Quantitative PET Imaging for Oncologic Immune Response Prediction

摘要 免疫检查点抑制剂显著改善了许多癌症的总生存期， 反过来又引发了巨大的科学和财政投资，以进一步扩大这种治疗方法， 范例然而，目前，免疫疗法的益处仅在少数患者中实现。 使问题进一步复杂化的是，许多免疫疗法具有严重不良免疫事件的风险， 检测治疗效果的方法，如解剖分期和18F-FDG PET成像， 可能存在的免疫浸润这些入侵的免疫细胞可能会引起潜在的反应， 肿瘤的大小和18F-FDG消耗增加，这使得它们无法与进展区分 恶性肿瘤。由于目前缺乏诊断能力，许多患者接受的唯一选择是 免疫治疗必须确定他们是否有反应是总生存期，这是一个长期的和潜在的 危险的方法来确定治疗效果。此外，随着药物数量的增加， 以及临床试验的组合，在早期阶段监测治疗效果的能力将 可能有助于更快地批准新的治疗方法。目前，没有批准的生物标志物用于 确定治疗效果，以及在治疗前对肿瘤标志物如PD-L1进行活检分析， 仅导致结果的适度改善。因此，预测反应的生物标志物将允许 在临床前和临床研究方面都取得了重大进展。 颗粒酶B，其由T效应细胞在活化后分泌，并作为一种有效的诱导剂， 细胞凋亡是免疫治疗应答的强预测因子。我开发了一种新颖的选择性PET 一种成像肽，可检测颗粒酶B的分泌和活性形式， 对免疫疗法的主动应答和无应答，其中含有颗粒酶B的“耗尽的”T细胞 可能存在，但不主动分泌酶。颗粒酶B肽的PET成像允许 在肿瘤体积变化之前高度敏感和特异地预测对免疫治疗的反应， 小鼠同基因癌症模型。这种表型并不限于小鼠，因为人类样本分析 通过抗体和我的肽显示显着更高水平的颗粒酶B在响应与非 回应患者因此，颗粒酶B PET成像提供了一个独特的洞察早期反应， 目前可以使用任何其他技术。目前的方法不能准确地定义响应之前， 破坏性抽样，作为一种反应被定义为缺乏进展。鉴于这些限制，我建议 使用颗粒酶B PET成像，根据颗粒酶B水平对小鼠进行分层，然后进行生化和 响应和非响应肿瘤的遗传分析。PET成像的非侵入性性质不会 仅在任何解剖学变化之前提供反应的准确区分，但也将允许 基于初始PET成像结果的二次治疗操作。

Abstract Immune checkpoint inhibitors have markedly improved overall survival in a number of cancers, which has in turn sparked tremendous scientific and financial investment into further expansion of this treatment paradigm. Currently, however, the benefits of immunotherapy have only been realized in a minority of patients. Further complicating the issue, many immunotherapies carry risks of severe adverse immune events, and methods to detect therapeutic efficacy such as anatomical staging and 18F-FDG PET imaging are confounded by the potential presence of immune infiltrate. These invading immune cells can cause potentially responding tumors to increase in size and in 18F-FDG consumption, which make them indistinguishable from progressing malignancies. Because of the lack of current diagnostic capabilities, the only option many patients undergoing immunotherapy have to determine if they are responding is overall survival, which is a long and potentially dangerous approach to determining therapeutic efficacy. Additionally, given the increasing number of drugs and combinations being clinically trialed, the ability to monitor therapeutic efficacy at an earlier stage would potentially help bring new treatments to approval much faster. Currently, there is no approved biomarker for determining therapeutic efficacy, and biopsy analysis of tumor markers such as PD-L1 prior to treatment have only resulted in modest improvements of outcome. Thus a biomarker that predicted response would permit significant advances in both the pre-clinical and clinical investigations. Granzyme B, which is secreted by T effector cells following activation and acts as a potent inducer of apoptosis, is a strong predictor of immunotherapy response. I have developed a novel and selective PET imaging peptide that detects the secreted and active form of granzyme B, permitting differentiation between active response to immunotherapy and non-response in which “exhausted” T cells that contain granzyme B may be present but are not actively secreting the enzyme. PET imaging with the granzyme B peptide permits highly sensitive and specific prediction of response to immunotherapy prior to changes in tumor volume in murine syngeneic models of cancer. This phenotype is not limited to mice, as human samples analyzed both by antibody and my peptide show significantly higher levels of granzyme B in responding versus non- responding patients. Thus, granzyme B PET imaging offers a unique insight into early response that is not currently possible using any other technique. Current methods cannot accurately define a response prior to destructive sampling, as a response is defined as lack of progression. Given these limitations, I am proposing to use granzyme B PET imaging to stratify mice based on granzyme B levels, followed by biochemical and genetic analysis of responding and non-responding tumors. The non-invasive nature of PET imaging will not only provide accurate differentiation of response prior to any anatomic changes, but will also allow for secondary therapeutic manipulations based on initial PET imaging results.