PO.CL05.07 · 临床研究

预先存在的T细胞在溶瘤病毒疗法后驱动胶质母细胞瘤的持久抗肿瘤免疫

Pre-existing T cells drive durable anti-tumor immunity after oncolytic virus therapy in glioblastoma

编号 7743 展板 3 时间 4/22 09:00–12:00 区域 Section 42 主讲 Maxime Meylan, PhD

分会场 Immune Response to Therapies

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

Maxime Meylan¹, Ye Tian¹, Lijian Wu¹, Alexander L. Ling², Daniel Kovarsky³, Graham L. Barlow¹, Linh D. Nguyen¹, Jason Pyrdol¹, Lucas Westphal¹, Michel Julius¹, Nicolas L. Gonzalez Castro⁴, Sydney D. Dumont⁴, Andres Santos², Itay Tirosh³, Mario L. Suva⁴, E Antonio Chiocca², Kai W. Wucherpfennig¹

¹Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA,²Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery and Center for Tumors of the, Mass General Brigham Cancer Institute, Boston, MA,³Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel,⁴Department of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA

摘要 Abstract

中文摘要

背景:复发性胶质母细胞瘤(rGBM)由于T细胞浸润稀疏且受抑制,仍对免疫疗法难以奏效。我们近期报道,在接受溶瘤性HSV-1(oHSV)rQNestin34.5v.2(CAN-3110)治疗的rGBM患者中,生存期与免疫激活特征相关。在此,我们提供原位和分子证据,表明单次溶瘤病毒注射即可在rGBM中诱导持久的、肿瘤反应性的T细胞免疫。方法:我们整合了高度多重化的空间蛋白质组学(CODEX)、带有针对病毒、免疫和TCR靶点的定制探针的空间转录组学(Xenium),以及对一项1期临床试验(NCT03152318)配对的治疗前和治疗后标本进行的批量TCR测序。结果:治疗后T细胞密度显著增加,深度浸润至存活肿瘤区域,并在单次瘤内oHSV注射后持续长达两年。细胞毒性GZMB+ T细胞与切割型caspase 3+凋亡肿瘤细胞紧密邻近,且较短的T细胞-肿瘤距离与更长的无进展生存期相关,表明存在持续的抗肿瘤免疫。空间转录组学识别出表达早期TCR激活(NR4A1、CD69)和组织驻留(ZNF683[HOBIT]、ITGAE[CD103])程序的CD8+ T细胞状态,富集于肿瘤床,而干细胞样T细胞则定位于淋巴样聚集体内。批量和空间TCR分析揭示了预先存在的肿瘤内T细胞克隆的原位扩增,其扩增程度与生存期相关。扩增克隆呈现组织驻留表型,且相比未扩增的T细胞更靠近肿瘤细胞。病毒残留物仅限于坏死区域,不与T细胞共定位,提示存在持续的肿瘤识别而非病毒抗原识别。结论:这些结果提供了原位证据,表明单次瘤内溶瘤病毒注射可扩增预先存在的T细胞克隆,并诱导持续的T细胞介导的肿瘤细胞毒性,即使在病毒清除后亦然。这提示溶瘤病毒疗法是rGBM中一种强效的T细胞激活策略。

查看英文原文 English abstract

Background: Recurrent glioblastoma (rGBM) remains refractory to immunotherapy due to sparse and suppressed T cell infiltration. We recently reported that survival correlated with immune activation signatures in rGBM patients receiving the oncolytic HSV-1 (oHSV) rQNestin34.5v.2 (CAN-3110). Here, we provide in-situ and molecular evidence that a single oncolytic virus injection can induce durable, tumor-reactive T cell immunity in rGBM. Methods: We integrated highly multiplexed spatial proteomics (CODEX), spatial transcriptomics (Xenium) with custom probes for viral, immune and TCR targets, and bulk TCR-sequencing on paired pre- and post-treatment specimens from a phase 1 clinical trial (NCT03152318). Results: T cell densities strongly increased after treatment, with deep infiltration into viable tumor regions persisting up to two years after a single intratumoral oHSV injection. Cytotoxic GZMB+ T cells were located in close proximity with cleaved-caspase 3+ apoptotic tumor cells, and shorter T cell-tumor distance correlated with longer-progression free survival, demonstrating ongoing anti-tumor immunity. Spatial transcriptomics identified CD8+ T cells states expressing early TCR activation (NR4A1, CD69) and tissue residency (ZNF683 [HOBIT], ITGAE [CD103]) programs enriched in the tumor bed while stem-like T cells localized within lymphoid aggregates. Bulk and spatial TCR analyses revealed in-situ expansion of pre-existing tumoral T cell clones whose amplification correlated with survival. Expanded clones featured tissue resident phenotypes and were positioned closer to tumor cells than non-expanded T cells. Viral remnants were limited to necrotic regions and did not co-localize with T cells, suggesting persistent tumor recognition rather than viral antigen. Conclusion: These results provide in-situ evidence that a single intratumoral oncolytic virus injection can amplify pre-existing T cells clones and induce sustained T cell mediated tumor cytotoxicity even after virus clearance. This suggests that oncolytic virotherapy is as potent T cell activating strategy in rGBM.

利益披露 Disclosure

M. Meylan, L'institut Servier ). Y. Tian, None.. L. Wu, None.. A. L. Ling, None.. D. Kovarsky, None.. G. L. Barlow, None.. L. D. Nguyen, None.. J. Pyrdol, None.. L. Westphal, None.. M. Julius, None.. N. L. Gonzalez Castro, None.. S. D. Dumont, None.. A. Santos, None.. I. Tirosh, None. M. L. Suva, Immunitas Therapeutics g., Board of Directors, non-salaried role). E. Chiocca, Bionaut Labs g., Board of Directors, non-salaried role), Stock Option. Seneca Therapeutics g., Board of Directors, non-salaried role), Stock Option. Calidi Biotherapeutics g., Board of Directors, non-salaried role). ReIgnite Therapeutics g., Board of Directors, non-salaried role), Stock Option. Ternalys Therapeutics g., Board of Directors, non-salaried role), Stock Option. Candel Therapeutics Other, Patents related to oHSV and CAN-3110 are under the possession of Brigham and Women’s Hospital with E.A.C. and is named as co-inventor. These patents have been licensed to Candel Therapeutics. Present and future milestone license fees and future royalty fees are distributed to Brigham and Women’s Hospital from Candel. K. W. Wucherpfennig, DEM BioPharma g., Board of Directors, non-salaried role). Solu Therapeutics g., Board of Directors, non-salaried role). D2M Biotherapeutics g., Board of Directors, non-salaried role). DoriNano g., Board of Directors, non-salaried role). Nextechinvest g., Board of Directors, non-salaried role). Immunitas Therapeutics g., Board of Directors, non-salaried role), Stock. Fate Therapeutics ). TScan Therapeutics Stock.

← 返回 AACR 2026 检索