Multicolor PET to interrogate cancer biology

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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.