PO.CL06.02 · 临床研究

错配修复缺陷型IDH1突变胶质瘤的跨物种分析揭示了独特的基因组和免疫格局，从而对免疫联合靶向治疗产生良好反应

Trans-species analysis of mismatch repair deficient IDH1 mutant gliomas reveals a unique genomic and immune landscape resulting in favorable response to combination immune and targeted therapy

编号 1173 展板 26 时间 4/19 02:00–05:00 区域 Section 45 主讲 Vienna Mazzoli

分会场 Mechanistic Insights for Targeted Therapies in Pediatric Cancer

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作者与单位 Authors & Affiliations

Vienna Mazzoli¹, Nicholas R. Fernandez¹, Zoya Aamir¹, Olha Kos¹, Emma Gattoni¹, Owen Crump¹, Lucie Stengs¹, Nuno M. Nunes¹, Katharine O'Flaherty¹, Hope Friedman¹, Olfat Ahmad², Abigail Suwala², Kevin Bielamowicz³, Gadi Abebe-Campino⁴, Shani Caspi⁴, Per Nyman⁵, Richard Graham⁶, John Y. H. Kim⁷, Mari Wilhelmsson⁸, Mette Jorgensen⁹, Orli Michaeli¹⁰, Maria Baro¹¹, Alyssa Reddy¹², Nicolas Jose Llosa¹³, Amanda Li¹, Adrian Levine¹, Logine Negm¹, Melissa Edwards¹, Vanessa Bianchi¹, Birgit Ertl-Wagner¹, Julie Bennett¹, Stefan M. Pfister², Peter B. Dirks¹, Eric Bouffet¹, Cynthia E. Hawkins¹, Anirban Das¹, Uri Y. Tabori¹

¹The Hospital for Sick Children, Toronto, ON, Canada,²German Cancer Research Centre, Heidelberg, Germany,³Arkansas Children’s Hospital, Little Rock, AR, Canada,⁴Chaim Sheba Medical Center, Ramat Gan, Israel,⁵Crown Princess Victoria Children’s Hospital, Linkoping, Sweden,⁶Cincinnati Children’s Hospital Medical Center, Cincinnati, OH,⁷Kaiser Permanente, Oakland, CA,⁸Karolinska Universitetssjukhuset, Stockholm, Sweden,⁹Great Ormond Street Hospital, London, United Kingdom,¹⁰Schneider Children’s Medical Center of Israel, Petah Tikva, Israel,¹¹University Hospital 12 de Octubre, Madrid, Spain,¹²University of California San Francisco, San Francisco, CA,¹³Johns Hopkins University School of Medicine, Baltimore, MD

摘要 Abstract

中文摘要

高级别胶质瘤是儿童和青年（CAYA）中的致死性肿瘤。错配修复缺陷（MMRD）存在于5-10%的CAYA胶质瘤中，通常与对免疫检查点抑制剂（ICI）的良好反应相关。有趣的是，一部分携带IDH1突变的MMRD-CAYA胶质瘤对ICI无反应。在分子层面，MMRD与突变型IDH（mIDH）的相互作用以及ICI耐药的原因尚不明确。为应对这一挑战并为这些癌症开发有效的治疗策略，我们对人类和小鼠肿瘤进行了跨物种的临床、多组学和免疫分析。在分子层面，MMRD-mIDH胶质瘤表现出类似于错配修复功能正常（MMRP）星形细胞瘤的特征，其特点是频繁的TP53（83%）和ATRX（76%）突变，以及缺乏少突胶质细胞瘤相关改变（1p/19q共缺失）。然而，与更常表现为低级别肿瘤的MMRP-mIDH胶质瘤不同，>91%的MMRD-mIDH胶质瘤为高级别，表现出显著更差的结局（p<0.001）。与MMRD-IDH野生型胶质瘤相比，MMRD-mIDH胶质瘤表现出较低的肿瘤突变负荷（TMB，113对28个突变/Mb，p<0.05）和免疫浸润（以肿瘤炎症特征和CD8+ T细胞密度量化），这部分解释了它们在ICI治疗下较差的生存期。为研究肿瘤发生、代谢和免疫特征以及对联合治疗的反应，我们开发了一种新型MMRD-mIDH胶质瘤小鼠模型（Olig2-Cre+/Msh2 LoxP/LoxP/Trp53 LoxP/LoxP/LSL-Idh1 R132H/+）。小鼠MMRD-mIDH胶质瘤表现出人类胶质瘤的特征，包括TMB（20个突变/Mb）、胶质瘤驱动基因改变（ATRX、NF1）、弥漫性脑受累以及与MMRD-IDH野生型模型相比较低的免疫浸润（p<0.05）。初步数据显示，mIDH抑制在体外不影响MMRD-mIDH小鼠胶质瘤细胞的增殖和干性能力，而对mIDH抑制在基因组、转录组和免疫特征上的影响的详细分析正在进行中。引人注目的是，根据我们跨物种分析的启示，一项在ICI基础上加用IDH抑制剂的初步试验（n=13例患者）与ICI单药治疗相比，产生了客观的影像学反应并延长了12个月时的生存期（p=0.01）。 MMRD-mIDH胶质瘤是一组在遗传学和生物学上独特的肿瘤，治疗选择有限。对来自患者和新型小鼠模型的MMRD-mIDH胶质瘤进行分子和免疫分析，有助于研究胶质瘤发生的潜在生物学机制并检验改进的治疗方法。

