Temporal analysis of the GBM tumor microenvironment during myeloid cell activating therapy

骨髓细胞激活治疗期间 GBM 肿瘤微环境的时间分析

• 批准号: 10704328
• 负责人: RALPH WEISSLEDER, MD, PHD
• 金额: $ 57.73万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704328
• 关键词: Address; Adjuvant; Biological Markers; Cancer Model; Cells; Clinical; Clinical Trials; Complex; Cyclodextrins; Data; Disease; Dose; Environment; Excision; Female; Fine needle aspiration biopsy; Future; Genomics; Glioblastoma; Glioma; Goals; Hand; Immune; Immune response; Immunohistochemistry; Immunologic Stimulation; Immunophenotyping; Immunosuppression; Immunotherapy; In Situ; Interferon Type II; Interleukin-12; Investigational Therapies; Knowledge; Malignant Neoplasms; Maps; Measurement; Methods; Modeling; Mus; Myelogenous; Myeloid Cells; NF-kappa B; Operative Surgical Procedures; Pathway interactions; Peripheral; Pharmaceutical Preparations; Production; Resolution; Sampling; Shapes; Signal Transduction; Specimen; Stat3 protein; T-Lymphocyte; TLR7 gene; Technology; Testing; Therapeutic Intervention; Time; Treatment Efficacy; Work; cytokine; design; drug distribution; efficacy evaluation; experimental study; imaging modality; improved; in vivo; innovation; insight; interest; intravital microscopy; male; mouse model; nano; nanoparticle; new technology; novel; novel therapeutic intervention; pre-clinical; resistance mechanism; response; small molecule; systemic toxicity; therapeutic target; tool; transcriptomics; treatment response; tumor; tumor microenvironment; tumor-immune system interactions

ABSTRACT The tumor microenvironment (TME) in glioblastome multiforme (GBM) is often complex, overall immunosuppressive, and can change quickly in response to different therapeutic interventions. The reason for our limited understanding of the highly dynamic network is largely because i) current transcriptomic analyses nearly always represent single time point data from surgical resection specimen, ii) the TME can change rapidly during treatment and iii) the fact that peripheral immune cell composition generally does not reflect what occurs inside tumors. In order to design more effective GBM therapies, we will i) require new therapeutic approaches (drugs, carriers and combinations); ii) tools to serially interrogate TME changes over time so that emerging compensatory mechanisms of resistance and immunosuppression can be identified. The goals of this project are to i) test the novel myeloid cell targeted CANDI IL-12 activating therapies as they have shown remarkable efficacy in preclinical GBM[Lugani et al., 2022, Adv Mat, in review] and other cancer models[Koch et al., 2020, Cell Chem Biol, 27, 94-104.e5; Rodell et al., 2018, Nat Biomed Eng, 2, 578-588] and ii) improve our temporal understanding of the GBM TME by performing serial multiplexed analyses. This proposal builds on three recent novel technologies to address the above problems in new ways: i) FAST-FNA[Ko et al., 2020, Angew Chem Weinheim Bergstr Ger, 132, 6906-6913; Oh et al., 2021, Clin Cancer Res] to perform serial, deep multiplexed analyses of GBM, ii) multiplexed SAFE-intravital microscopy (IVM)[Ko et al., 2022, Adv Sci (Weinh), e2200064; Ko et al., 2022, Nat Biotechnol] to analyze GBM drug distribution and cellular effects at single cell resolution in vivo and iii) CANDI[Lugani et al., 2022, Adv Mat, in review; Rodell et al., 2018, Nat Biomed Eng, 2, 578-588], a novel myeloid cell targeted dual immunostimulatory approach to efficiently jumpstart a GBM immune response. We propose three aims: i) serial analysis of the TME in two murine models (CT2A and 005) using the new bioorthogonal approaches (“baseline study”); ii) determine the efficacy of CANDI myeloid activating therapies in GBM and iii) perform mechanistic studies to gain further insight into the effects of CANDI and how to enhance this therapy in GBM. Findings from these mechanistic studies will be important because they could reveal at a mechanistic level the treatment's mechanisms of action, and from a clinical perspective, define which TME components that should be studied clinically. Ultimately, we hope to improve our temporal understanding of the GBM TME and apply the gained knowledge to the design of future trials.

摘要 多形性胶质母细胞瘤（GBM）中的肿瘤微环境（TME）通常是复杂的， 免疫抑制，并且可以响应于不同的治疗干预而迅速改变。的原因 我们对高度动态网络的有限理解主要是因为i）当前的转录组学分析 几乎总是代表来自手术切除标本的单个时间点数据，ii）TME可以改变 和iii）外周免疫细胞组成通常不反映在治疗过程中快速发生的免疫反应的事实， 发生在肿瘤内部。为了设计更有效的GBM疗法，我们将i）需要新的治疗方法， 方法（药物、载体和组合）; ii）连续询问TME随时间变化的工具， 可以鉴定抗性和免疫抑制的新兴补偿机制。的目标 该项目是i）测试新的髓样细胞靶向CANDI IL-12激活疗法，如他们所示 在临床前GBM中的显著功效[Lugani等人，2022，Adv Mat，综述中]和其他癌症模型[Koch 例如，2020，Cell Chem Biol，27，94- 104. e5; Rodell等人，2018，Nat Biomed Eng，2，578-588]和ii）改善 我们的时间的理解GBM TME通过执行一系列多重分析。这一建议建立 关于以新方式解决上述问题的三种最近的新技术：i）FAST-FNA[Ko等人，2020, Angew Chem魏因海姆Bergstr格尔，132，6906-6913; Oh等人，2021年，临床癌症研究]进行系列， GBM的深度多重分析，ii）多重SAFE活体显微术（IVM）[Ko等人，2022年，高级科学 （Weinh），e2200064; Ko等人，2022，Nat Biotechnol]分析GBM药物分布和细胞效应， 体内单细胞分辨和iii）CANDI[Lugani等人，2022，Adv Mat，综述中; Rodell等人，2018年，纳特 Biomed Eng，2，578-588]，一种新的髓样细胞靶向双重免疫刺激方法，以有效地 启动GBM免疫反应我们提出了三个目标：i）系列分析的TME在两个小鼠 使用新的生物正交方法（“基线研究”）的模型（CT 2A和005）; ii）确定疗效 和iii）进行机制研究，以进一步了解 CANDI的效果以及如何在GBM中加强这种治疗。这些机制研究的结果将是 重要的是，因为它们可以在机械水平上揭示治疗的作用机制， 临床角度，定义应进行临床研究的TME组件。最终，我们希望 提高我们对GBM TME的时间理解，并将获得的知识应用于未来的设计 审判