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

总结 先天免疫系统在启动CD 8 + T细胞产生肿瘤特异性应答中的关键作用 强调了开发下一代免疫疗法的潜在重要临床策略。在 这个建议，我们追求的假设，小分子识别在高通量筛选先天性 免疫激动剂可以显著提高溶瘤NDV（纽卡斯尔疫）的治疗效果 病毒）通过激活抗原呈递细胞（APC）和增强抗癌免疫应答。 为了解决这个问题，我们提出了具体的目标，重点是通过体外和体内的命中验证 在B16-F10小鼠黑色素瘤模型中表征化合物并评估体内功效。第一、 利用正交试验，我们将验证化合物在离体人中的免疫增强特性。 原代单核细胞衍生的树突状细胞（MDDC）。具体而言，我们建议评估复合效应， 通过检查转录谱、DC活化的表达和MDDC的活化和成熟 标记物和细胞因子。然后，将基于已验证的命中进行聚类 每个簇中最有效的化合物将被带到抗肿瘤功效 在小鼠黑色素瘤模型中进行测试。化合物将单独添加或与肿瘤内施用一起添加。 注射溶瘤NDV。协同和增强NDV抗肿瘤活性的化合物， 保护和远位活动将优先考虑后续的早期电极导线优化。 基于从这些命中验证方法产生的数据，我们提出描绘离体免疫 可以用作体内功效的替代物的特征。选择性的攻击所引发的免疫信号 在MDDC（离体）和肿瘤微环境（TME -体内）两者内的细胞将被整合以构建 计算模型，以评估能够将MDDC分子和表型 对体内功效的反应。将对TME中的免疫激活读数进行类似分析。这 这将是一个渐进的过程，从实验研究中获得的信息将用于改进 与功效相关的离体和体内生物标志物的预测。从这获得的信息 拟议的研究一旦完成，将大大促进进一步的点击到领先和领先优化活动 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.