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，多个参数被组合起来以获得更具包容性的结果。 预先对患者的肿瘤进行全面的表征可以提供个性化医疗评估。 更好的结果，即更好的洞察力提供更高的生存率，相比之下，PET 几乎不合时宜。 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，缺乏合适的成像工具，可以可视化更多内容。 需要患者体内的一个目标，类似于体内细胞计数，利用了多个部分。 频谱同时可视化多个目标，但这对于全身临床成像来说是不可行的，因为 单光子发射计算机断层扫描 (SPECT) 可以区分光的有限穿透力。 几种同位素基于其发射的能量，但光谱经常重叠并且所需的准直 不同的示踪剂可以使用 PET 连续成像，但需要多次扫描。 增加所需 CT 扫描的剂量暴露，还需要一种示踪剂随时间的推移而充分衰减。 能够对剩余的同位素进行成像，从而降低了患者对三种或四种不同同位素的便利性。 这需要更复杂的协调作为解决方案，我们提出了多色 PET 的新模式。 (mPET)，它允许同时采集多达四种不同的放射性示踪剂。 这种新的成像范例利用一个标准（纯）正电子发射器和正电子伽马发射器 产生三重（正电子-伽马）巧合，其中立即伽马发射紧随 我们已经借助标准 PET 扫描仪对两种同位素进行了成像。 附加伽马信号，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”，而空间信息则由 511 keV 携带 湮没光子需要在没有空间解码的情况下进行检测，这是通过一个 附加伽玛探测器具有足够的能量辨别力和时间分辨率，与 我们已经建立了这个系统，并在这里对三种同位素进行了成像。 1 优化 mPET 设置，然后利用 mPET 解决临床重要/生物学问题：在目标 2 中， 我们将剖析肿瘤微环境，探究对预后重要的特征。 使用 mPET 询问检查点抑制疗法中的重要参与者（CD4+ / CD8+ / PD-L1 / 巨噬细胞）随着时间的推移同时预测反应，并将通过遵循以下方法探索细胞疗法 将细胞注射到目标区域，这项研究的总体影响将是巨大的，因为 mPET 代表了真正的 范式转变，允许同时对多种放射性示踪剂进行成像，我们展示了这部小说的力量。 与临床相关的方法相比，更多的示踪剂可以比单独使用一种示踪剂更好地评估肿瘤。 提供对相关肿瘤特征的更深入了解，从而改善患者的治疗结果。