Leeman Hayley, Kaminska Elwira, Green Deborah, Bodman-Smith Mark, Gravett Andrew, Bodman-Smith Katherine, Copier John, Coulton Gary, Fusi Alberto, Dalgleish Angus G
St George's University of London, Cranmer Terrace, London SW17 0RE.
School of Biosciences and Medicine, University of Surrey, Guildford, Surrey GU2 7XH.
Transl Oncol. 2019 Mar;12(3):397-403. doi: 10.1016/j.tranon.2018.11.002. Epub 2018 Dec 8.
Despite the majority of patients do not gain any benefit from dendritic cells (DC) vaccines, this approach has occasionally given rise to dramatic responses in melanoma. Biomarkers are crucial to identify which patients are more likely to respond. We looked for correlations between pre- or post- vaccination biomarkers and clinical outcomes to DC therapy in a cohort of patients with stage IV melanoma receiving a vaccine with autologous ex-vivo expanded DCs pulsed with allogeneic tumor cell lysate.
Serial serum samples were collected at baseline, week 4 and 12 and they were analyzed for a panel of different inflammatory markers using cytometric bead array technology and ELISA.
Twenty-one patients were evaluable for response. Patients were separated into responders and non-responders based on clinical benefit. Responders were defined as patients who achieved a complete response, partial response or stable disease the latter lasting for at least 6 months. Responders (N = 9) showed a significantly longer Progression-free Survival (PFS; HR 0.23; 95% CI 0.08-062; P < .001) and Overall Survival (OS; HR 0.22; 95% CI 0.08-0.59; P < .001). The clinical non-responder phenotype correlated with an elevated pre-vaccination level of cytokines associated with inflammation compared to clinical responders (Apolipoprotein C111; IL-12 p40; MiP1α; Stem Cell Factor and TNFα). Apolipoprotein E (ApoE) was also significantly elevated in the pre-vaccine sera of the clinically non-responding group and in addition it was found to correlate with outcomes. Patients with increased levels of ApoE had a significantly shorter PFS (HR 3.02; 95% CI 1.09-8.35; P = .015) and OS (HR 2.40; 95% CI 0.9-6.3; P = .034).
Our findings support the notion that treating the inflammatory background may have an impact on clinical outcome for patients receiving immunotherapy. A larger study is needed to confirm the significance of ApoE as a predictive biomarker for response to DC vaccines.
尽管大多数患者未从树突状细胞（DC）疫苗中获益，但这种方法偶尔会在黑色素瘤患者中引发显著反应。生物标志物对于确定哪些患者更可能产生反应至关重要。我们在一组接受同种异体肿瘤细胞裂解物脉冲处理的自体体外扩增DC疫苗的IV期黑色素瘤患者队列中，寻找接种前或接种后生物标志物与DC治疗临床结果之间的相关性。
在基线、第4周和第12周采集系列血清样本，并使用细胞计数珠阵列技术和酶联免疫吸附测定法分析一组不同的炎症标志物。
21例患者可评估反应。根据临床获益情况将患者分为反应者和无反应者。反应者定义为实现完全缓解、部分缓解或疾病稳定（后者持续至少6个月）的患者。反应者（N = 9）显示无进展生存期（PFS；风险比0.23；95%置信区间0.08 - 0.62；P <.001）和总生存期（OS；风险比0.22；95%置信区间0.08 - 0.59；P <.001）显著更长。与临床反应者相比，临床无反应者表型与接种前与炎症相关的细胞因子水平升高相关（载脂蛋白CIII；IL - 12 p40；巨噬细胞炎症蛋白1α；干细胞因子和肿瘤坏死因子α）。载脂蛋白E（ApoE）在临床无反应组的接种前血清中也显著升高，此外还发现其与结果相关。ApoE水平升高的患者PFS显著缩短（风险比3.02；95%置信区间1.09 - 8.35；P = 0.015）和OS显著缩短（风险比2.40；95%置信区间0.9 - 6.3；P = 0.034）。
我们的研究结果支持这样一种观点，即治疗炎症背景可能会影响接受免疫治疗患者的临床结果。需要进行更大规模的研究来证实ApoE作为DC疫苗反应预测生物标志物的意义。
