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

描述(申请人提供)：本申请的目的是监测含有嵌合抗原受体(CARS)的基因改变的人类T淋巴细胞的激活和共刺激。可以对T细胞进行基因工程，以确保其治疗效果，并表达可由非侵入性成像跟踪的标记。对带有核或光学报告基因的淋巴细胞进行基因标记，可以对临床前癌症模型和癌症患者的T细胞命运进行非侵入性成像。这项建议的重点是前列腺癌，基于前列腺特异性膜抗原(PSMA)的基因靶向。我们正在追求的目标将增加我们对体内T细胞激活、共刺激和抗肿瘤反应持续时间的了解。具体地说，利用体内报告基因成像，我们将探索选定的促进生存/增殖的共刺激途径的作用，这些途径增强了基因靶向T细胞的治疗效力。我们假设，用新的通路特异性报告结构对T淋巴细胞进行遗传标记将允许对T细胞的激活和共刺激进行重复的非侵入性监测，并提供PSMA特异性过继T细胞免疫治疗期间的早期治疗结果评估。成像的作用对于更好地了解T细胞激活、持续和T细胞增殖的持续时间和大小将是至关重要的。治疗性CARS和影像报告基因的联合使用将为癌症免疫治疗提供一种创新的研究技术和强大的临床工具。

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.