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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的多形性胶质母细胞瘤 (GBM) 中的肿瘤微环境 (TME) 通常很复杂，总体而言免疫抑制，并且可以根据不同的治疗干预措施而迅速改变。我们对高度动态网络的理解有限很大程度上是因为 i) 当前的转录组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 可以改变治疗过程中快速进行，以及 iii) 外周免疫细胞组成通常不反映什么的事实为了设计更有效的 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，以便可以确定新兴的抵抗和免疫抑制的补偿机制。该项目的目的是 i) 测试新型骨髓细胞靶向 CANDI IL-12 激活疗法，正如他们所表明的那样在临床前 GBM [Lugani 等人，2022，Adv Mat，综述] 和其他癌症模型 [Koch] 中具有显着疗效 et al., 2020, Cell Chem Biol, 27, 94-104.e5; Rodell et al., 2018, Nat Biomed Eng, 2, 578-588] 和 ii) 改进我们通过执行串行多重分析来建立对 GBM TME 的时间理解。最近的三项新技术以新的方式解决上述问题：i) FAST-FNA[Ko et al., 2020, Angew Chem Weinheim Bergstr Ger, 132, 6906-6913; Oh et al., 2021, Clin Cancer Res] 进行系列研究， GBM 的深度多重分析，ii) 多重 SAFE 活体显微镜 (IVM)[Ko et al., 2022, Adv Sci (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率和 iii) CANDI[Lugani 等人，2022，Adv Mat，综述；Rodell 等人，2018，Nat； Biomed Eng, 2, 578-588]，一种新型骨髓细胞靶向双重免疫刺激方法，可有效我们提出了三个目标：i) 对两只小鼠的 TME 进行连续分析。使用新的生物正交方法（“基线研究”）的模型（CT2A 和 005）确定疗效； GBM 中 CANDI 骨髓激活疗法的研究，以及 iii) 进行机制研究以进一步深入了解 CANDI 的效果以及如何增强 GBM 的治疗效果将是这些机制研究的结果。重要的是因为它们可以在机械层面上揭示治疗的作用机制，并从最终，我们希望从临床角度确定哪些 TME 成分应该进行临床研究。提高我们对 GBM TME 的时间理解，并将所获得的知识应用于未来的设计试验。