Role of IDO in malignancy

IDO 在恶性肿瘤中的作用

• 批准号: 9079377
• 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/9079377
• 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-Lymphocyte-Associated Protein 4; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Dose; Effectiveness; FOXO3A gene; 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; phase I trial; 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.

描述（由申请人提供）：肿瘤会积极抑制对自己的免疫反应。 这为成功的免疫疗法带来了基本障碍，但基本的分子机制仍然很少了解。 该提议建立在新发现的基础上：三个关键分子途径 - 吲哚胺2,3-二氧酶（IDO），CD40/CD40L和CTLA-4-都在肿瘤宿主中紧密相连，可以作为单个集成调节网络一起起作用。 这种创新的模型得到了上一个支持期间的重要新发现的支持，包括IDO在激活肿瘤宿主中高度抑制的Treg中的作用；并鉴定了一个新的“可重编程” Foxp3+ Treg的子集，该子集能够在适当的条件下转化为促炎性，表达CD40L的助手T细胞。 当前的提案将使用信息丰富的小鼠临床前模型来开发临床上可申请的基于机械的免疫疗法方案。 这些方案将结合人类IDO抑制剂1-甲基-D- tryppophan（1MT），现在正在I期临床试验中，结合化学疗法和主动免疫疗法。 AIM 1将检验以下假设：通过同时阻止IDO并通过CD40/CD40L途径，可以通过同时阻止IDO并提供强大的促炎信号，从而消除肿瘤淋巴结（TDLN）中高度抑制的TREG。 AIM 2将检验以下假设：TDLN中的DC可以通过防止IDO激活的Treg通过CTLA-4/B7/B7/B7/FOXO3途径以及通过IDO激活的Treg引起的耐受性DC表型来获得稳健且有效的内源性肿瘤抗原的交叉表现。同时驱动DC激活/许可CD40/CD40L途径。 AIM 3将检验以下假设：CD8+细胞毒性T细胞反应的后期阶段（克隆扩张，效应子分化和长期记忆形成）可以通过阻止CTLA-4对CD8+的细胞内抑制作用来显着增强CD8+细胞，并且CTLA-4的这种细胞中性效应与 - 在初始启动阶段中断IDO/CTLA-4环中断的上游细胞超级效应协同作用。 这些具体目的继续该项目的强烈转化和临床前的治疗重点。 当前建议的总体目标是开发新型的高功率组合方案，以利用IDO抑制剂药物的协同作用与CD40激动剂抗体，化学疗法和CTLA-4阻滞结合使用。 提出的策略是及时的，高影响力的，并且有通向诊所的明确途径。 拟议的研究带来了新的机械见解，以鉴定出识别高度有效和协同的多功能免疫疗法方案的困难而重要的临床问题，并在分子水平上提供可测试的结果指标，以评估每种提出的战略干预措施是否达到其假设目标。

项目成果

Lineage-specific transcription factors in unexpected places.

谱系特异性转录因子出现在意想不到的地方。

• DOI: 10.1002/eji.200940238
• 发表时间: 2010
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Munn,DavidH