PO.TB04.01 · 肿瘤生物学
使用Nilogen的3D-EXpress平台在卵巢肿瘤类球体中离体评估一种MUC1靶向双特异性T细胞衔接器
Ex vivo evaluation of a MUC1-targeted bispecific T-cell engager in ovarian tumoroids using Nilogen's 3D-EXpress platform
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摘要 Abstract
中文摘要
背景:黏蛋白1(MUC1)因其在上皮性恶性肿瘤中的表达而成为双特异性T细胞衔接器的相关靶点。Nilogen Oncosystems的3D-EXpress离体肿瘤类球体平台能够在生理上保存的肿瘤-免疫微环境中直接评估患者特异性对免疫疗法的反应。本研究评估了一种市售重组Anti-CD3 x Anti-MUC1双特异性T细胞衔接器抗体(MUC1-TCE)在冻存卵巢肿瘤来源类球体中的活性,以使用Nilogen整合了流式细胞术、细胞因子分析和RNA转录组分析的平台表征免疫激活。
方法:审阅了所有组织的病理报告,并确认了与高级别卵巢癌一致的特征性组织学特征。对组织进行MUC1表达评估,显示高至低不等的表达水平。类球体通过机械解离生成,不进行酶消化或体外扩增。解冻后,用MUC1-TCE、同型对照或阳性对照处理类球体。多参数流式细胞术测量T细胞激活。同时收集上清液进行多重细胞因子分析,并分离RNA用于下游转录分析。
结果:MUC1-TCE处理在多个组织中诱导了明显的免疫激活。CD4+ T细胞上调了4-1BB、CD25、CD69、OX40和PD-1,而CD8+ T细胞上调了4-1BB、CD25、ICOS和OX40。细胞因子分析显示炎症介质的强烈诱导,其中IFN-gamma和TNF反应最大。初步RNA分析揭示了免疫激活、炎症和细胞因子驱动通路的富集,与效应细胞的接合一致。
结论:这些发现证明了使用冻存患者来源类球体在保留天然肿瘤-免疫微环境的同时,对双特异性T细胞衔接器进行离体检测的可行性。细胞因子测量、转录组读出和免疫表型分析的整合,提供了一种可扩展的方法来表征MUC1靶向药物的作用机制,并支持继续开发用于实体瘤的双特异性免疫疗法。
查看英文原文 English abstract
BACKGROUND: Mucin 1 (MUC1) is a relevant target for bispecific T-cell engagers due to its expression in epithelial malignancies. Nilogen Oncosystems' 3D-EXpress ex vivo tumoroid platform enables direct assessment of patient-specific responses to immunotherapies in a physiologically preserved tumor-immune microenvironment. This study evaluated the activity of a commercially available recombinant Anti-CD3 x Anti-MUC1 bispecific T cell engager antibody (MUC1-TCE) in cryopreserved ovarian tumor-derived tumoroids to characterize immune activation using Nilogen's integrated platform combining flow cytometry, cytokine profiling, and RNA transcriptomic analysis.
METHODS: Pathology reports were reviewed for all tissues and confirmed characteristic histological features consistent with high-grade ovarian carcinoma. Tissues were evaluated for MUC1 expression, showing high to low levels. Tumoroids were generated by mechanical dissociation without enzymatic digestion or in vitro propagation. After thawing, tumoroids were treated with MUC1-TCE, isotype control, or positive control. Multiparametric flow cytometry measured T-cell activation. Parallel supernatants were collected for multiplex cytokine profiling, and RNA was isolated for downstream transcriptional analysis.
RESULTS: MUC1-TCE treatment induced clear immune activation across multiple tissues. CD4+ T cells upregulated 4-1BB, CD25, CD69, OX40, and PD-1, while CD8+ T cells upregulated 4-1BB, CD25, ICOS, and OX40. Cytokine profiling showed strong induction of inflammatory mediators, with IFN-gamma and TNF displaying the greatest response. Preliminary RNA analysis revealed enrichment of immune-activated, inflammatory, and cytokine-driven pathways consistent with effector engagement.
CONCLUSIONS: These findings demonstrate the feasibility of using cryopreserved patient-derived tumoroids for ex vivo testing of bispecific T-cell engagers while preserving the native tumor-immune microenvironment. Integration of cytokine measurements, transcriptomic readouts, and immune phenotyping provides a scalable approach for characterizing mechanisms of action of MUC1-targeted agents and supports continued development of bispecific immunotherapies for solid tumors.
利益披露 Disclosure
V. Garrido, None..
J. DeBlasi, None..
A. Mockabee, None..
S. Currlin, None..
J. Silberman, None..
J. Linkous, None..
A. Humphrey, None..
J. Ehrhart, None.