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

项目总结/摘要 免疫疗法被证明是癌症治疗的转折点。尽管这些令人鼓舞的 患者对免疫治疗反应的预测因子仍有待确定，因为实际反应 异构且难以实时研究。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微环境， 并计数相关的细胞类型。成像免疫细胞浸润到肿瘤中的程度 因此，鉴定相关的淋巴细胞亚群可能是对应答者进行分层的有吸引力的手段 和无应答者。如本申请中所提出的，经由免疫PET成像的非侵入性监测可以 因此，改变治疗的应用和评估方式，使许多患者受益。 具体来说，这里提出的研究将集中在开发修饰的单域抗体， 不同的免疫细胞亚群，以及肽-MHC复合物来成像抗原特异性T细胞。拟议 成像工具将使我们能够非侵入性地更全面地了解免疫浸润 肿瘤微环境对治疗的反应状态。这些结果可能有助于我们更好地理解 肿瘤微环境被塑造成更具免疫抑制性或抗肿瘤性。反过来，这可能 帮助改善或定制治疗。最终，我们可能会找到预测标准。因为基本 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 最终获得临床应用。 博士Mohammad Rashidian（资助PI）是Hidde Ploegh博士实验室的博士后研究员。他 获得博士学位他在明尼苏达大学的化学生物学项目中研究蛋白质 和抗体标记方法。他在博士期间发表了五篇第一作者论文，并开发了几个 用于快速和有效的位点特异性蛋白质和抗体修饰的方法。在普洛实验室里， 开创了一种方法，可以在真实的环境中进行全身成像和跟踪抗肿瘤免疫反应， 时间基于这一发现，他现在将研究在多大程度上可以对抗肿瘤成像。 免疫反应。博士学位培训使他为必要的化学方法做好了准备， Ploegh实验室Rashidian博士迅速熟悉了免疫学和癌症免疫疗法， 应用于VHH及其在免疫应答成像中的用途。在他在普洛格博士医院的剩余时间里， 实验室，直到他获得一个独立的教师职位，他将专注于开发新的PET剂， 也专注于提高他在免疫学方面的专业知识。Karp/BCH和Ploegh实验室的设备非常齐全 以支持他的项目并促进他的癌症免疫学培训。从长远来看，Rashidian博士将专注于 免疫治疗异质性反应的根本原因。他计划开展一项独立研究， 在学术机构的职业生涯，他可以继续专注于他的研究目标，并培养研究生 学生和博士后在他的实验室！

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.!