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.

抽象的胶质母细胞体多形（GBM）中的肿瘤微环境（TME）通常很复杂，总体免疫抑制作用，并且可以响应不同的治疗干预措施而迅速变化。原因我们对高动态网络的有限理解很大，因为i）当前的转录组分析几乎总是代表手术切除标本中的单个时间点数据，ii）TME可以更改在治疗期间迅速以及ii）事实，外周种免疫细胞组成通常不会反映什么发生在肿瘤内。为了设计更有效的GBM疗法，我们将需要新的疗法方法（药物，携带者和组合）； ii）串行询问TME随时间变化的工具，以便可以确定抗药性和免疫抑制的新兴补偿机制。目标该项目是i）测试新颖的髓样细胞靶向Candi IL-12激活疗法，因为它们已显示临床前GBM的显着效率[Lugani等，2022，Adv Mat，in Review]和其他癌症模型[Koch 等，2020，细胞化学生物，27，94-104.e5; Rodell等，2018，Nat Biomed Eng，2，578-588]和II）改进我们通过执行串行多路复用分析对GBM TME的暂时理解。该建议建立在最近以新的方式解决上述问题的三种新型技术中 Angew Chem Weinheim Bergstr Ger，132，6906-6913; Oh等，2021，Clin Cancer res]进行连续剧， GBM的深层多路复用分析，ii）多路复用的安全感染显微镜（IVM）[Ko等，2022，Adv Sci （Weinh），E2200064； Ko等，2022，NAT Biotechnol]，分析GBM药物分布和细胞作用单细胞分辨率在体内和III）[Lugani等，2022，adv Mat，in Review; Rodell等，2018，Nat Biomed Eng，2，578-588]，一种新型的髓样细胞，靶向双重免疫刺激方法有效启动GBM免疫反应。我们提出了三个目标：i）在两个鼠中对TME的序列分析使用新的生物正交方法（“基线研究”）模型（CT2A和005）； ii）确定效率 GBM和III中的Candi髓样激活疗法的疗法）进行机械研究，以进一步了解 Candi的影响以及如何在GBM中增强这种疗法。这些机械研究的发现将是重要的是因为它们可以在机械层面揭示治疗机理，并从临床观点，定义了哪些应该在临床上进行研究的TME组件。最终，我们希望提高我们对GBM TME的暂时理解，并将获得的知识应用于未来的设计试验。