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.

问题：在分子医学中，多个参数被组合在一起，以获得更具包容性的结果。 评估个性化医疗。对患者肿瘤的前期彻底表征提供了 更好的结果，即，更好的洞察力提供更高的存活率。相反，几乎是不合时宜的，PET 成像（最灵敏和定量的成像方法）是“单色”的，因为它只能评估一个 当时的参数，缺乏信息的深度。合适的成像工具，允许可视化超过 需要患者体内的一个靶点，类似于体内细胞术。光学成像利用多个部分的 光谱同时可视化几个目标，但这对于全身临床成像是不可行的， 到光线的有限穿透。单光子发射计算机断层扫描（SPECT）可以区分 几种同位素的发射能量，但光谱往往重叠，所需的准直 大大降低了灵敏度。不同的示踪剂可以用PET顺序成像，但需要多次扫描 增加所需CT扫描的剂量暴露。它还需要一种示踪剂随时间的充分衰变 以便能够对剩余的一个成像，从而降低了患者的便利性。三四种不同的同位素 这就需要更加复杂的协调。作为一种解决方案，我们提出了一种新的模式， （mPET），其允许同时进行多达四种不同放射性示踪剂的同时PET采集。 这种新的成像模式利用一个标准的（纯）正电子发射器与正电子-γ发射器 产生三重（正电子-伽马）符合，其中即时伽马发射紧随其后， 正电子并识别同位素。我们已经在标准的PET扫描仪中成像了两种同位素， 附加伽马信号，但没有能量鉴别。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”，而空间信息由511 keV 湮灭光子即时伽马需要在没有空间解码的情况下进行检测，这是通过 具有足够的能量鉴别和时间分辨率的附加伽马探测器， PET扫描仪我们已经建立了这个系统，并将三种同位素一起成像。在这里，我们将在目标 1优化mPET设置，然后使用mPET解决重要的临床/生物学问题：在目标2中， 我们将解剖肿瘤的微环境，询问对预后很重要的信号。在目标3中，我们 使用mPET询问检查点抑制治疗中的重要参与者（CD 4 + /CD 8 + / PD-L1 / 巨噬细胞），以预测反应，并将探索细胞疗法， 将细胞注射到他们的目标。这项研究的总体影响将是重大的，因为mPET代表了真正的 范式转变，允许同时成像几种放射性示踪剂。我们展示了这部小说的力量 与临床相关的方法。更多的示踪剂比一个示踪剂更能发现肿瘤，威尔 更深入地了解相关肿瘤特征，从而改善患者预后。