PO.IM01.11 · 免疫学

将联合PD1和LAG3抑制从临床前模型转化至难治性DNA复制修复缺陷（RRD）胶质母细胞瘤患者：一项IRRDC研究

Translating combined PD1 and LAG3 inhibition from preclinical models to patients with refractory, DNA replication repair deficient (RRD) glioblastoma: An IRRDC study

编号 2796 展板 1 时间 4/20 02:00–05:00 区域 Section 7 主讲 Anirban Das, MD

分会场 Immune Checkpoints

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作者与单位 Authors & Affiliations

Anirban Das¹, Vienna Mazzoli¹, Owen Crump¹, Olha Kos¹, Nuno M. Nunes¹, Lucie Stengs¹, Amanda Li¹, Adrian Levine¹, Yoshiko Nakano¹, Hope Friedman¹, Katharine O'Flaherty¹, Alexander Stein², Gadi Abebe-Campino³, Annika Bronsema², Vanessa Bianchi¹, Melissa Edwards¹, Stergios Zacharoulis⁴, Birgit Ertl-Wagner¹, Daniel A. Morgenstern¹, Trevor J. Pugh⁵, Pamela Ohashi⁶, Eric Bouffet¹, Cynthia E. Hawkins⁷, Peter B. Dirks¹, Uri Y. Tabori¹

¹The Hospital for Sick Children, Toronto, ON, Canada,²University Hospital Hamburg-Eppendorf, Hamburg, Germany,³Chaim Sheba Medical center, Ramat Gan, Israel,⁴Bristol Myers-Squibb, New Brunswick, NJ,⁵UHN Princess Margaret Cancer Centre, Toronto, ON, Canada,⁶Princess Margaret Cancer Cente, Toronto, ON, Canada,⁷Staff Neuropathologist, Dept. of Pathology, The Hospital for Sick Children, Toronto, ON, Canada

摘要 Abstract

中文摘要

背景与目的：由DNA复制修复缺陷（RRD）驱动的胶质母细胞瘤占儿童和年轻成人所有高级别胶质瘤的10%，具有高肿瘤突变负荷（TMB），可对抗PD1免疫检查点抑制（ICI）产生反应。然而，并非所有患者都有反应，且大多数最终会进展，这凸显了需要联合治疗以实现持续的免疫监视。方法：我们对人RRD胶质母细胞瘤标本进行了转录组分析以检测免疫检查点表达，据此在免疫功能正常小鼠模型中测试了联合ICI。基于这些临床前数据，我们通过单患者试验/同情用药途径，使用抗PD1+抗LAG3联合治疗难治性患者。进行了包括循环肿瘤DNA（ctDNA）在内的补充免疫基因组生物标志物分析，以研究机制并追踪反应。结果：人RRD胶质母细胞瘤（n=80）表现出高LAG3表达，为治疗性靶向提供了充分依据。我们在三个免疫功能正常的RRD胶质母细胞瘤小鼠模型中测试了联合抗PD1+抗LAG3抑制。在抗PD1反应性（Nestin-CreMSH2 LoxP/LoxP-POLE S459F/+）模型中，抗PD1+抗LAG3导致普遍的肿瘤反应，且生存优于ICI单药治疗。在抗PD1耐药模型（Mlh1-/-/NestinCre+/Trp53 LoxP/LoxP和治疗诱导的超突变ENU/Trp53-/-胶质瘤）中，抗PD1+抗LAG3改善了生存，克服了对ICI单药治疗缺乏反应的问题。从生物学角度看，抗PD1治疗后在CD8 T细胞中观察到的高LAG3表达和免疫耗竭，在添加抗LAG3后被消除。经抗PD1治疗后的肿瘤在连续移植后显示反应，在体内证实抗PD1耐药可被抗PD1+抗LAG3消除。七名在抗PD1治疗后进展的难治性RRD胶质母细胞瘤患儿接受了抗PD1+抗LAG3治疗，产生了客观影像学反应和持续延长的生存。耐受性优于此前针对类似患者的CTLA4和PD1联合抑制研究。配对免疫基因组肿瘤分析、连续血液流式细胞术、T细胞受体克隆型和CSF ctDNA分析为免疫激活机制和首次人体影像学反应提供了新见解。结论：LAG3是难治性RRD胶质母细胞瘤中的一个有效靶点。与抗PD1抑制联合在患者中表现出影像学反应、延长生存和可控毒性，并揭示了免疫反应的机制。该组合现将在RRD胶质母细胞瘤和其他免疫炎性实体瘤中进行生物标志物驱动的临床试验测试。

