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

摘要 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 强调了下一代免疫疗法发展的潜在重要临床战略。在……里面 这一提议，我们追求的假设是，在高通量筛选中识别出的小分子为先天 免疫激动剂可显著提高溶瘤新城疫(新城疫)的治疗效果 病毒)通过激活抗原提呈细胞(APC)和增强抗癌免疫反应。 为了解决这一问题，我们提出了通过体外和体内验证HIT的具体目标 化合物的特征和在B16-F10小鼠黑色素瘤模型中的体内疗效评估。第一, 利用正交法，我们将验证化合物在体外人体内的免疫增强特性 原代单核细胞来源的树突状细胞(MDDC)。具体地说，我们建议评估对 通过转录谱检测MDDC的激活和成熟，DC激活的表达 标记物和细胞因子在复合治疗中被分泌。然后，验证的命中将基于 关于它们的活性，每个簇中最有效的化合物将被推广到抗肿瘤功效上 在小鼠黑色素瘤模型中进行测试。化合物将单独添加或与肿瘤内一起添加 注射溶瘤新城疫病毒。协同增强新城疫病毒抗肿瘤活性的化合物，提供持久的 保护和异常活动将优先用于后续的早期销售线索优化。 基于这些HIT验证方法产生的数据，我们建议描绘体外免疫 可作为体内疗效的替代物的签名。由选定的命中激发的免疫签名 在MDDC(体外)和肿瘤微环境(TME-体内)将被整合，以构建 评估能够将MDDC分子和表型联系起来的相关签名的计算模型 对体内疗效的反应。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，将利用从实验研究中获得的信息来完善 与疗效相关的体外和体内生物标志物的预测。从这个过程中获得的信息 拟议的研究在完成后将大大促进进一步的点击到领先和领先的优化活动 在药物开发过程的后续阶段。

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.