PO.CT01.04 · 临床试验

Pembrolizumab联合azacitidine的表观遗传修饰可重编程铂耐药上皮性卵巢癌的肿瘤微环境：一项II期研究的临床与转化研究结果

Pembrolizumab and epigenetic modification with azacitidine reprogram the tumor microenvironment of platinum-resistant epithelial ovarian cancer: clinical and translational findings from a phase II study

编号 CT260 展板 25 时间 4/21 02:00–05:00 区域 Section 50 主讲 Blair Landon, BS;PhD

分会场 Phase II Clinical Trials

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作者与单位 Authors & Affiliations

Blair V. Landon¹, Julia L. Boland², Andrea E. Wahner Hendrickson³, Deborah K. Armstrong¹, Boris Winterhoff⁴, Jaime Wehr¹, Akshaya V. Annapragada¹, Christopher Cherry¹, Archana Balan¹, Guneet Kaleka², Victor E. Velculescu¹, Stephen B. Baylin¹, Cynthia A. Zahnow¹, Dennis J. Slamon², Gottfried E. Konecny², John A. Glaspy², Valsamo (Elsa) Anagnostou¹

¹Johns Hopkins University School of Medicine, Baltimore, MD,²University of California Los Angeles, Los Angeles, CA,³Mayo Clinic, Rochester, MN,⁴University of Minnesota, Minneapolis, MN

摘要 Abstract

中文摘要

引言：表观遗传调节剂可能通过重编程肿瘤微环境使铂耐药卵巢癌（PROC）对免疫检查点抑制敏感。方法：我们报告一项pembrolizumab联合口服azacitidine的II期非随机研究在34例PROC女性中的临床与转化研究结果（NCT02900560）。关键入组标准包括年龄≥18岁、ECOG体能状态0-1、可测量疾病以及铂耐药的经组织学确诊的上皮性卵巢癌、输卵管癌或原发性腹膜癌。主要终点包括安全性、耐受性、总体缓解率（ORR）及疾病控制率（DCR）。次要终点包括CA-125缓解。通过对72例连续活检肿瘤进行转录组分析，评估联合表观遗传调节与免疫治疗的效果。采用靶基因表达分析识别差异表达基因和通路，采用批量RNA测序进行基因集富集分析（GSEA）并推断T细胞受体（TCR）组成。结果：azacitidine与pembrolizumab的联合方案耐受性中等良好，最常见的3-4级不良事件为胃肠道副作用和贫血。ORR为2.9%，DCR为50%；27例可评估患者中有3例达到CA-125缓解。差异基因表达分析显示，治疗6周时炎症和溶细胞基因（FDR校正p=0.005）及共抑制检查点（p=0.005）上调。治疗期间干扰素信号（p=0.006）、抗原提呈（p=0.003）、共刺激信号（p=0.002）以及免疫细胞黏附和迁移（p=0.005）通路的上调显著，同时CD8+ T细胞密度增加（p=0.05）。GSEA分析与这些结果一致，显示治疗期间免疫和炎症基因集富集，以及与IFN-gamma应答、自然杀伤细胞介导的细胞毒性和免疫调节相互作用相关的基因集上调（p<10e-13）。这些结果不受组织学亚型的混杂影响。评估显著TCR克隆型扩增和消退的TCR丰度分析显示，瘤内TCR库在治疗期间发生了重塑。此外，具有CA-125和/或临床缓解的患者在基线时显示标志性炎症基因集富集（p<10e-10），并在治疗期间显示适应性和保守免疫应答基因集富集（p<10e-09）。结论：我们的研究结果凸显了表观遗传调节剂将PROC肿瘤微环境重塑为更具炎症表型的潜力，并可能指向增强免疫治疗应答的方法。

