Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Department of Immunology, University of Toronto, Toronto, Canada.
J Immunother Cancer. 2019 Mar 13;7(1):72. doi: 10.1186/s40425-019-0541-0.
Immune checkpoint inhibitors (ICIs) demonstrate unprecedented efficacy in multiple malignancies; however, the mechanisms of sensitivity and resistance are poorly understood and predictive biomarkers are scarce. INSPIRE is a phase 2 basket study to evaluate the genomic and immune landscapes of peripheral blood and tumors following pembrolizumab treatment.
Patients with incurable, locally advanced or metastatic solid tumors that have progressed on standard therapy, or for whom no standard therapy exists or standard therapy was not deemed appropriate, received 200 mg pembrolizumab intravenously every three weeks. Blood and tissue samples were collected at baseline, during treatment, and at progression. One core biopsy was used for immunohistochemistry and the remaining cores were pooled and divided for genomic and immune analyses. Univariable analysis of clinical, genomic, and immunophenotyping parameters was conducted to evaluate associations with treatment response in this exploratory analysis.
Eighty patients were enrolled from March 21, 2016 to June 1, 2017, and 129 tumor and 382 blood samples were collected. Immune biomarkers were significantly different between the blood and tissue. T cell PD-1 was blocked (≥98%) in the blood of all patients by the third week of treatment. In the tumor, 5/11 (45%) and 11/14 (79%) patients had T cell surface PD-1 occupance at weeks six and nine, respectively. The proportion of genome copy number alterations and abundance of intratumoral 4-1BB+ PD-1+ CD8 T cells at baseline (P < 0.05), and fold-expansion of intratumoral CD8 T cells from baseline to cycle 2-3 (P < 0.05) were associated with treatment response.
This study provides technical feasibility data for correlative studies. Tissue biopsies provide distinct data from the blood and may predict response to pembrolizumab.
免疫检查点抑制剂（ICIs）在多种恶性肿瘤中表现出前所未有的疗效；然而，其敏感性和耐药性的机制尚不清楚，且预测生物标志物也很匮乏。INSPIRE 是一项 2 期篮子研究，旨在评估 pembrolizumab 治疗后外周血和肿瘤的基因组和免疫图谱。
患有不可治愈的局部晚期或转移性实体瘤的患者，这些肿瘤在标准治疗后进展，或对于没有标准治疗或标准治疗不适合的患者，接受 200mg 静脉注射 pembrolizumab，每 3 周一次。在基线、治疗期间和进展时采集血液和组织样本。对一个核心活检进行免疫组化，其余核心进行合并并分为基因组和免疫分析。在这项探索性分析中，对临床、基因组和免疫表型参数进行单变量分析，以评估与治疗反应的相关性。
2016 年 3 月 21 日至 2017 年 6 月 1 日期间共招募了 80 例患者，共采集了 129 个肿瘤和 382 个血液样本。血液和组织之间的免疫生物标志物有显著差异。所有患者在治疗的第三周时血液中的 T 细胞 PD-1 被完全阻断（≥98%）。在肿瘤中，分别有 5/11（45%）和 11/14（79%）患者在第 6 周和第 9 周时的 T 细胞表面 PD-1 占有率分别为 5/11（45%）和 11/14（79%）。基线时基因组拷贝数改变的比例和肿瘤内 4-1BB+PD-1+CD8 T 细胞的丰度（P<0.05），以及从基线到第 2-3 周期的肿瘤内 CD8 T 细胞的倍增（P<0.05）与治疗反应相关。
本研究为相关研究提供了技术可行性数据。组织活检提供了与血液不同的数据，并且可能预测对 pembrolizumab 的反应。
