[18F]-AraG -PET imaging to evaluate immunological response to checkpoint inhibitor therapy (CKI) in patients with advanced solid tumors

联系PD/PI：Kummar，Shivaani 项目摘要/摘要 免疫疗法，特别是检查点抑制物(CKI)疗法，已导致戏剧性和 各种晚期癌症患者的持续肿瘤反应，如黑色素瘤， 非小细胞肺癌、头颈部癌等。然而，只有一部分患者 晚期实体肿瘤获得临床益处，其中很大一部分进展超过 时间到了。更好地选择可能对CKI治疗有反应的患者的能力将优化交付； 并减少接触不太可能治疗他们的疾病的药物的患者数量。那里 以血液或组织为基础的生物标记物是否正在进行多次努力；以及免疫的数量 肿瘤病变中的细胞，尤其是T细胞与肿瘤对CKI治疗的反应有关。 然而，在给定的患者中重复活检实体瘤病变仍然是困难和危险的。 由于可以在多个时间点安全地执行成像，并且可以 同时进行评估，它为患者选择提出了一个有吸引力的策略。[18F]F-Arag，a 18F标记的阿拉伯呋喃糖基鸟嘌呤类似物(Arag)已被证明是选择性服用的 在实验室模型和最初的人类研究中，T细胞上的UP。我们假设[18F]F-Arag CKI后肿瘤内产生T细胞免疫反应的患者信号将增加 治疗，这将与随后的临床益处相关。在目标1中，我们将关联更改 [18F]F-Arag信号转导治疗前后肿瘤活检组织中T细胞的数量 长江基建。在我们的第二个目标中，我们将把治疗后[18F]F-Arag信号的变化与 观察到的临床益处，定义为肿瘤稳定或缩小。在第三个目标中， 肺和胃肠道[18F]-Arag信号的变化与随后高血压病的发生 免疫相关不良事件分级。拟议研究产生的数据将提供信息 开发一种新的免疫治疗反应的成像生物标志物，优化患者 选择和结果。此外，我们预测哪些患者会进一步发展的能力 严重的毒副作用将使机构更早地接受治疗，以减轻这些副作用，以及 对不良事件进行个性化管理。

Contact PD/PI: Kummar, Shivaani PROJECT SUMMARY/ABSTRACT Immunotherapy, specifically checkpoint inhibitor (CKI) therapy, has resulted in dramatic and sustained tumor responses in patients with a variety of advanced cancers, such as melanoma, non-small cell lung cancer, head and neck cancer and others. However, only a subset of patients with advanced solid tumors derive clinical benefit, and of those a substantial portion progress over time. The ability to better select patients likely to respond to CKI therapy would optimize delivery; and reduce the number of patients exposed to agents not likely to work on their disease. There are multiple ongoing efforts focusing on blood or tissue based biomarkers; and number of immune cells, especially T cells, in the tumor lesions has correlated with tumor response to CKI treatment. However, it remains difficult and risky to biopsy solid tumor lesions repeatedly in a given patient. Since imaging can be safely performed at multiple time points, and multiple disease sites can be assessed simultaneously, it presents an attractive strategy for patient selection. [18F]F-AraG, a 18F-labeled analog of arabinofuranosylguanine (AraG), has been shown to be selectively taken up by T cells in laboratory models and in initial human studies. We hypothesize that [18F]F-AraG signal will increase in patients who develop T-cell immune responses in tumor following CKI therapy, and this will correlate with subsequent clinical benefit. In aim 1, we will correlate changes in [18F]F-AraG signal to number of T cells in tumor biopsies obtained pre and post-treatment with CKI. In our second aim, we will correlate the change in [18F]F-AraG signal following treatment to observed clinical benefit, defined as either tumor stabilization or shrinkage. In the third aim, correlate change in [18F]-AraG signal in lung and GI tract with the subsequent occurrence of higher grade immune related adverse events. Data generated from the proposed study will inform development of a novel imaging biomarker of response to immunotherapies, optimizing patient selection and outcome. In addition, our ability to predict which patients will go on to develop more severe toxicities will inform institution of therapies earlier to mitigate these side effects, as well as personalize management of adverse events.