MusIC: A multi-scale technology for integrating dynamic cellular function and molecular profiles

我们的目标是开发并严格验证一种变革性技术， 功能/活动与他们的深分子签名在单细胞分辨率，在高通量。 免疫疗法已经成为治疗人类癌症的一种非常有效的方法，并且通过以下方式起作用： 利用免疫系统的力量及其识别和消除癌细胞的能力。 免疫疗法具有明显的优势，包括：（i）持续和持久的反应;（ii）明确的机制 （iii）比传统方法具有更高的特异性和更少的脱靶效应。沿着抗体 免疫疗法，用于重定向免疫反应的基因工程T细胞最近收到了食物 并获得美国药品监督管理局（FDA）批准。免疫细胞疗法（ACT），基于体外扩增T细胞的输注， 携带T细胞受体（TCR）或嵌合抗原受体（CAR）的细胞已经显示出显著的 和持久的反应，即使在大量预治疗的患者中。尽管这些初步的临床成功，患者 答复各不相同。最近的相关数据表明，制造的T细胞产物的可变性可能 是临床成功的主要决定因素。由于细胞输注产品是以下物质的异质混合物： 细胞，绘制群体的复杂性需要识别功能和分子谱的能力 单细胞分辨率的细胞。对于能够映射这种复杂性的技术， 在T细胞的功能，并能够链接功能的分子概况在单细胞分辨率。我们提出 多尺度智能融合（MusIC）的开发和验证。MusIC将提供多尺度 从分子到亚细胞动力学到细胞间相互作用生物学的数据， 信元考虑到用于ACT的细胞组成的异质性，它是用于ACT的理想系统。 MusIC的开发和验证。我们的研究团队在单细胞技术方面很有经验 开发和免疫治疗，机器学习，图像分析和数据建模。我们预计 该提案的成功实施将使MusIC成为一个研究平台， 多尺度细胞生物学这反过来将导致T细胞输注产品的更可靠的生物制造， 更有效的免疫细胞工程可以对免疫疗法产生广泛的影响。

Our objective is develop and rigorously validate a transformative technology that integrates cellular functions/activities with their deep molecular signatures at single-cell resolution, in high-throughput. Immunotherapy has emerged as a highly effective approach for the treatment of human cancer, and works by harnessing the power of the immune system and its ability to recognize and eliminate cancer cells. Immunotherapy has distinct advantages, including: (i) sustained and durable responses; (ii) defined mechanisms of action; and (iii) higher specificity and fewer-off target effects than traditional approaches. Along with antibody immunotherapy, genetically engineering T cells for redirecting immune responses has recently received Food and Drug Administration (FDA) approval. Adoptive cell therapy (ACT), based on infusing in vitro expanded T cells bearing either T-cell receptors (TCR), or chimeric antigen receptors (CAR), have demonstrated dramatic and durable responses, even in heavily pretreated patients. Despite these initial clinical successes, patient responses vary widely. Recent correlative data indicate that variability in the manufactured T cell products may be the primary determinant of clinical success. Since cellular infusion products are a heterogeneous mixture of cells, mapping the complexity of the population requires the ability to identify the function and molecular profiles of cells at single-cell resolution. There is an essential need for technologies that are able to map this complexity in T-cell functionality and being able to link function to molecular profiles at single-cell resolution. We propose the development and validation of Multiscale Intelligent Convergence (MusIC). MusIC will provide multi-scale data from molecules to subcellular dynamics to cell-cell interaction biology on the same cells across thousands of cells. Given the heterogeneity in the composition of cells being used for ACT, it serves as the ideal system for the development and validation of MusIC. Our team of investigators has expertise in single-cell technology development and immunotherapy, machine learning, and image analysis and data modeling. We anticipate that the successful implementation of this proposal will enable the validation of MusIC as a platform for studying multi-scale cell biology. This in turn, will lead to the more reliable biomanufacturing of T-cell infusion products, and the engineering of more potent immune cells can have a broad impact on immunotherapy.