Development of IDO PET agents for immunotherapy

用于免疫治疗的 IDO PET 制剂的开发

基本信息

批准号：
10058250
负责人：
Zibo Li
金额：
$ 40.41万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-07 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058250
关键词：
Address Amino Acid Transporter Animal Model Apoptosis Applications Grants Biopsy CD8-Positive T-Lymphocytes CD8B1 gene Cancer cell line Cell Line Cells Clinical Clinical Pathways Clinical Research Clinical Trials Collaborations Complement Complex Cutaneous Melanoma Cytotoxic T-Lymphocytes Data Development Diagnosis Dioxygenases Disease Economic Burden Enzymes Essential Amino Acids Evaluation Exposure to FDA approved Foundations Future Gene Expression Goals Half-Life Healthcare Image Immune Immune checkpoint inhibitor Immune system Immunooncology Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Interferon Type II Knock-out Kynurenine Label Lead Lymphocyte Lymphoid Cell Malignant Neoplasms Mediating Metabolic Methods Modeling Modification Molecular Monitor Mothers Multi-Institutional Clinical Trial Mus Nature North Carolina Organ PD-1 inhibitors PD-1/PD-L1 PDL1 pathway Pathway interactions Patients Pharmaceutical Preparations Pharmacology Physicians Play Positioning Attribute Positron-Emission Tomography Predictive Value Prognosis Property Protein Biosynthesis Radiation exposure Regulatory T-Lymphocyte Research Role Scientist Selection for Treatments Solid Solid Neoplasm Specificity Stromal Cells T-Cell Activation T-Lymphocyte Testing Time Tracer Transportation Tryptophan Tumor Tissue Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Universities analog base cancer cell checkpoint therapy clinical application clinical development clinical imaging clinical translation cytokine density design dosage effector T cell enzyme activity experience experimental study fluorodeoxyglucose immune activation improved in vivo inhibitor/antagonist interest molecular marker novel patient screening personalized medicine predicting response profiles in patients prognostic programmed cell death protein 1 radiotracer response screening side effect success targeted agent treatment planning tumor tumor microenvironment uptake

项目摘要

Abstract Several PD-1/PD-L1 pathway inhibitors were recently FDA approved for various solid tumor malignancies. While for every 10 patients with cutaneous melanoma 3-4 patients will have shrinkage and perhaps durable response, less than 2 out of 10 patients with any other cancer will have any clinical benefit. This is an extremely important problem to be solved because the checkpoint immunotherapies are expensive, lifelong treatments with potential side effect and considerable economic burden in health care in the years to come. In order to solve the low response rate of checkpoint immunotherapy, its combination with other treatment methods are also being widely evaluated to improve the overall response rate. Among them, the combination of PD-1 inhibitor with Indoleamine2,3-dioxygenase (IDO1) inhibition draws special interest in the field due to the special role of IDO1 played in immunotherapy. IDO1 is an enzyme whose gene expression is positively regulated by interferon-gamma (IFN), an immune cytokine that is only produced by immune cell subsets (natural killer, natural killer T cells, CD4 and CD8 T cells, innate lymphoid cells). Therefore, only tumors bearing tumor-infiltrating immune cells (the so called ‘inflamed’) are expected to produce IDO1. Second, IDO1 breaks down the essential amino acid tryptophan that is required for immune cell activation. Elevated IDO1 expression and activity will not only cause tryptophan depletion, but the resulting accumulation of kynurenine metabolites will also block T cell activation, induce T cell apoptosis, and promote the differentiation of naïve T cells into CD4+ regulatory T cells that further inhibit CD8+ effector T cells. Clinical importance of the IDO1 pathway is reflected upon the clinical development of specific IDO1 inhibitors who in combination with PD-1 inhibitors have shown significantly higher antitumor activity across various solid tumors in early clinical studies compared with either agent alone. This fast advancement and dynamic nature of immune system prompt the urgent need to monitor IDO activity repetitively in vivo. In this proposal, we aim to synthesize and evaluate novel 18F labeled agents for IDO1 PET imaging based on both IDO1 substrate and IDO1 inhibitors. Compared with 11C-AMT, our agents not only allow easy synthesis and longer half-life, but also has improved target specificity (for example by blocking hydroxynation at 5 position of Trp ring). We anticipate that results from this grant proposal will allow us to monitor IDO1 activity non-invasively and repetitively in vivo, which will provide the foundation for testing these probes in future multicenter clinical trials using PD-1 inhibitors alone to evaluated whether there is tumor-infiltrating immune cells; or in combination with IDO1 inhibitors across various cancers to monitor IDO1 expression profile during the treatment and select the best time point and effect dosage based on each patient’s profile (personalized medicine).

抽象的多种PD-1/PD-L1通路抑制剂最近被FDA批准用于多种实体瘤而每 10 名皮肤黑色素瘤患者中，就有 3-4 名患者出现萎缩和恶化。也许持久的反应，不到十分之二的患有任何其他癌症的患者会获得任何临床益处。这是一个极其重要的需要解决的问题，因为检查点免疫疗法非常昂贵，终身治疗具有潜在的副作用，并且在未来几年内会给医疗保健带来相当大的经济负担为了解决检查点免疫疗法反应率低的问题，将其与其他疗法联合使用。治疗方法也正在被广泛评估，以提高总体缓解率。 PD-1抑制剂与吲哚胺2,3-双加氧酶（IDO1）抑制的组合引起了人们特别的兴趣由于IDO1在免疫治疗中发挥的特殊作用，IDO1是一种基因表达为的酶。受到干扰素-γ (IFN-) 的正向调节，干扰素-γ 是一种仅由免疫细胞产生的免疫细胞因子子集（自然杀伤细胞、自然杀伤 T 细胞、CD4 和 CD8 T 细胞、先天淋巴细胞）。携带肿瘤浸润免疫细胞（所谓的“发炎”）的肿瘤预计会产生 IDO1。其次，IDO1 分解免疫细胞激活所需的氨基酸色氨酸。 IDO1 表达和活性升高不仅会导致色氨酸消耗，还会导致色氨酸积累犬尿氨酸代谢物还会阻断 T 细胞活化，诱导 T 细胞凋亡，并促进将幼稚 T 细胞分化为 CD4+ 调节性 T 细胞，进一步抑制 CD8+ 效应 T 细胞。 IDO1 通路的重要性反映在特定 IDO1 抑制剂的临床开发上，这些抑制剂在与 PD-1 抑制剂联合使用，对各种实体瘤显示出显着更高的抗肿瘤活性在早期临床研究中，与单独使用任何一种药物相比，这种快速进展和动态性质。免疫系统提示迫切需要在体内重复监测 IDO 活性。合成并评估基于 IDO1 底物和 IDO1 PET 成像的新型 18F 标记试剂与11C-AMT相比，我们的IDO1抑制剂不仅合成容易，半衰期更长。提高了靶点特异性（例如通过阻断色氨酸环 5 位的羟基化）。这项拨款提案的结果将使我们能够在体内非侵入性地重复监测 IDO1 活性，这将为未来使用 PD-1 进行多中心临床试验测试这些探针奠定基础单独使用抑制剂来评估是否存在肿瘤浸润的免疫细胞；或与IDO1联合使用；各种癌症的抑制剂，用于监测治疗期间的 IDO1 表达谱并选择最佳抑制剂根据每个患者的情况确定时间点和有效剂量（个性化医疗）。