查看英文原文 English abstract

Background and Aims: Glioblastoma driven by DNA Replication Repair Deficiency (RRD) account for 10% of all high-grade glioma in children and young adults, harbour high tumor mutation burden (TMB) and can respond to anti-PD1 immune-checkpoint inhibition (ICI). However, not all respond, and the majority ultimately progress, highlighting the need for combinatorial therapies for sustained immune-surveillance. Methods: We performed transcriptomic analyses of human RRD-glioblastoma specimens for immune checkpoint expression, and accordingly, tested combined ICI in immunocompetent murine models. Based on these preclinical data, we treated refractory patients using a combination of anti-PD1+anti-LAG3 through single-patient trial/compassionate access. Complimentary immuno-genomic biomarker analyses including circulating tumor DNA (ctDNA) were performed to investigate mechanisms and track responses. Results: Human RRD-glioblastoma (n=80) demonstrated high LAG3 expression, providing a strong rationale for therapeutic targeting. We tested combined anti-PD1+anti-LAG3 inhibition in three immunocompetent RRD-glioblastoma murine models. In the anti-PD1-responsive (Nestin-CreMSH2 LoxP/LoxP -POLE S459F/+ ) model, anti-PD1+anti-LAG3 resulted in universal tumor response and superior survival to ICI-monotherapy. In the anti-PD1 resistant models (Mlh1 -/- /NestinCre+/Trp53 LoxP/LoxP and therapy-induced hypermutant ENU/Trp53 -/- gliomas), anti-PD1+antiLAG3 improved survival, overcoming the lack of response to ICI-monotherapy. Biologically, high LAG3 expression and immune-exhaustion observed in CD8 T-cells after treatment with anti-PD1 was ablated following the addition of anti-LAG3. Serially transplanted, post-anti-PD1 treated tumors showed response, confirming, in-vivo, that resistance to anti-PD1 could be abrogated by anti-PD1+anti-LAG3. Seven children with refractory RRD-glioblastoma who had progressed after anti-PD1 treatment were treated using anti-PD1+anti-LAG3, resulting in objective radiological responses and prolonged ongoing survival. Tolerability was better than a previous study of combined CTLA4 and PD1 inhibition for similar patients. Paired immuno-genomic tumor analyses, serial blood flow-cytometry, T-cell receptor clonotype, and CSF ctDNA analyses provided novel insights into the mechanisms of immunological invigoration and first-in-human, radiological responses. Conclusions: LAG3 is an effective target in refractory RRD-glioblastoma. Combined inhibition with anti-PD1 inhibition demonstrated radiological response, prolonged survival and manageable toxicities in patients, and unearthered mechanisms of immune-responses. The combination will now be tested in biomarker-driven clinical trials in RRD-glioblastoma and other immune-inflamed solid tumors.

利益披露 Disclosure

A. Das, None.. V. Mazzoli, None.. O. Crump, None.. O. Kos, None.. N. M. Nunes, None.. L. Stengs, None.. A. Li, None.. A. Levine, None.. Y. Nakano, None.. H. Friedman, None.. K. O'Flaherty, None.. A. Stein, None.. G. Abebe-Campino, None.. A. Bronsema, None.. V. Bianchi, None.. M. Edwards, None.. S. Zacharoulis, None.. B. Ertl-Wagner, None.. D. A. Morgenstern, None.. P. Ohashi, None.. E. Bouffet, None.. P. B. Dirks, None.. U. Y. Tabori, None.

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