PO.CL01.04 · 临床研究

放疗-树突状细胞联合疗法驱动肝癌全身细胞免疫的改变

Radiation-dendritic cell combination therapy drives systemic cellular immune shifts in liver cancer

编号 3741 展板 13 时间 4/20 02:00–05:00 区域 Section 41 主讲 Melody Wu, BS

分会场 Biomarkers Predictive of Therapeutic Benefit 4

查看 PDF 下载 PDF 🔒 查看 / 下载完整 PDF 需登录并开通下载套餐 · 查看套餐 / 开通 AACR 官方页面

作者与单位 Authors & Affiliations

Melody Wu¹, Panwen Wang², Chen Wu³, Ying Li⁴, Christopher L. Hallemeier⁵, Thomas D. Atwell⁶, Nguyen H. Tran⁷, Andre de Menezes Silva Corraes⁷, Kevin Regan⁷, Zuoyi Shao⁷, Rayaan Kamal⁷, Haidong Dong⁸, Lewis R. Roberts⁹, Sean Park⁵, Yi Lin¹⁰, Lionel Aurelien Kankeu Fonkoua⁷

¹Medical Scientist Training Program, Mayo Clinic College of Medicine and Science, Rochester, MN,²Mayo Clinic - Department of Biomedical Informatics, Scottsdale, AZ,³Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN,⁴Mayo Clinic - Department of Quantitative Health Sciences, Jacksonville, FL,⁵Mayo Clinic - Department of Radiation Oncology, Rochester, MN,⁶Mayo Clinic - Department of Radiology, Rochester, MN,⁷Mayo Clinic, Rochester, MN,⁸Mayo Clinic - Department of Immunology, Urology, Rochester, MN,⁹Mayo Clinic - Department of Gastroenterology & Hepatology, Rochester, MN,¹⁰Mayo Clinic - Department of Hematology & Oncology, Rochester, MN

摘要 Abstract

中文摘要

引言：肝癌仍是全球癌症死亡的主要原因之一，对于不可切除的肝细胞癌[HCC]和肝内胆管癌[iCCA]患者(pts)而言治疗选择有限[1,2,3,4]。我们假设，在外照射放疗(EBRT)之后进行瘤内树突状细胞(DC)疫苗接种，在不联合(I期)和联合(II期)全身性阿替利珠单抗和贝伐珠单抗(atezo/bev用于HCC)的情况下，将增强肿瘤特异性免疫并改善临床结局，并在此呈现我们I/II期临床试验(NCT03942328)的初步结果。方法：在基线(PRE)、放疗后(EBRT)以及完成不联合或联合atezo/bev的DC治疗后(POST)采集外周血单个核细胞(PBMCs)。采用单细胞RNA测序联合TCR测序，使用CellRanger v7.0.1、Immunopipe、Seurat v5.3.0及基因集富集分析(GSEA)进行分析。长EFS(EFS-L)定义为I期≥12个月(mo)、II期≥18个月，短EFS(EFS-S)则低于该阈值。结果：迄今已分析17例患者(I期：n=8[4例HCC，4例iCCA]；II期：n=9例HCC)。共测序674,106个细胞(146,843个PRE；168,838个EBRT；114,437个POST)。在I期与II期之间，EFS-L与EFS-S在PRE、EBRT和POST时点的GSEA结果相当。EFS-S与干扰素α(IFNalpha；PRE和POST时点的初始B细胞、单核细胞、pDC、cDC2、NK、Treg、CD8 Tcm和Tem；EBRT时点的中间B细胞、CD4 Tem和NK)及活性氧(ROS；PRE：pDC、CD8 Tcm、Tem。EBRT：CD4 Tem。POST：初始CD8 T Tem、CD4 Tcm及Tem、cDC2)通路的富集相关。相反，EFS-L与WNT-β-catenin(WNT；EBRT及POST时点的CD14单核细胞，EBRT时点的中间B细胞)、TGFb(PRE：NK；EBRT：中间B细胞、CD4 Tem；POST：单核细胞、初始CD4及Tem、pDC、cDC2)和血管生成(EBRT：NK；POST：单核细胞、cDC2)通路的富集相关。有趣的是，NK细胞中蛋白分泌通路的富集与EFS-L相关，但在其他细胞中则与EFS-S相关(PRE：CD16单核细胞、Treg；POST：CD16单核细胞、CD4及CD8 Tem)。与I期相比，II期患者加用atezo/bev与Gini系数的显著升高相关(p<0.0001)，提示某些TCR克隆的扩增，同时I期和II期均呈现从Pre到Post时Gini系数升高的趋势。结论：本研究联合EBRT与瘤内DC疫苗接种±PD-L1/VEGF阻断的初步分析，发现了与治疗相关的全身细胞免疫谱的明显变化。II期中TCR克隆多样性的增强提示PD-L1/VEGF阻断带来了额外的免疫学获益。随着入组的继续，整合分析将确定与临床获益及对该多模式免疫治疗方案耐药相关的全身免疫标志物。

