Site-Specific Immune Cell Activation Detection for Improving Individualized Cancer Immunotherapy

摘要 癌症免疫治疗的最新进展使整个癌症领域重新焕发生机并不断扩大。 免疫学。一些最致命的癌症的长期缓解给人们带来了难以置信的希望 给病人和肿瘤学家。然而，癌症免疫治疗的现实是，大多数患者不会受益。 因此，在决定是否开始免疫治疗时，肿瘤学家面临着艰难的两难境地。 接受免疫治疗的长期缓解与患者从 治疗费用昂贵，可能会产生严重的副作用。此外，免疫疗法中的药物开发已经 也迅速扩大，产生了对这些试验结果未知的患者的大量需求 几个月或更长时间。目前对患者进行分层的方法既包括护理标准的免疫治疗，也包括 临床试验已经改善了反应，尽管只是轻微的改善。这些表征方法中的大多数是 专注于活组织检查衍生的措施，这些措施一次只对单个肿瘤的一小部分进行采样 单一时间点。对于这项提议，我提议开发正电子发射断层扫描(PET)- 基于诊断的，有可能识别对免疫治疗有反应的患者，表征他们的 治疗后已开始反应，并在临床症状出现前检测不良事件。所有这一切都可以是 通过单一试剂完成，靶向我已经发现的、目前正在研究的颗粒酶B FDA的研究新药状态审查。颗粒酶B是一种由免疫细胞释放的酶， 诱导肿瘤杀伤，我和其他人已经证明它在肿瘤中大量存在， 正在接受免疫治疗。我设计了一种只检测活动性的PET显像剂 和释放形式的颗粒酶B，有效地区分存在的免疫细胞和 精疲力竭的免疫细胞参与了肿瘤的杀灭。这项工作的目标将是使用该代理 分析患者治疗前后颗粒酶B的定量水平，并将其与总的 此外，我们还可以将PET成像与强大的基于组织的基因测序和组织学相结合。 由于扫描覆盖整个身体，因此除了分析患者的所有肿瘤损伤外，还将分析 潜在的不良事件发生地点。通过监测反应和不良事件，回顾分析 使用该试剂扫描的患者可以获得早期不良事件检测的临床诊断参数。 综上所述，这种方法代表了一种非传统但潜在强大的调查整体 身体免疫细胞激活，这有可能为受益的患者提供免疫治疗， 同时允许那些不会受益的人寻求替代选择，包括新的临床试验。

Abstract The recent advances in cancer immunotherapy have revitalized and expanded the entire field of cancer immunology. Long-term remissions in some of the deadliest cancers have given an incredible amount of hope to patients and oncologists. However, the reality of cancer immunotherapy is that most patients will not benefit. When deciding whether to begin immunotherapy, an oncologist is therefore faced with difficult dilemma of trying for a long-term remission with immunotherapy versus the likelihood that the patient will derive no benefit from an expensive treatment with potential for severe side effects. In addition, drug development in immunotherapy has also rapidly expanded, creating a large demand for patients whose outcomes from these trials will not be known for many months or longer. Current methods for stratifying patients both for standard of care immunotherapy and clinical trials have improved response, albeit only modestly. Most of these methods of characterization are focused around biopsy derived measures, which suffer from sampling only a small part of a single tumor at a single time point. For this proposal, I am proposing the development of a positron emission tomography (PET)- based diagnostic that has the potential to identify patients who will respond to immunotherapy, characterize their response after therapy has begun, and detect adverse events before clinical symptoms. All of this can be accomplished through a single agent, targeting granzyme B that I have discovered and is currently under investigational new drug status review at the FDA. Granzyme B is an enzyme released by immune cells that induces tumor killing, and it has been shown by myself and others to be present in high amounts in tumors that are undergoing response to immunotherapy. I have designed a PET imaging agent that only detects the active and released form of granzyme B, effectively distinguishing between immune cells that are present but exhausted and immune cells that are engaged in tumor killing. The goal of this work would be to use this agent to analyze patients before and after therapy to quantify levels of granzyme B and correlate them with overall response, as well as combine PET imaging with powerful tissue based genetic sequencing and histology. Because the scan covers the entire body, all of a patient’s tumor lesions would be analyzed, in addition to potential sites of adverse events. By monitoring both response and adverse events, a retrospective analysis of patients scanned with this agent could lead to clinical diagnostic parameters for early adverse event detection. Taken together, this approach represents an unconventional but potentially powerful way of investigating whole body immune cell activation, which has the potential to deliver immunotherapy to patients for whom it will benefit, while allowing those who would not benefit to pursue alternative options, including novel clinical trials.