Characterization of an inflammasome-unleashing approach to improve anti-PD-1 therapy in cancer

改善癌症抗 PD-1 治疗的炎性体释放方法的表征

• 批准号: 10290553
• 负责人: MARCELO HILL
• 金额: $ 15.5万
• 依托单位: ARDAN PHARMA S A S
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10290553
• 关键词: Bioinformatics; CD8-Positive T-Lymphocytes; Cancer Model; Cations; Cell Differentiation process; Cells; Clinical; Clinical Research; Clinical Trials Design; Colon; Complement; Data; Dendritic Cells; Future; Genetic; Human; Immune; Immunologics; Immunooncology; Immunotherapeutic agent; In Vitro; Inflammasome; Inflammation; Interleukin-1 beta; Interleukin-17; Knowledge; Lead; Leukocytes; Lung; Lymphoma; Malignant Neoplasms; Modality; Modeling; Molecular Target; Mus; Outcome; PD-1 blockade; PD-1/PD-L1; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Play; Positioning Attribute; Progression-Free Survivals; Protocols documentation; Psychological reinforcement; Publishing; Reporting; Research; Resistance; Role; Solid; T-Lymphocyte; Testing; Transference; Tumor Immunity; anti-CTLA4; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; base; cancer immunotherapy; cohort; cytokine; exhaust; exhaustion; immune checkpoint blockade; immune checkpoint blockers; improved; in vivo; inhibitor/antagonist; insight; melanoma; mouse model; neoplasm immunotherapy; novel; pre-clinical; progenitor; programs; research clinical testing; response; transcriptomics; tumor; tumor growth

ABSTRACT Blockade of the immune checkpoint PD-1/PD-L1 has increased overall and progression-free survival in various cancers. However, only a restricted number of patients show clinical benefits. Understanding the mechanisms by which anti-PD-1 antibodies modulate exhausted CD8+ T cells is mandatory to improve this approach. In this context, the role played by inflammation in T cell exhaustion and tumor immunotherapy is controversial. Observations on various mouse models and on human melanoma cohorts support the notion that activation of innate immune players such as inflammasomes, may play a key role in anti-PD-1 therapy. However, we need to identify molecular targets to trigger inflammasome activation potentially leading to improved anti-PD-1 therapy. TMEM176B is an intracellular cation channel strongly expressed by conventional type 2 dendritic cells (cDC2) that inhibits inflammasome activation through ionic mechanisms. Boritinib, a potent TMEM176B inhibitor, induced tumor growth control and reinforced the antitumor activity of anti-PD-1 antibodies in a Tmem176b, inflammasome and CD8+ T cell-dependent manner in lymphoma, melanoma, lung and colon mouse cancer models. However, the mechanism underlying CD8+ T cell reinforcement remains unknown. This project aims at characterizing the mechanisms by which Boritinib improves anti-PD-1 therapy, setting the ground for the clinical evaluation of the compound. Our published and unpublished results led us to propose that inflammasome activation triggered by Boritinib therapy may modulate subsets of exhausted CD8+ T cells, through a mechanism involving Th17 cells. We will carry out a research program involving functional in vivo studies and bioinformatics analysis based on three specific aims. In Specific Aim 1 we wish to confirm and complement our unpublished results suggesting that Boritinib modulates CD8+ T cell exhaustion. In specific aim 2 we will then assess whether Th17 cells are Boritinib/inflammasome-triggered effectors leading to modulation of exhausted CD8+ T cells. In Specific Aim 3 we will study the impact of timing when combining both therapies. We speculate that the timing at which anti-PD-1 therapy and inflammasome modulation occur might determine the fate of exhausted CD8+ T cells and, perhaps, the clinical outcome of immunotherapeutic modalities. On this basis, future research will then complete ongoing preclinical pharmacological characterization of Boritinib before engaging a clinical study of the compound. This knowledge may position Boritinib as a potential candidate to be a first-in-class drug in immuno- oncology.

摘要 免疫检查点PD-1/PD-L1的阻断增加了各种患者的总体生存期和无进展生存期 癌的然而，只有有限数量的患者显示出临床获益。了解机制 抗PD-1抗体通过其调节耗尽的CD 8 + T细胞是改进该方法的必要条件。在这 背景下，炎症在T细胞耗竭和肿瘤免疫治疗中所起的作用是有争议的。 对各种小鼠模型和人黑色素瘤队列的观察支持了以下观点： 先天性免疫参与者，如炎性小体，可能在抗PD-1治疗中起关键作用。但我们需要 识别分子靶点以触发炎性小体激活，从而可能改善抗PD-1治疗。 TMEM 176 B是由常规2型树突状细胞（cDC 2）强烈表达的细胞内阳离子通道 通过离子机制抑制炎性小体活化。博瑞替尼，一种有效的TMEM 176 B抑制剂， 在Tmem 176 b中诱导肿瘤生长控制并增强抗PD-1抗体的抗肿瘤活性， 淋巴瘤、黑色素瘤、肺癌和结肠癌小鼠中炎性小体和CD 8 + T细胞依赖性方式 模型然而，CD 8 + T细胞强化的机制仍然未知。该项目旨在 表征Boritinib改善抗PD-1治疗的机制，为临床治疗奠定基础。 化合物的评价。我们发表和未发表的结果使我们提出炎性小体 博瑞替尼治疗触发的活化可能通过一种机制调节耗尽的CD 8 + T细胞亚群， 包括Th 17细胞。我们将开展一项涉及体内功能研究和生物信息学的研究计划 基于三个具体目标的分析。在具体目标1中，我们希望确认和补充我们未发表的 结果表明Boritinib调节CD 8 + T细胞耗竭。在具体目标2中，我们将评估 Th 17细胞是Boritinib/炎性小体触发的效应子，导致耗尽的CD 8 + T细胞的调节。在 具体目标3我们将研究联合两种治疗时时机的影响。我们推测 抗PD-1治疗和炎性小体调节发生的时间可能决定耗尽的CD 8 + T细胞的命运。 细胞，也许还有免疫疗法的临床结果。在此基础上，今后的研究将 在进行Boritinib的临床研究之前，完成正在进行的Boritinib临床前药理学表征。 化合物.这一知识可能使Boritinib成为免疫治疗领域的一流药物的潜在候选者。 肿瘤学