Macro-to-micro (M2µ) Activity Apportionment for αRPT

αRPT 的宏观到微观 (M2µ) 活动分配

• 批准号: 10713712
• 负责人: Robert Francois Hobbs
• 金额: $ 49.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713712
• 关键词: Alpha Particle Emitter; Alpha Particles; Anatomy; Animals; Antibodies; Bone Marrow; Clinical; Clinical Trials; Combined Modality Therapy; Data; Dose; Dose Limiting; Drug Kinetics; ERBB2 gene; FDA approved; FOLH1 gene; Family suidae; Fractionation; Goals; Human; Image; Kidney; Lacrimal gland structure; Link; Literature; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Medicine; Metastatic Neoplasm to the Bone; Methodology; Methods; Microscopic; Miniature Swine; Modality; Modeling; Mus; Organ; Organ Model; Patients; Peptides; Pre-Clinical Model; Process; Publishing; Radiobiology; Radioisotopes; Radiopharmaceuticals; Reporting; Risk; Salivary Glands; Small Intestines; Standardization; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Translating; Translations; Uncertainty; United States National Institutes of Health; Work; absorption; cancer therapy; clinical practice; clinically relevant; design; dosimetry; interest; mouse model; particle; particle therapy; porcine model; pre-clinical; predicting response; programs; response; single photon emission computed tomography; small molecule; spatiotemporal; targeted delivery; targeted treatment; translation to humans; treatment planning

Recent advances in the targeted delivery of radionuclides and the increased availability of -emitters appropriate for clinical use have led to patient trials of multiple α-emitter radiopharmaceutical therapeutics (RPTs). One of these, Xofigo (223RaCl2) was FDA-approved and is in routine clinical practice, with many others likely to follow. One of the stated goals (pillars) of the NIH is a greater level of personalization in medicine. In the realm of radiopharmaceutical therapy (RPT) this translates directly as a need for more accurate personalized dosimetry in order to enable fractionation and administered activity tailored to each patient. However, current dosimetry paradigms are poorly suited to RPT. This reality is reflected by the discrepancies between clinical (or experimental) toxicity and expected toxicity calculated using standard organ-level (or voxel-level) dosimetry, including most notably: (a) hematotoxicity in 223Ra therapy of bone metastases, (b) renal and salivary gland toxicity in pre-clinical models and patients. The objective of this work is to create a dosimetric methodology more suited to αRPT, namely the Macro to micro (M2) methodology, which requires sub-organ activity apportionment factors for organs at risk. This will be accomplished via the following Aims: 1. In murine models, measure αRPT activity concentration in selected whole organs and in relevant organ sub-regions; generate apportionment factor histograms. The translation to human assumes that the link between macroscopic and microscopic spatiotemporal relationship for a given agent measured in a pre-clinical model will apply to the human as the distribution of the agent to the different microscopic compartments should remain the same. We will test and quantify the validity of this assumption and refine the human apportionment factors by introducing a third species, the mini-pig In Aim 2. We will assess apportionment factor transferability, by obtaining corresponding apportionment factor histograms for a porcine model. In Aim 3. We will demonstrate that M2µ predicts toxicity in the porcine model. 4. Apply the M2µ methodology to clinical trial data to quantify the potential benefit of personalized M2µ dosimetry and/or derive dose–response relationships. Successful completion of the proposal will reconcile experimental and clinical results not currently understood and provide a robust standardized dosimetry for personalized dosimetry-based treatment planning of αRPT. Such standardization will enable the dosimetry to be normalized to EQD2, thus enabling rational combinations with other RPTs or external beam therapy as well as relevant absorbed dose reporting. Here we plan to expand this approach to encompass the wide range of RPT/organ combinations that have either been shown to be or are potentially dose-limiting and that require the Macro to micro (M2) methodology to properly correlate dosimetry with toxicity thresholds and provide a deliverable that will allow end-users to convert macroscopically-measured activity to standardized dosimetry at the organ and (clinically relevant) sub-organ-level for a wide range of RPTs and correspondingly relevant organs.

靶向放射线的目标交付的最新进展以及适当的e发射器的可用性增加 为了临床用途，导致了多种α-发射体放射药物治疗（RPTS）的患者试验。之一 这些，Xofigo（223RACL2）经过FDA批准，并处于常规临床实践中，许多其他人可能会遵循。 NIH的既定目标之一是医学的个性化水平。在 放射性药物治疗（RPT）直接翻译成更准确的个性化剂量测定法 为了实现分馏和为每个患者量身定制的活动。但是，当前的剂量法 范式适合RPT。临床之间的差异反映了这种现实（或 实验性的毒性和预期的毒性，使用标准器官级（或体素级）剂量测定法计算出毒性， 最值得注意的是：（a）223RA骨转移治疗中的血毒性，（b）肾脏和唾液腺 临床前模型和患者的毒性。这项工作的目的是更多地创建剂量学方法 适用于αRPT，即宏到微（M2）方法，这需要亚器官活动分配 器官有风险的因素。这将通过以下目的完成：1。在鼠模型中，测量αRpt 选定的整个器官和相关器官子区域中的活性浓度；产生批准因素 直方图。对人类的翻译假定宏观与微观之间的联系 在临床前模型中测得的给定药物的时空关系将适用于人作为人类 代理到不同显微镜室的分布应保持不变。我们将测试和 量化该假设的有效性，并通过引入第三种， AIM 2中的Mini-PIG。我们将通过获得相应 猪模型的分配因子直方图。在AIM 3中。我们将证明M2µ预测毒性 猪模型。 4。将M2µ方法应用于临床试验数据，以量化 个性化的M2µ剂量法和/或得出剂量反应关系。成功完成提案 将调和实验和临床结果当前尚不理解并提供可靠的标准化 基于个性化剂量法的剂量测定αRPT。这样的标准化将使 剂量测定要归一化为eqd2，从而可以与其他RPT或外部梁合理组合 治疗以及相关的吸收剂量报告。在这里，我们计划扩展这种方法，以包含 已证明是或潜在的剂量限制的范围广泛的RPT/器官组合 这需要宏与微（M2）方法，以将剂量法与毒性阈值正确相关 提供可允许最终用户将宏观测量活动转换为标准化的可送达 在器官和（临床上相关的）子管道级的剂量测定范围内，相应的RPT范围 相关器官。