Noninvasive monitoring and evaluation of anti-tumor responses as a predictive tool

项目摘要/摘要 事实证明，免疫疗法是癌症治疗的一个转折点。尽管有这些令人鼓舞的事情 患者对免疫治疗的反应的体征、预测因素仍有待定义，就像实际的反应一样 异构性和难于实时研究。问题是：成功或失败的背后是什么 免疫疗法？为了解决这个问题，我们需要新的方法来探索肿瘤的非微环境。 并列举相关的细胞类型。免疫细胞在肿瘤中的渗透程度的成像 因此，识别相关的淋巴细胞亚群可能是对应答者进行分层的一种有吸引力的手段 和无响应者。通过免疫-PET成像的非侵入性监测，如本申请中所建议的，可以 因此，改变治疗的应用和评估方式，使许多患者受益。 具体地说，这里提出的研究将集中在开发针对图像的修改的单域抗体 不同的免疫细胞亚群，以及多肽-MHC复合体，以成像抗原特异性T细胞。建议数 成像工具将使我们能够非侵入性地获得对免疫渗透的更全面的了解 肿瘤微环境对治疗的反应状态。这一结果可能有助于我们更好地理解 肿瘤微环境要么更具免疫抑制作用，要么更具抗肿瘤作用。反过来，这可能会 帮助改进或定制治疗方法。最终，我们可能会找到预测性标准。因为基本的 这里提出的方法很容易转化为人类环境，可以预见，这种方法将 最终找到临床应用。 穆罕默德·拉希迪安博士是希德·普洛夫博士实验室的博士后研究员。他 他在明尼苏达大学化学生物学项目获得博士学位，在那里他从事蛋白质研究 和抗体标记方法。他在博士期间发表了五篇第一作者论文，并发展了几篇 快速有效的位点特异性蛋白质和抗体修饰方法。在Ploegh实验室，Rashidian博士 开创了一种允许全身成像和跟踪实时抗肿瘤免疫反应的方法- 时间到了。在这一发现的基础上，他现在将检查抗肿瘤成像的可能性 免疫反应。他的博士培训使他为必要的化学方法做好了准备，在 Ploegh实验室的Rashidian博士迅速熟悉了免疫学和癌症免疫疗法，因为 应用于VHH及其在免疫反应成像中的应用。在他在Ploegh医生的剩余时间里 在他获得独立的教职员工职位之前，他将专注于开发新的PET试剂和 还专注于增强他在免疫学方面的专业知识。KARP/BCH和Ploegh实验室装备精良 以支持他的项目，并促进他的癌症免疫学培训。从长远来看，拉希迪安博士将专注于 论免疫治疗异质性反应的根本原因。他计划发起一项独立研究 在学术机构的职业生涯，在那里他可以继续并专注于他的研究目标和培训毕业生 他的实验室里有学生和博士后。

Project Summary/Abstract Immunotherapy is proving to be a turning point in the treatment of cancer. Notwithstanding these encouraging signs, predictors of a patient's response to immunotherapy remain to be defined, as actual responses are heterogeneous and difficult to study in real-time. The question is: what is behind the success or failure of immunotherapy? To tackle this issue, we need new methods to explore the microenvironment of tumors non- invasively and to enumerate the relevant cell types. Imaging the extent of infiltration of immune cells into tumors and identifying the relevant lymphocyte subsets may therefore be an attractive means of stratifying responders and non-responders. Non-invasive monitoring via immuno-PET imaging, as proposed in this application, could therefore change how therapies are applied and assessed, to the benefit of many patients. Specifically, the study proposed here will focus on developing modified single domain antibodies to image different subsets of immune cells, and peptide-MHC complexes to image antigen-specific T cells. The proposed imaging tools will allow us to noninvasively acquire a more comprehensive understanding of the immune infiltrate status in the tumor microenvironment in response to therapy. The results may help us to better understand how the tumor microenvironment is shaped to be either more immunosuppressive or anti-tumor. This, in turn, may help improve or customize treatments. Ultimately, we may find predictive criteria. Because the basic methodology proposed here is easily translated to a human setting, it is envisioned that this approach will ultimately find clinical application. Dr. Mohammad Rashidian (PI of the grant) is a postdoctoral fellow in the laboratory of Dr. Hidde Ploegh. He received his Ph.D. from the University of Minnesota in the chemical biology program where he worked on protein and antibody labeling approaches. He published five first author papers during Ph.D., and developed several methods for rapid and efficient site-specific protein and antibody modifications. In the Ploegh lab, Dr. Rashidian had pioneered an approach that allows whole-body imaging and tracking anti-tumor immune responses in real- time. Building off of this finding, he will now examine the extent to which it is possible to image anti-tumor immune responses. His Ph.D. training has prepared him for the necessary chemical approaches, and in the Ploegh lab Dr. Rashidian has rapidly familiarized himself with the immunology and cancer immunotherapy, as applied to VHHs and their use in imaging of immune responses. During the remaining of his time in Dr. Ploegh's lab and until he secures an independent faculty position, he will focus on developing the new PET agents and also focus on enhancing his expertise in immunology. The Karp/BCH and the Ploegh lab are very well equipped to support his project and to facilitate his cancer immunology training. In the long term, Dr. Rashidian will focus on the root cause of heterogeneous response of immunotherapy. He plans to launch an independent research career at an academic institution where he can continue and focus on his research goals and train graduate students and post-docs in his lab.!