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For details see Bensch et al. adoptively transferred therapeutic T-cells as well as the value of traceable cancer cell models in immunotherapy development. Our emphasis is usually on cell tracking methodology, including important aspects and caveats specific to immunotherapies. We discuss a variety of associated experimental design aspects including parameters such as cell type, observation occasions/intervals, and detection sensitivity. The focus is on non-invasive 3D cell tracking around the whole-body level including aspects relevant for both preclinical experimentation and clinical translatability of the underlying methodologies. distribution, persistence and survival of cell-based immunotherapies as well as their efficacy at target and non-target sites, and there is a need to investigate these aspects during their development and translation into the clinics. The Need for Imaging in Immunotherapy Development During the early stages of drug development, animal models are frequently employed to investigate the efficacies of drug candidates in defined disease settings. For instance, multiple animal tumor models have been used in the development of chemotherapeutics and targeted therapies (Cekanova and Rathore, 2014). Comparable experimentation has also been necessary for the development of immunotherapies to establish targeting efficiencies, pharmacokinetics/pharmacodynamics, whether there is spatial heterogeneity to therapy delivery, and whether therapy presence is related to efficacy. Novel and accurate biomarkers are also essential to guideline immunotherapy development to ensure optimal benefit for cancer patients. Notably, imaging biomarkers differ from conventional tissue/blood-based biomarkers in several important aspects (OConnor et al., 2017). Foremost, imaging biomarkers are non-invasive, thus overcoming sampling limitations and associated tissue morbidities of conventional tissue/blood biomarkers, and they provide whole-body information albeit usually for only one target at the time. Furthermore, dynamic imaging can provide pharmacokinetic information. As with other Lp-PLA2 -IN-1 biomarkers, imaging biomarkers should be standardized across multiple centers to unleash their full potential for diagnosis, patient stratification and treatment monitoring. Pathways for the development and standardization of dedicated imaging biomarkers have been structured and excellently described by a large team of cancer researchers (OConnor et al., 2017), and we refer the reader to this publication for specific details. Whole-body imaging technologies (Physique 1) that can interrogate cancers and therapeutics in preclinical models are very useful tools in this context. They show great potential to provide answers to various challenges central to immunotherapy: Open in a separate windows FIGURE 1 Properties of various whole-body imaging modalities. Imaging modalities are ordered according to the electromagnetic spectrum they exploit for imaging (top, high energy; bottom, low energy). Routinely achievable spatial resolution (left end) and fields of view (right end) are shown in red. Where bars are blue, they overlap red bars and indicate the same parameters but achievable with Lp-PLA2 -IN-1 instruments used routinely in the clinic. Imaging depth is usually shown in black alongside next to sensitivity ranges. Instrument cost estimations are classified as ($) 125,000 $, ($$) 125-300,000 $ and ($$$) 300,000 $. #Generated by positron annihilation (511keV). *Contrast brokers sometimes used to obtain different anatomical/functional information. **In emission mode comparable to other fluorescence modalities (nM). ***Fluorophore detection can suffer from photobleaching by excitation light. ****Highly dependent on contrast agent. & Dual isotope PET is usually feasible but not routinely in use; it requires two tracers, one with a positron emitter (e.g. 18F and 89Zr) and the other with a positron-gamma emitter (e.g. 124I, 76Br, and 86Y), and is based on recent reconstruction algorithms to differentiate Lp-PLA2 -IN-1 the two isotopes based on the prompt-gamma emission (Andreyev and Celler, 2011; Cal-Gonzalez et al., 2015; Lage et al., 2015). &?&Multichannel MRI ARHGEF7 imaging has been shown to be feasible (Zabow et al., 2008). PET, positron emission tomography; SPECT, single photon emission computed tomography; CT, computed tomography; BLI, bioluminescence imaging; Lp-PLA2 -IN-1 FLI, fluorescent lifetime imaging; FRI, fluorescent reflectance imaging; FMT, fluorescence molecular tomography; OCT, optical coherence tomography; OPT, optical projection tomography; PAT, photoacoustic tomography; MSOT, multispectral optoacoustic tomography; RSOM, raster-scan optoacoustic mesoscopy; MRI, magnetic resonance imaging; US, ultrasound. (1) Which immune cell classes are present in Lp-PLA2 -IN-1 tumors and are they critical for response? (2) What role do other components of the tumor microenvironment play? (3) What are the consequences of heterogeneity within tumors and between lesions? (4) What are biomarkers of true response and true progression? (5) What is the relationship between target expression levels, affinity, and response? (6) Can resistance be detected early or even be predicted? (7) How can the distribution, fate, persistence and efficacy of cell-based immunotherapies be.