查看英文原文 English abstract

High-grade gliomas are deadly tumors in children and young adults (CAYA). Mismatch Repair Deficiency (MMRD) is present in 5-10% of CAYA gliomas and is typically associated with favorable response to immune checkpoint inhibitors (ICI). Interestingly, a subset of MMRD-CAYA gliomas harboring IDH1 mutations fails to respond to ICI. At the molecular level, the interaction of MMRD with mutant IDH (mIDH) and the causes of ICI resistance are not well understood. To tackle this challenge and develop effective therapeutic strategies for these cancers, we performed trans-species clinical, multi-omic, and immune analysis of human and murine tumors. Molecularly, MMRD-mIDH gliomas displayed a profile resembling mismatch repair proficient (MMRP) astrocytomas, characterized by frequent TP53 (83%) and ATRX (76%) mutations and absence of oligodendroglioma-associated alterations (1p/19q codeletion). Nevertheless, in contrast to MMRP-mIDH gliomas, which more commonly present as low-grade tumors, >91% of MMRD-mIDH gliomas were high-grade, exhibiting significantly worse outcomes (p<0.001). Compared with MMRD-IDH wildtype gliomas, MMRD-mIDH gliomas exhibited reduced tumor mutation burden (TMB, 113 vs 28 mutations/Mb, p<0.05) and immune infiltration, quantified by Tumor Inflammation Signature and CD8+ T cell density, partially explaining their inferior survival under ICI treatment. In order to study tumor development, metabolic and immune profiles, as well as response to combination therapy, we developed a novel MMRD-mIDH glioma mouse model ( Olig2-Cre + /Msh2 LoxP/LoxP /Trp53 LoxP/LoxP /LSL-Idh1 R132H/+ ). Mouse MMRD-mIDH gliomas displayed characteristic features of human gliomas, including TMB (20 mutations/Mb), altered glioma driver genes ( ATRX, NF1) , diffuse cerebral involvement, and low immune infiltrates (p<0.05) as compared with MMRD-IDH wildtype models. Preliminary data reveals that mIDH inhibition does not impact proliferative and stemness capacity of MMRD-mIDH mouse glioma cells in vitro, while detailed analysis of the effect of mIDH inhibition on genomic, transcriptomic, and immune profiles are ongoing. Strikingly, informed by our trans-species analysis, an initial trial using the addition of IDH inhibitor to ICI (n=13 patients) led to objective radiological responses and prolonged survival at 12-months compared to ICI monotherapy (p=0.01). MMRD-mIDH gliomas are a genetically and biologically distinct group of tumors with limited therapeutic options. Molecular and immune profiling of MMRD-mIDH gliomas, from both patients and a novel mouse model, enables investigation of the biology underlying glioma development and testing of improved therapeutic approaches.

利益披露 Disclosure

V. Mazzoli, None.. N. R. Fernandez, None.. Z. Aamir, None.. O. Kos, None.. E. Gattoni, None.. O. Crump, None.. L. Stengs, None.. N. M. Nunes, None.. K. O'Flaherty, None.. H. Friedman, None.. O. Ahmad, None.. A. Suwala, None.. K. Bielamowicz, None.. G. Abebe-Campino, None.. S. Caspi, None.. P. Nyman, None.. R. Graham, None.. J. Y. H. Kim, None.. M. Wilhelmsson, None.. M. Jorgensen, None.. O. Michaeli, None.. M. Baro, None.. A. Reddy, None.. A. Li, None.. A. Levine, None.. L. Negm, None.. M. Edwards, None.. V. Bianchi, None.. B. Ertl-Wagner, None.. J. Bennett, None.. S. M. Pfister, None.. P. B. Dirks, None.. E. Bouffet, None.. C. E. Hawkins, None.. A. Das, None.. U. Y. Tabori, None.

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