam M, Lindemann A-S, Abhari B A, Gouda M A, Castillo L, Zarifa A, How J A, Rodriguez E, Moyers J T, Hong D S, Fu S, Meric-Bernstam F, Naing A
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA.
Division of Immunology, Allergy & Retrovirology, William T. Shearer Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, Houston, USA.
ESMO Open. 2025 Aug 4;10(8):105518. doi: 10.1016/j.esmoop.2025.105518.
Immune checkpoint inhibitors (ICIs) have limited response rates in selected patients and can cause potentially life-threatening immune-related adverse events (irAEs). This underscores the urgent need for the development of biomarkers predictive of ICI response. Pre-existing autoantibodies (AAbs) have been linked with responses to ICIs and the development of irAEs. We conducted AAb profiling to assess associations between baseline AAbs and clinical benefit (CB) in patients with rare tumors treated with anti-programmed cell death protein 1-based therapy.
We conducted AAb profiling using Oncimmune's SeroTag multiplex antibody discovery technology and immune oncology array containing 1168 antigens. The study included 41 patients with rare tumors who received pembrolizumab compared with healthy controls. We carried out a significance analysis of microarrays to identify baseline AAbs present in these cancer patients and associations between these AAbs and CB (defined as complete response, partial response, or stable disease for ≥6 months). We also investigated associations between baseline AAbs and time to progression (TTP) and overall survival (OS) using Cox proportional hazards and Kaplan-Meier models.
Compared with healthy controls, patients with rare tumors had significantly higher levels of several AAbs at baseline, including those against interferon alpha antigens. Ten patients (24%) had CB. Several AAbs, including those targeting DNA ligase III (LIG3), were associated with CB, TTP, and OS.
The predictive potential of AAbs as biomarkers of ICI therapy is promising. Further evaluation in larger cohorts is needed to validate our findings and elucidate the underlying mechanism.
免疫检查点抑制剂（ICI）在部分患者中的缓解率有限，且可引发潜在危及生命的免疫相关不良事件（irAE）。这凸显了开发预测ICI反应的生物标志物的迫切需求。预先存在的自身抗体（AAb）已被证明与ICI反应及irAE的发生有关。我们进行了AAb谱分析，以评估接受基于抗程序性细胞死亡蛋白1治疗的罕见肿瘤患者基线AAb与临床获益（CB）之间的关联。
我们使用Oncimmune公司的SeroTag多重抗体发现技术和包含1168种抗原的免疫肿瘤阵列进行AAb谱分析。该研究纳入了41例接受派姆单抗治疗的罕见肿瘤患者，并与健康对照进行比较。我们对微阵列进行了显著性分析，以确定这些癌症患者中存在的基线AAb，以及这些AAb与CB（定义为完全缓解、部分缓解或疾病稳定≥6个月）之间的关联。我们还使用Cox比例风险模型和Kaplan-Meier模型研究了基线AAb与疾病进展时间（TTP）和总生存期（OS）之间的关联。
与健康对照相比，罕见肿瘤患者在基线时几种AAb水平显著更高，包括那些针对干扰素α抗原的抗体。10例患者（24%）有临床获益。几种AAb，包括那些靶向DNA连接酶III（LIG3）的抗体，与临床获益、疾病进展时间和总生存期相关。
AAb作为ICI治疗生物标志物的预测潜力很有前景。需要在更大的队列中进行进一步评估，以验证我们的发现并阐明潜在机制。
