Baseline serum anti-glycan antibodies of 113 subjects in a clinical trial of PROSTVAC-VF, a therapeutic cancer vaccine [Validation IgM 1:50]

Purpose: There is evidence that therapeutic cancer vaccines can lengthen survival for some cancer patients, but responses vary widely from one person to another. Methods to predict clinical outcomes will advance the field and provide new insights into critical determinants of in vivo efficacy. This study uses a high-throughput glycan microarray to assess correlations between a subject's overall survival after receiving PROSTVAC-VF and his baseline serum anti-glycan antibody levels. Results: Pre-vaccination antibody levels to blood group A trisaccharide (BG-Atri) were found to have a statistically significant correlation with survival. Long-term survival was approximately doubled in subjects with abundant anti-BG-Atri IgM relative to subjects with little or no pre-existing IgM for BG-Atri. This survival correlation was specific to vaccine treatment, as no correlation was observed in control patients immunized with wild-type poxviruses lacking the key tumor antigen, prostate specific antigen (PSA). Moreover, anti-BG-Atri IgM levels were not correlated with general measures of disease severity, such as PSA levels, Gleason score, or Halabi predicted survival. Conclusion: In addition to reporting a new potentially predictive biomarker for PROSTVAC-VF, this study highlights the potential of glycan microarray technology for personalized medicine. The overall study was a retrospective analysis of 141 subjects from phase II trials of PROSTVAC-VF, a poxvirus based cancer vaccine currently in phase III clinical trials for advanced prostate cancer. The subjects were divided into a training set (n=28) and a validation set (n=113). A glycan microarray was used to profile pre-vaccination anti-glycan antibody populations in sera as potential biomarkers for PROSTVAC-VF. For both the training set and validation set, the anti-glycan profiles were measured using four variations of serum dilution and isotype specific secondary antibody (IgM at 1:50, IgG at 1:50, total Ig at 1:50, and total Ig at 1:200). IgM levels for the validation set measured at serum dilution of 1:50 are detailed here. The screen for predictive biomarkers identified anti-glycan antibodies that consistently stratified subjects into groups with different Kaplan Meier survival estimates. Due to the potential for overfitting, a permutation test was used to estimate the false discovery rate. Raw data on superSeries GSE42184 record.

研究目的：现有证据表明，治疗性癌症疫苗可延长部分癌症患者的生存期，但不同患者的应答差异显著。可精准预测临床结局的方法将推动该领域发展，并为体内疗效的关键决定因素提供全新研究视角。
本研究采用高通量糖芯片（glycan microarray）技术，评估受试者接受PROSTVAC-VF治疗后的总生存期与基线血清抗糖抗体水平之间的相关性。
研究结果：
研究发现，针对血型A三糖（blood group A trisaccharide, BG-Atri）的疫苗接种前抗体水平与患者生存期存在统计学意义上的显著关联。与基线时抗BG-Atri IgM水平较低或未检测到该抗体的受试者相比，抗体水平充足的受试者长期生存期约提升一倍。该生存期关联仅针对疫苗治疗组：在仅接种缺失关键肿瘤抗原前列腺特异性抗原（prostate specific antigen, PSA）的野生型痘病毒的对照组患者中，未观察到此类关联。此外，抗BG-Atri IgM水平与疾病严重程度的通用指标（如PSA水平、格里森评分（Gleason score）或Halabi预测生存期）均无相关性。
研究结论：
本研究不仅报道了一种可用于PROSTVAC-VF的潜在新型预测生物标志物，同时凸显了糖芯片技术在个性化医疗中的应用潜力。本研究为回顾性分析，共纳入141名来自PROSTVAC-VF II期临床试验的受试者——该疫苗为基于痘病毒的癌症疫苗，目前正针对晚期前列腺癌开展III期临床试验。受试者被分为训练集（n=28）与验证集（n=113）。本研究采用糖芯片技术对受试者接种前血清中的抗糖抗体谱进行分析，以此作为PROSTVAC-VF的潜在生物标志物。针对训练集与验证集，均通过四种血清稀释度与同型特异性二抗组合进行抗体谱检测：IgM（1:50稀释）、IgG（1:50稀释）、总Ig（1:50稀释）与总Ig（1:200稀释）。本文详细展示了验证集在1:50血清稀释度下检测得到的IgM水平数据。本研究通过预测生物标志物筛选，成功识别出可稳定将受试者划分为具有不同卡普兰-迈耶（Kaplan-Meier）生存预估的抗糖抗体。鉴于存在过拟合风险，本研究采用置换检验（permutation test）估算错误发现率（false discovery rate）。本研究的原始数据收录于超级数据集GSE42184中。