Multicolor PET to interrogate cancer biology

多色 PET 探索癌症生物学

• 批准号: 10598692
• 负责人: Jan Grimm
• 金额: $ 65.99万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598692
• 关键词: Address; Advanced Malignant Neoplasm; Affect; American Society of Clinical Oncology; Animals; Antibodies; Bar Codes; Biological; Biological Assay; Biopsy; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Biology; Cancer Patient; Cell Therapy; Cells; Clinical; Collimator; Color; Complex; Cytometry; Detection; Discrimination; Dose; Evaluation; Event; FDA approved; Fibroblasts; Gamma Rays; Genomics; Image; Imaging Device; Immune; Immune system; Immunotherapy; Individual; Isotopes; Lead; Light; Literature; Location; Macrophage; Malignant Neoplasms; Measures; Memorial Sloan-Kettering Cancer Center; Methods; Modality; Modernization; Molecular Medicine; Molecular Profiling; Monitor; Mutation; Oncology; Outcome; Patient-Focused Outcomes; Patients; Penetration; Photons; Positron; Positron-Emission Tomography; Prognosis; Radiolabeled; Resolution; Rest; Role; Scanning; Signal Transduction; Survival Rate; System; T-Lymphocyte; Testing; Therapeutic; Time; Tracer; Tumor Antigens; Tumor Volume; Visualization; X-Ray Computed Tomography; actionable mutation; cancer imaging; cancer therapy; checkpoint inhibition; chimeric antigen receptor T cells; clinical care; clinical imaging; clinically relevant; cost; detector; fluorodeoxyglucose; frontier; imaging modality; improved; in vivo; insight; nanomedicine; neoplasm immunotherapy; neoplastic cell; next generation; novel; novel strategies; optical imaging; patient stratification; personalized medicine; predicting response; programmed cell death ligand 1; public health relevance; quantitative imaging; radiotracer; reconstruction; response; single photon emission computed tomography; success; temporal measurement; tool; treatment response; tumor; tumor microenvironment; tumor progression; virtual biopsy

SUMMARY: The problem: In molecular medicine multiple parameters are combined for a more inclusive evaluation towards personalized medicine. A thorough characterization of a patient’s tumor upfront provides better outcomes, i.e., better insight affords higher survival rates. In contrast and almost anachronistically, PET imaging (the most sensitive and quantitative imaging method) is “monochromatic” as it can only assess one parameter at the time, lacking depth of information. Suitable imaging tools that allow visualization of more than one target in patients are needed, akin an in vivo cytometry. Optical imaging utilizes multiple parts of the spectrum to visualize several targets simultaneously, but this is not feasible for whole-body clinical imaging due to the limited penetration of light. Single-photon emission computed tomography (SPECT) can distinguish several isotopes based on the energy of their emissions, but spectra often overlap and the required collimation significantly decreases sensitivity. Different tracers could be imaged sequentially with PET but multiple scans increase the dose exposure from the required CT scans. It also requires sufficient decay of one tracer over time to be able to image the remaining one, decreasing convenience for patients. For three or four different isotopes this requires an even more complex coordination. As a solution, we propose the new modality of multicolor PET (mPET), which allows for simultaneous PET acquisitions of up to four different radiotracers at the same time. This new imaging paradigm utilizes one standard (pure) positron emitter together with positron-gamma emitters that produce triple (positron-gamma) coincidences, where a prompt gamma emission immediately follows the positron and identifies the isotope. We already imaged two isotopes in a standard PET scanner with the aid of the additional gamma signal but without energy discrimination. Here, we utilize the energy of the gamma signal as “barcode identifier” for the corresponding isotope while the spatial information is carried with the 511 keV annihilation photons. The prompt gamma requires detection without spatial decoding, which is achieved by an add-on gamma detector with sufficient energy discrimination and temporal resolution that is synchronized with the PET scanner. We established this system already and imaged three isotopes together. Here, we will in Aim 1 optimize the mPET set-up and then employ mPET to address important clinical/biological problems: In Aim 2, we will dissect the tumor microenvironment, interrogating signatures important for prognosis. In Aim 3, we will use mPET to interrogate important players in checkpoint inhibition therapy (CD4+ / CD8+ / PD-L1 / macrophages) simultaneously over time to predict response and will explore cellular therapies by following the injected cells to their target. The overall impact of this study will be significant, as mPET represents a true paradigm shift, allowing imaging of several radiotracers simultaneously. We demonstrate the power of this novel approach with clinically relevant approaches. More tracers asses a tumor better than one tracer alone, will provide a deeper insight into relevant tumor signatures, resulting in improved patient outcome.

摘要：问题：在分子医学中，多个参数合并为更具包容性 对个性化医学的评估。预先对患者肿瘤的透彻表征可提供 更好的结果，即更好的见解可提供更高的生存率。相比之下，几乎过时，宠物 成像（最敏感和定量的成像方法）是“单色”，因为它只能评估一个 当时参数，缺乏信息深度。合适的成像工具可视化不仅仅是 需要患者一个目标，类似于体内细胞仪。光学成像利用了 简单地可视化几个目标的频谱，但这对于全身临床成像不可行 光线渗透有限。单光子发射计算机断层扫描（SPECT）可以区分 基于其排放能量的几种同位素，但是光谱经常重叠和所需的协作 可以用宠物顺序对不同的示踪剂进行成像，但多次扫描 增加所需CT扫描的剂量暴露。随着时间的流逝，它还需要足够的轨迹 为了能够对剩余的成像，请减少患者的便利性。对于三个或四个不同的同位素 这需要更加复杂的协调。作为解决方案，我们提出了多色宠物的新方式 （MPET），可以同时简单地获取多达四个不同的放射性示踪剂。 这种新的成像范式利用一个标准（纯）发射极和正电子发射器 产生三重（正电子）的巧合，其中及时的伽马排放紧随其后 正电子并识别同位素。我们已经在标准PET扫描仪中成像了两个同位素 额外的伽马信号，但没有能量歧视。在这里，我们利用伽马信号的能量 作为相应同位素的“条形码标识符”，同时使用511 keV携带空间信息 歼灭照片。及时伽玛需要检测而无需空间解码，这是由 附加伽马检测器具有足够的能量辨别和临时分辨率，并与 宠物扫描仪。我们已经建立了该系统，并将三个同位素成像。在这里，我们将瞄准 1优化MPET设置，然后员工MPET解决重要的临床/生物学问题：在AIM 2中， 我们将剖析肿瘤微环境，询问对发病症重要的特征。在AIM 3中，我们将 使用MPET在检查点抑制疗法中询问重要参与者（CD4+ / CD8+ / PD-L1 / 随着时间的流逝，巨噬细胞预测反应，并将通过遵循 向其靶标注入细胞。这项研究的总体影响将很大，因为MPET代表了一个真实 范式转移，可以简单地对几种放射性示例进行成像。我们演示了这本小说的力量 临床相关方法的方法。更多的示踪剂比单独使用一个示踪剂更好地肿瘤，将 对相关的肿瘤特征提供更深入的了解，从而改善患者的结局。