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

位点特异性免疫细胞激活检测可改善个体化癌症免疫治疗

• 批准号: 10001195
• 负责人: Benjamin M Larimer
• 金额: $ 222.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10001195
• 关键词: Adverse event; Biopsy; Cells; Clinical; Clinical Trials; Detection; Development; Diagnostic; Disease remission; Enzymes; Generations; Genetic; Goals; Granzyme; Histology; Immune; Immunotherapy; Investigational Drugs; Lead; Lesion; Malignant Neoplasms; Measures; Methods; Monitor; Oncologist; Outcome; Patient Selection; Patients; Positron-Emission Tomography; Sampling; Scanning; Site; Symptoms; Time; Tissues; Work; base; cancer immunotherapy; clinical diagnostics; design; drug development; exhaust; imaging agent; immune activation; immunotherapy clinical trials; improved; novel; patient stratification; resistance mechanism; response; side effect; standard of care; tumor; tumor immunology; tumor progression

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.

摘要 癌症免疫治疗的最新进展使整个癌症领域重新焕发活力并得到扩展 免疫学一些最致命的癌症的长期缓解带来了令人难以置信的希望 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。 当决定是否开始免疫治疗时，肿瘤学家因此面临着尝试的困难困境 对于免疫治疗的长期缓解与患者将从免疫治疗中获益的可能性， 昂贵的治疗，并有可能产生严重的副作用。此外，免疫疗法中的药物开发 也迅速扩大，为这些试验结果未知的患者创造了大量需求 几个月或更长时间。目前用于对患者进行标准护理免疫疗法和免疫治疗的分层的方法 临床试验改善了反应，尽管只是适度的。大多数这些表征方法是 聚焦于活检衍生的测量，其遭受仅在一个肿瘤的一小部分上取样， 单个时间点。对于这个建议，我建议开发一种正电子发射断层扫描（PET）- 基于诊断，有可能识别对免疫疗法有反应的患者， 治疗开始后的反应，并在临床症状出现之前检测不良事件。所有这一切都可以 通过一个单一的代理完成，针对颗粒酶B，我已经发现，目前正在 FDA的研究性新药状态审查。颗粒酶B是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， 对免疫疗法有反应我设计了一种PET显像剂， 和颗粒酶B的释放形式，有效地区分存在但 疲惫不堪的免疫细胞参与肿瘤杀伤。这项工作的目标是使用这种代理 分析治疗前后患者的颗粒酶B水平，并将其与总体 反应，以及结合联合收割机PET成像与强大的组织为基础的基因测序和组织学。 由于扫描覆盖整个身体，除了分析患者的所有肿瘤病变外， 不良事件的潜在部位。通过监测反应和不良事件， 使用该试剂扫描的患者可以获得用于早期不良事件检测的临床诊断参数。 总而言之，这种方法代表了一种非传统但潜在强大的整体调查方式 身体免疫细胞激活，这有可能为患者提供免疫治疗， 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。