Role of IDO in malignancy

IDO 在恶性肿瘤中的作用

• 批准号: 8372814
• 负责人: David H. Munn
• 金额: $ 24.09万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372814
• 关键词: Active Immunotherapy; Address; Adopted; Agonist; Antibodies; Antigens; Automobile Driving; Blocking Antibodies; CD28 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Vaccines; Cells; Clinic; Clinical; Clonal Expansion; Cross Presentation; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Dose; Effectiveness; Feedback; Goals; Helper-Inducer T-Lymphocyte; Human; Immune response; Immune system; Immunization; Immunologics; Immunotherapy; In Situ; Inflammatory; Interleukin-6; Intervention; Licensing; Link; Mainstreaming; Malignant Neoplasms; Mediating; Memory; Modeling; Molecular; Mus; Outcome Measure; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phenotype; Pre-Clinical Model; Prior Chemotherapy; Recombinants; Regimen; Regulatory T-Lymphocyte; Role; Signal Pathway; Signal Transduction; Source; Staging; T cell response; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic; Toxic effect; Tryptophan; Tryptophan 2,3 Dioxygenase; Tumor Antigens; Ursidae Family; Vaccines; base; cancer cell; cancer therapy; chemotherapy; crosslink; immunogenic; in vivo; inhibitor/antagonist; innovation; insight; killings; long term memory; lymph nodes; network models; novel; pre-clinical; preclinical study; prevent; response; tumor

DESCRIPTION (provided by applicant): Tumors actively suppress immune response against themselves. This creates a fundamental barrier to successful immunotherapy, but the underlying molecular mechanisms are still poorly understood. This proposal builds upon the novel discovery that three key molecular pathways - indoleamine 2,3-dioxygenase (IDO), CD40/CD40L and CTLA-4 - all become tightly linked in tumor-bearing hosts, functioning together as a single integrated regulatory network. This innovative model is supported by important new discoveries made during the previous period of support, including the role of IDO in activating highly suppressive Tregs in tumor-bearing hosts; and identification of a novel subset of "reprogrammable" Foxp3+ Tregs that is capable of converting into pro-inflammatory, CD40L-expressing helper T cells under suitable conditions. The current proposal will use informative mouse preclinical models to develop clinically-applicable, mechanistically-based immunotherapy regimens. These regimens will incorporate the first-in human IDO-inhibitor drug 1-methyl-D-tryptophan (1MT), now in Phase I clinical trials, in combination with chemotherapy and active immunotherapy. Aim 1 will test the hypothesis that the highly suppressive Tregs in tumor-draining lymph nodes (TDLNs) can be de-activated and rendered non-suppressive by simultaneously blocking IDO and providing a strong proinflammatory signal through the CD40/CD40L pathway. Aim 2 will test the hypothesis that DCs in TDLNs can be licensed for robust and effective cross-presentation of endogenous tumor antigens by preventing the tolerogenic DC phenotype that is induced by IDO-activated Tregs via the CTLA-4/B7/FOXO3 pathway, and simultaneously driving the DC-activating/licensing CD40/CD40L pathway. Aim 3 will test the hypothesis that the late stages of the CD8+ cytotoxic T cell response (clonal expansion, effector differentiation, and long-term memory formation) can be markedly enhanced by blocking the cell-intrinsic inhibitory effect of CTLA-4 on the CD8+ cells, and that this cell-intrinsic effect of CTLA-4 different from - and acts synergistically with - the upstream cell-extrinsic effects of interrupting the IDO/CTLA-4 loop during the initial priming stage. These Specific Aims continue the project's strongly translational and pre-clinical therapeutic focus. The overall goal of the current proposal is to develop novel high-potency combination regimens that leverage the synergy of IDO-inhibitor drugs in combination with CD40 agonist antibodies, chemotherapy, and CTLA-4 blockade. The strategies proposed are timely, high-impact, and have a clear path to the clinic. The proposed studies bring new mechanistic insights to bear on the difficult and important clinical problem of identifying highly potent and synergistic multi-aget immunotherapy regimens, and provide testable outcome measures at the molecular level to evaluate whether each proposed strategic intervention is hitting its hypothesized target. PUBLIC HEALTH RELEVANCE: Clinical strategies that use the body's own immune system to kill cancer cells are now poised to enter mainstream cancer therapy. The current proposal addresses a key unmet need in this field, asking what is the best way to combine powerful immunologic therapies so that they take advantage of the natural synergies between the complementary mechanisms and pathways, while minimizing the degree of toxicity to the patient.

描述（由申请人提供）：肿瘤主动抑制针对自身的免疫反应。 这为成功的免疫治疗造成了根本障碍，但其潜在的分子机制仍知之甚少。 该提议建立在三个关键分子途径——吲哚胺2,3-双加氧酶（IDO）、CD40/CD40L和CTLA-4——的新发现之上，它们在荷瘤宿主中都紧密相连，作为一个单一的综合调控网络一起发挥作用。 这一创新模型得到了前期支持期间取得的重要新发现的支持，包括IDO在激活荷瘤宿主中高度抑制性Tregs中的作用；并鉴定出“可重编程”Foxp3+ Tregs 的新子集，该子集能够在适当的条件下转化为促炎、表达 CD40L 的辅助 T 细胞。 目前的提案将使用信息丰富的小鼠临床前模型来开发临床适用的、基于机制的免疫治疗方案。 这些方案将采用目前处于 I 期临床试验的首个人类 IDO 抑制剂药物 1-甲基-D-色氨酸 (1MT)，与化疗和主动免疫疗法相结合。 目标 1 将检验以下假设：通过同时阻断 IDO 并通过 CD40/CD40L 通路提供强促炎信号，可以使肿瘤引流淋巴结 (TDLN) 中的高度抑制性 Tregs 失活并使其不再具有抑制性。 目标 2 将检验以下假设：TDLN 中的 DC 可以通过阻止 IDO 激活的 Tregs 通过 CTLA-4/B7/FOXO3 途径诱导的耐受性 DC 表型来获得稳健且有效的内源性肿瘤抗原交叉呈递的许可，以及同时驱动 DC 激活/许可 CD40/CD40L 通路。 目标 3 将检验以下假设：通过阻断 CTLA-4 对 CD8+ 的细胞内在抑制作用，可以显着增强 CD8+ 细胞毒性 T 细胞反应的后期阶段（克隆扩增、效应分化和长期记忆形成）。 CTLA-4 的这种细胞内在效应不同于在 IDO/CTLA-4 循环过程中中断 IDO/CTLA-4 环的上游细胞外在效应，并且与之协同作用。初始启动阶段。 这些具体目标延续了该项目的强烈转化和临床前治疗重点。 当前提案的总体目标是开发新型高效联合治疗方案，利用 IDO 抑制剂药物与 CD40 激动剂抗体、化疗和 CTLA-4 阻断的协同作用。 所提出的策略是及时的、高影响力的，并且有明确的临床路径。 拟议的研究为解决确定高效且协同的多年龄免疫治疗方案这一困难而重要的临床问题带来了新的机制见解，并在分子水平上提供了可测试的结果指标，以评估每个提出的战略干预措施是否达到了其假设的目标。 公共健康相关性：利用人体自身免疫系统杀死癌细胞的临床策略现已准备好进入主流癌症治疗。 目前的提案解决了该领域一个关键的未满足的需求，询问结合强大的免疫疗法的最佳方法是什么，以便它们利用互补机制和途径之间的自然协同作用，同时最大限度地减少对患者的毒性程度。