Early development of small molecule dendritic cell immunopotentiators for the treatment of solid tumors

用于治疗实体瘤的小分子树突状细胞免疫增强剂的早期开发

• 批准号: 10180915
• 负责人: SUMIT K CHANDA
• 金额: $ 37.1万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-11 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180915
• 关键词: Abscopal effect; Address; Agonist; Antigen Presentation; Antigen-Presenting Cells; Antineoplastic Agents; Biological Assay; Biological Markers; CD8-Positive T-Lymphocytes; Catalogs; Cells; Chemicals; Clinical; Collaborations; Computer Models; Cytotoxic T-Lymphocytes; DNA; Data; Dendritic Cells; Dendritic cell activation; Development; Dose; Feedback; Gene Expression Profile; Genes; Genomics; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Adjuvants; Immunotherapeutic agent; Immunotherapy; Infiltration; Injections; Innate Immune System; Interferons; Lead; Link; Lymphocyte; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Molecular Profiling; Mus; Myelogenous; Newcastle disease virus; Oncolytic; Oncolytic viruses; Pathway interactions; Phase; Process; Property; Quantitative Reverse Transcriptase PCR; Role; Series; Signal Transduction; Solid Neoplasm; Stimulator of Interferon Genes; T cell response; T-Cell Activation; Therapeutic; Therapeutic Agents; Transcriptional Activation; Treatment Efficacy; Tumor Antigens; Validation; Viral; analog; anti-cancer; anticancer activity; antitumor agent; base; cancer immunotherapy; cancer therapy; clinical development; cytokine; drug development; efficacy testing; experimental study; high throughput screening; immune activation; immunoregulation; improved; in vivo; individual patient; lead optimization; machine learning algorithm; melanoma; molecular phenotype; monocyte; next generation; novel; response; small molecule; small molecule libraries; success; transcriptome sequencing; tumor; tumor growth; tumor microenvironment

Summary The critical role of the innate immune system in priming CD8+ T cells to generate tumor specific responses underscores a potentially important clinical strategy for the development of next-generation immunotherapies. In this proposal, we pursue the hypothesis that small molecules identified in a high throughput screen for innate immune agonists can significantly improve the therapeutic efficacy of the oncolytic NDV (NewCastle Disease Virus) through activation of antigen presenting cells (APCs), and enhancement of anticancer immune responses. To address this, we propose specific aims that focus on hit validation through both ex vivo and in vivo characterization of compounds and assessing the in vivo efficacy in a B16-F10 mouse melanoma model. First, utilizing orthogonal assays, we will validate the immunopotentiation properties of compounds in ex vivo human primary monocyte derived dendritic cell (MDDC). Specifically, we propose to assess compound effects on MDDC activation and maturation through examination of transcriptional profiles, expression of DC activation markers, and cytokines being secreted upon compound treatment. Validated hits will then be clustered based on their activities, and the most potent compounds from each cluster will be carried forward to anti-tumor efficacy testing in a mouse melanoma model. Compounds will be added either alone or together with intratumoral injection of oncolytic NDV. Compound that synergize and enhance the anti-tumor activity of NDV, provide durable protection, and abscopal activity will be prioritized for subsequent early lead optimization. Based on data generated from these hit validation approaches, we propose to delineate ex vivo immune signatures that can be used as surrogates for in vivo efficacy. The immune signatures elicited by selected hits within both MDDCs (ex vivo) and the tumor microenvironment (TME - in vivo) will be integrated to construct a computational model to assess correlative signatures that are able to link MDDC molecular and phenotypic responses to in vivo efficacy. Similar analysis will be conducted on immune activation readouts in the TME. This will be a reiterative process, with information obtained from the experimental studies will be utilized to refine predictions of ex vivo and in vivo biomarkers that correlate with efficacy. The information gained from this proposed study upon completion will significantly facilitate further hit-to-lead and lead optimization activities during subsequent phases of the drug development process.

概括 先天免疫系统在启动 CD8+ T 细胞产生肿瘤特异性反应中的关键作用 强调了开发下一代免疫疗法的潜在重要临床策略。在 在这个提议中，我们追求这样的假设：在高通量筛选中鉴定出先天性的小分子 免疫激动剂可显着提高溶瘤新城疫病毒（NewCastle Medicine）的治疗效果 病毒）通过激活抗原呈递细胞（APC）并增强抗癌免疫反应。 为了解决这个问题，我们提出了具体目标，重点是通过离体和体内进行命中验证 化合物的表征并评估 B16-F10 小鼠黑色素瘤模型的体内功效。第一的， 利用正交测定，我们将验证化合物在离体人体中的免疫增强特性 原代单核细胞衍生的树突状细胞（MDDC）。具体来说，我们建议评估复合效应 通过检查转录谱、DC 激活的表达来激活 MDDC 并使其成熟 标记物和在化合物治疗后分泌的细胞因子。然后，经过验证的命中将基于 其活性，并且每个簇中最有效的化合物将被用于抗肿瘤功效 在小鼠黑色素瘤模型中进行测试。化合物将单独添加或与瘤内药物一起添加 注射溶瘤NDV。协同并增强 NDV 抗肿瘤活性的化合物，提供持久的抗肿瘤活性 保护和远隔活动将优先用于随后的早期先导优化。 基于这些命中验证方法生成的数据，我们建议描绘离体免疫 可用作体内功效替代物的特征。由选定的命中引发的免疫特征 MDDC（离体）和肿瘤微环境（TME - 体内）将被整合以构建一个 用于评估能够将 MDDC 分子和表型联系起来的相关特征的计算模型 对体内功效的反应。将对 TME 中的免疫激活读数进行类似的分析。这 将是一个反复的过程，从实验研究中获得的信息将用于完善 与功效相关的离体和体内生物标志物的预测。由此获得的信息 拟议的研究完成后将极大地促进进一步的先导化合物和先导化合物优化活动 在药物开发过程的后续阶段。