查看英文原文 English abstract

Introduction: Liver cancer remains a leading cause of cancer mortality globally with limited treatment options for patients (pts) with unresectable hepatocellular carcinoma [HCC] and intrahepatic cholangiocarcinoma [iCCA][1,2,3,4]. We hypothesize that combining the intratumoral dendritic cell (DC) vaccination after external beam radiotherapy (EBRT) without (phase I) and with (phase II) systemic atezolizumab and bevacizumab (atezo/bev for HCC) would enhance tumor-specific immunity and improve clinical outcomes, and present preliminary results from our phase I/II trial (NCT03942328). Methods: Peripheral blood mononuclear cells (PBMCs) were collected at baseline (PRE), after radiation (EBRT), and after completion of DC without or with atezo/bev (POST). Single-cell RNA sequencing with TCR sequencing were analyzed using CellRanger v7.0.1, Immunopipe, Seurat v5.3.0, & Gene-set enrichment analysis (GSEA). Long EFS (EFS-L) is defined as >=12 months (mo) for phase I and >=18mo for phase II, and short EFS (EFS-S) below that. Results: Seventeen patients have been analyzed to date (Phase I: n=8 [4 HCC, 4 iCCA]; Phase II: n=9 HCC). 674,106 cells were sequenced (146,843 PRE; 168,838 EBRT; 114,437 POST). GSEA for EFS-L vs EFS-S were comparable at PRE, EBRT and POST between phase I and phase II. EFS-S was associated with enrichment of interferon alpha (IFNalpha; B naïve, monocytes, pDC, cDC2, NK, Treg, CD8 Tcm and Tem at PRE and POST; B intermediate, CD4 Tem and NK at EBRT) and reactive oxygen species (ROS; PRE: pDC, CD8 Tcm, Tem. EBRT: CD4 Tem. POST: CD8 T naïve Tem, CD4 Tcm & Tem, cDC2) pathways. In contrast, EFS-L was associated with enrichment of WNT-beta-catenin (WNT; CD14 mono at EBRT & POST, B intermediate at EBRT), TGFb (PRE: NK; EBRT: B intermed, CD4 Tem; POST: monocytes, CD4 naïve & Tem, pDC, cDC2), and angiogenesis (EBRT: NK; POST: monocytes, cDC2) pathways. Interestingly, enrichment of protein secretion pathway in NK cells was associated with EFS-L, but among other cells were associated with EFS-S (PRE: CD16 mono, Treg; POST: CD16 mono, CD4 & D8 Tem). Compared to phase I, addition of atezo/bev in phase II pts was associated with a significant increase in Gini coefficient (p<0.0001), suggesting expansion of certain TCR clones, along with a trend for increased Gini coefficient from Pre to Post in both phase I and II. Conclusions: Preliminary analysis of this study combining EBRT with intratumoral DC vaccination +/- PD-L1/VEGF blockade identified distinct treatment-related changes in systemic cellular immune profiles. Enhanced TCR clonal diversity in phase II suggests added immunologic benefit from PD-L1/VEGF blockade. As accrual continues, integrated analyses will identify systemic immune correlates of clinical benefit and resistance to this multimodal immunotherapy approach.

利益披露 Disclosure

M. Wu, None.

← 返回 AACR 2026 检索