查看英文原文 English abstract

Introduction: Epigenetic modulators may sensitize platinum-resistant ovarian cancer (PROC) to immune checkpoint inhibition by reprogramming the tumor microenvironment. Methods: We report clinical and translational findings from a phase II non-randomized study of pembrolizumab and oral azacitidine in 34 women with PROC (NCT02900560). Key eligibility criteria included age ≥ 18 years, ECOG performance status of 0-1, measurable disease and platinum-resistant, histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma. Primary endpoints included safety, tolerability, overall response rate (ORR), and disease control rate (DCR). Secondary endpoints included CA-125 response. The effect of combined epigenetic modulation and immunotherapy was evaluated by transcriptomic analyses of 72 serially biopsied tumors. Target gene expression analyses were used to identify differentially expressed genes and pathways, and bulk RNA sequencing was used for gene set enrichment analyses (GSEA) and to infer T cell receptor (TCR) assemblies. Results: The combination of azacitidine and pembrolizumab was moderately well tolerated, and the most common grade 3-4 adverse events were gastrointestinal side effects and anemia. ORR was 2.9% and DCR was 50%; with 3 of the 27 evaluable patients attaining a CA-125 response. Differential gene expression analyses revealed an upregulation of inflammatory and cytolytic genes (FDR-adjusted p=0.005) and co-inhibitory checkpoints (p=0.005) 6 weeks on-therapy. Upregulation of interferon signaling (p=0.006), antigen presentation (p=0.003), costimulatory signaling (p=0.002), and immune cell adhesion and migration (p=0.005) pathways were prominent on-therapy, together with an increase in CD8+ T-cell density (p=0.05). GSEA analyses were concordant with these findings, showing enrichment of immune and inflammatory gene sets on-therapy and upregulation of gene sets linked to IFN-gamma response, natural killer cell-mediated cytotoxicity, and immunoregulatory interactions (p < 10e-13). Findings were not confounded by histological subtype. TCR abundance analyses evaluating significant TCR clonotypic expansions and regressions showed that intra-tumoral TCR repertoires were reshaped on-therapy. Furthermore, patients with a CA-125 and/or clinical response showed enrichment of hallmark inflammatory gene sets at baseline (p < 10e-10) and of adaptive and conserved immune response gene sets on therapy (p < 10e-09). Conclusions: Our findings highlight the potential of epigenetic modulators to reshape the tumor microenvironment of PROC toward a more inflammatory phenotype and may point to approaches to augment immunotherapy response.

利益披露 Disclosure

B. V. Landon, None.. J. L. Boland, None.. A. E. Wahner Hendrickson, None.. D. K. Armstrong, None.. B. Winterhoff, None.. J. Wehr, None. A. V. Annapragada, Delfi Diagnostics Patent. Artemyx Stock, Patent. C. Cherry, C M Cherry Consulting LLC Other, Business Ownership. A. Balan, None.. G. Kaleka, None. V. E. Velculescu, Delfi Diagnostics Stock, Patent, Other, Founder, Serves on board of directors, and inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Artemyx Stock, Patent, Founder, Serves on board of directors as officer, and inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. LabCorp Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Qiagen Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Sysmex Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Agios Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Genzyme Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Esoterix Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Ventana Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. ManaT Bio Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to this entity.. Viron Therapeutics Other, Advisor. Epitope Other, Advisor. S. B. Baylin, None.. C. A. Zahnow, None. D. J. Slamon, BioMarin Other, Corporate board member, Equity ownership. TORL BioTherapeutics Other, Corporate board member, Equity ownership. 1200 Pharma Other, Corporate board member, Equity ownership. Lilly Other, Consultant. Novartis ), Other, Consultant, Speaker bureau, Travel support, Honoraria. Pfizer ), Other, Consultant, Equity ownership, Travel support. Seagen ), Other, Consultant, Equity ownership. Amgen Other, Equity ownership. Merck Sharp & Dohme Other, Equity ownership. Vertex Other, Equity ownership. G. E. Konecny, AstraZeneca Other, Speaker bureaus. Merck ), Other, Speaker bureaus. Immunogen/Genmab Other, Speaker bureaus. Lilly Inc. ). TORL Biotherapeutics Other, Travel support. Foundation Medicine Other, Honoraria. J. A. Glaspy, None. V. Anagnostou, AstraZeneca ), Other, Advisory Board Member. Bristol Myers Squibb ). Personal Genome Diagnostics/Labcorp ), Other, Honoraria. Delfi Diagnostics ). Neogenomics Other, Advisory Board Member. Foundation Medicine Other, Honoraria. Roche Other, Honoraria. ThermoFisher Other, Honoraria. Guardant Health Other, Honoraria.

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