McDonnell Alison M, Cook Alistair, Robinson Bruce W S, Lake Richard A, Nowak Anna K
School of Medicine and Pharmacology, The University of Western Australia, Crawley, WA, 6009, Australia.
National Centre for Asbestos Related Diseases, The University of Western Australia, Crawley, WA, 6009, Australia.
BMC Cancer. 2017 Jun 15;17(1):417. doi: 10.1186/s12885-017-3403-5.
CD40 signalling can synergise with chemotherapy in preclinical cancer models, and early clinical studies are promising. We set out to define the immunological changes associated with this therapeutic combination to identify biomarkers for a response to the therapy. Here, we present serial immunomonitoring examining dendritic cell and T cell subpopulations over sequential courses of chemoimmunotherapy.
Fifteen patients with mesothelioma received up to six 21-day cycles of pemetrexed plus cisplatin chemotherapy and anti-CD40 (CP-870,893). Peripheral blood was collected weekly, and analysed by flow cytometry. Longitudinal immunophenotyping data was analysed by linear mixed modelling, allowing for variation between patients. Exploratory analyses testing for any correlation between overall survival and immunophenotyping data were undertaken up to the third cycle of treatment.
Large statistically significant cyclical variations in the proportions of BDCA-1+, BDCA-2+ and BDCA-3+ dendritic cells were observed, although all subsets returned to baseline levels after each cycle and no significant changes were observed between start and end of treatment. Expression levels of CD40 and HLA-DR on dendritic cells were also cyclically modulated, again without significant change between start and end of treatment. CD8 and CD4 T cell populations, along with regulatory T cells, effector T cells, and markers of proliferation and activation, showed similar patterns of statistically significant cyclical modulation in response to therapy without changes between start and end of treatment. Exploratory analysis of endpoints revealed that patients with a higher than average proportion of BDCA-2+ dendritic cells (p = 0.010) or a higher than average proportion of activated (ICOS+) CD8 T cells (0.022) in pretreatment blood samples had better overall survival. A higher than average proportion of BDCA-3+ dendritic cells was associated with poorer overall survival at both the second (p = 0.008) and third (p = 0.014) dose of anti-CD40.
Substantial cyclical variations in DC and T cell populations during sequential cycles of chemoimmunotherapy highlight the critical importance of timing of immunological biomarker assessments in interpretation of results and the value of linear mixed modelling in interpretation of longitudinal change over a full treatment course.
Australia New Zealand Clinical Trials Registry number ACTRN12609000294257 (18th May 2009).
在临床前癌症模型中，CD40信号传导可与化疗协同作用，早期临床研究前景良好。我们着手确定与这种治疗组合相关的免疫变化，以识别对该疗法有反应的生物标志物。在此，我们展示了在化学免疫疗法的连续疗程中对树突状细胞和T细胞亚群进行的系列免疫监测。
15例间皮瘤患者接受了多达六个周期、为期21天的培美曲塞加顺铂化疗及抗CD40（CP-870,893）治疗。每周采集外周血，通过流式细胞术进行分析。纵向免疫表型数据采用线性混合模型进行分析，以考虑患者之间的差异。在治疗的第三个周期之前，进行探索性分析，检测总生存期与免疫表型数据之间的任何相关性。
观察到BDCA-1+、BDCA-2+和BDCA-3+树突状细胞比例存在具有统计学意义的大幅周期性变化，尽管每个周期后所有亚群均恢复至基线水平，且治疗开始和结束之间未观察到显著变化。树突状细胞上CD40和HLA-DR的表达水平也呈周期性调节，同样在治疗开始和结束之间无显著变化。CD8和CD4 T细胞群体，以及调节性T细胞、效应T细胞和增殖与激活标志物，在治疗反应中呈现出类似的具有统计学意义的周期性调节模式，治疗开始和结束之间无变化。对终点的探索性分析显示，预处理血样中BDCA-2+树突状细胞比例高于平均水平（p = 0.010）或活化（ICOS+）CD8 T细胞比例高于平均水平（0.022）的患者总生存期较好。在抗CD40治疗的第二个（p = 0.008）和第三个（p = 0.014）剂量时，BDCA-3+树突状细胞比例高于平均水平与较差的总生存期相关。
化学免疫疗法连续周期中DC和T细胞群体存在显著的周期性变化，突出了免疫生物标志物评估时间在结果解释中的关键重要性，以及线性混合模型在解释整个治疗过程中的纵向变化方面的价值。
澳大利亚新西兰临床试验注册中心编号ACTRN-12609000294257（2009年5月18日）。
