PO.TB10.03 · 肿瘤生物学
I期临床试验中复发性胶质母细胞瘤的空间谱分析揭示脑室内CAR T治疗诱导的有利免疫重塑
Spatial profiling of recurrent glioblastoma in a Phase I clinical trial reveals favorable immune remodeling induced by intracerebroventricular CAR T therapy
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摘要 Abstract
中文摘要
复发性胶质母细胞瘤（rGBM）是一种侵袭性脑肿瘤，在标准放化疗后中位生存期不足一年。抗原异质性、免疫排斥及抑制性肿瘤微环境（TME）限制了对免疫治疗的应答。一项针对EGFR扩增rGBM的脑室内EGFR/IL13Ralpha2 CAR T细胞（CART-EGFR-IL13Ralpha2）的首次人体I期试验被证明可行，产生了可控的神经毒性，并在一部分患者中诱导了影像学肿瘤消退（NCT05168423）。
为理解该治疗如何重塑局部TME，我们分析了入组该I期试验的6例患者的配对肿瘤切除标本，标本取自试验入组时（治疗前）及CART-EGFR-IL13Ralpha2输注后影像学进展时的原发颅内病灶部位。多模态空间谱分析包括区域转录组和蛋白质图谱（GeoMx）、单细胞全转录组成像（CosMx）及高分辨率空间转录组学（Visium HD）。我们注释了肿瘤、髓系、淋巴系和基质区室，并推导出干性、侵袭、细胞死亡和免疫调节的复合评分。使用基于邻域和相互作用的分析来比较细胞状态和细胞间通讯。
在所有患者中，尽管存在影像学进展，治疗后样本显示CAR靶抗原表达降低，且肿瘤内在程序向更少干细胞样、更少迁移性和更凋亡的状态转变。治疗后TME被重塑，抑制性髓系和B细胞富集生态位减少，干扰素应答性和T细胞相关激活程序增加。空间相互作用分析表明，治疗前的rGBM包含密集的髓系-肿瘤和髓系-T细胞接触网络，与抗原呈递和效应功能受损一致。相反，治疗后标本显示这些抑制性回路部分被破坏，并出现了对T细胞浸润和活性更为允许的微环境。
在母体I期试验中，CART-EGFR-IL13Ralpha2可行且在一部分患者中诱导了影像学肿瘤消退。这项相关性空间分析提示，先前的EGFR/IL13Ralpha2 CAR T暴露可在原发部位留下一个抑制性更低、免疫参与更强的TME，即便在影像学进展时获取的切除标本中亦然。总之，这些数据支持这样一种观点，即脑室内CAR T治疗可能使rGBM为后续免疫治疗做好条件准备。髓系和B细胞相互作用被突显为下一代CAR T细胞加固及设计合理联合与序贯策略的候选靶点。
查看英文原文 English abstract
Recurrent glioblastoma (rGBM) is an aggressive brain tumor with median survival under one year after standard chemoradiation. Antigen heterogeneity, immune exclusion, and a suppressive tumor microenvironment (TME) limit responses to immunotherapy. A first-in-human phase 1 trial of intracerebroventricular EGFR/IL13Ralpha2 CAR T cells (CART-EGFR-IL13Ralpha2) in EGFR-amplified rGBM was feasible, produced manageable neurotoxicity, and induced radiographic tumor regressions in a subset of patients (NCT05168423).
To understand how this therapy reshapes the local TME, we analyzed paired tumor resections from 6 patients enrolled in the phase 1 trial, with specimens obtained from the primary intracranial disease site at trial enrollment (pre-treatment) and at radiographic progression after CART‑EGFR‑IL13Ralpha2 infusion. Multimodal spatial profiling included regional transcriptomic and protein mapping (GeoMx), single-cell whole-transcriptome imaging (CosMx), and high-resolution spatial transcriptomics (Visium HD). We annotated tumor, myeloid, lymphoid, and stromal compartments and derived composite scores for stemness, invasion, cell death, and immune regulation. Neighborhood- and interaction-based analyses were used to compare cellular states and cell-cell communication.
Across patients, post-treatment samples showed reduced expression of CAR target antigen and a shift in tumor-intrinsic programs toward less stem-like, less migratory, and more apoptotic states, despite radiographic progression. The post-treatment TME was remodeled, with fewer suppressive myeloid- and B-cell-rich niches and increases in interferon-responsive and T cell-associated activation programs. Spatial interaction analyses indicated that pre-treatment rGBM contained dense networks of myeloid-tumor and myeloid-T-cell contacts consistent with impaired antigen presentation and effector function. Post-treatment specimens, in contrast, showed partial disruption of these suppressive circuits and the emergence of microenvironments more permissive to T-cell infiltration and activity.
In the parent phase 1 trial, CART-EGFR-IL13Ralpha2 was feasible & induced radiographic tumor regressions in a subset of patients. This correlative spatial analysis suggests that prior EGFR/IL13Ralpha2 CAR T exposure can leave a less suppressive, more immunologically engaged TME at the primary site, even in resections obtained at radiographic progression. Together, these data support the idea that intracerebroventricular CAR T therapy may condition rGBM for subsequent immunotherapy. Myeloid and B-cell interactions are highlighted as candidate targets for armoring next-generation CAR T cells and for designing rational combination and sequencing strategies.
利益披露 Disclosure
W. V. Wilson, None..
J. K. Jadlowsky, None.