Imaging T-cell Activation and Co-stimulation in Prostate Cancer Immunotherapy

描述（由申请方提供）：本申请的目的是监测含有嵌合抗原受体（汽车）的遗传改变的人T淋巴细胞的活化和共刺激。T细胞可以通过基因工程来确保其治疗效果，并表达可以通过非侵入性成像跟踪的标记物。用核或光学报告基因对淋巴细胞进行遗传标记允许在临床前癌症模型和癌症患者中对T细胞命运进行非侵入性成像。该提案基于前列腺特异性膜抗原（PSMA）的遗传靶向，重点关注前列腺癌。我们正在追求的目标将增加我们对T细胞活化，共刺激和体内抗肿瘤反应持续时间的动态知识。具体地，使用体内报告基因成像，我们将探索所选择的促存活/增殖共刺激途径的作用，其增强遗传靶向T细胞的治疗效力。我们假设，用新的途径特异性报告基因构建体对T淋巴细胞进行遗传标记将允许对T细胞中的活化和共刺激进行重复的非侵入性监测，并在PSMA特异性过继性T细胞免疫治疗期间提供治疗结果的早期评估。成像的作用将是至关重要的，在获得更好地了解T细胞活化，持久性和T细胞增殖的持续时间和幅度。治疗性汽车和成像报告基因的组合使用将为癌症免疫治疗提供创新的研究技术和强大的新型临床工具。

DESCRIPTION (provided by applicant): The objective of this application is to monitor the activation and co-stimulation of genetically altered human T-lymphocytes containing chimeric antigen receptors (CARs). T-cells can be genetically engineered to ensure their therapeutic efficacy, and to express markers that can be tracked by non-invasive imaging. Genetic labeling of lymphocytes with nuclear or optical reporter genes allows for non-invasive imaging of T-cell fate in both pre-clinical cancer models and in patients with cancer. This proposal focuses on prostate cancer, based on the genetic targeting of prostate-specific membrane antigen (PSMA). The objectives we are pursuing will increase our knowledge about the dynamics of T-cell activation, co-stimulation and duration of anti-tumor response in vivo. Specifically, using reporter gene imaging in vivo we will explore the role of selected pro- survival/proliferation co-stimulatory pathways which augment the therapeutic potency of genetically targeted T-cells. We hypothesize that genetic labeling of T lymphocytes with novel pathway-specific reporter constructs will allow for repetitive non-invasive monitoring of activation and co-stimulation in T-cells and provide an early assessment of treatment outcome during PSMA-specific adoptive T-cell immunotherapy. The role of imaging will be essential in gaining a better understanding of the duration and magnitude of T-cell activation, persistence and T-cell proliferation. The combined use of therapeutic CARs and imaging reporter genes will provide an innovative research technique and a powerful novel clinical tool in cancer immunotherapy.