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contrast-enhanced MRI have been used to evaluate glioblastoma patients on immunomodulatory gene therapy [89]. In a recent study, Saida et al. combined DCE-MRI with
hyperpolarized 13C MRI imaging of 13C-pyruvate and 13C-fumarate to detect early
changes in tumor glycolysis and necrosis after combination PDL1 and CTLA4 blockade
[90]. Early increased perfusion and vessel permeability were noted in concert with
decreased pyruvate metabolism and increased necrosis, as imaged by fumarate to malate
conversion. Diffusion MRI can provide information about tumor cellularity and anisotropy (when obtained with diffusion tensor imaging, DTI). Zakaria et al. analyzed DTI
images of brain metastases, finding the low fractional anisotropy was associated with high
T-cell densities and improved survival [91]. Daghighi et al. reported that a new diffusion
MRI technique, restriction-spectrum imaging, may differentiate pseudoprogression
from progression in glioblastoma patients [92].
Standardized evaluation of tumor response to ICI remains challenging, in part given
the variability of timing between scans, and highlights the need to better understand ICI
response mechanisms. However, recent studies highlight the added value of longitudinal
monitoring of tumor response dynamics. For example, Nishino et al. noted that patients
with melanoma and NSCLC with a tumor burden increase of less than 20% during their
ICI show improved overall survival [93]. Champiat et al. describe a “hyperprogressive
disease” phenotype [94] of patients who may be poor responders to ICI. These imaging
strategies, along with other imaging techniques that directly probe immune cell response
to ICI (as discussed later in the chapter), may be useful in combination to better understand ICI responses in patients.
441Image-guided cancer immunotherapy
4.1.3.3 Integrating imaging with big data analysis
Radiomic and artificial intelligence approaches are increasingly applied to imaging
datasets, which augment the predictive value of imaging when integrated with pathology
or treatment outcomes. These approaches have recently been applied for immunotherapy [88, 95, 96]. For example, Dercle et al. used machine learning approaches to identify
longitudinal radiomic signatures (including increased CT tumor volume growth,
increased spatial heterogeneity, and border invasiveness) from patients with nonsmall cell
lung cancer on nivolumab (CheckMate017 and CheckMate063) and gefitinib that were
associated with shorter overall survival [97]. Trebeschi et al. combined radiomics with
genomic information [98]. They examined the CT features from patients with melanoma
and nonsmall cell lung cancer undergoing anti-PD1 therapy. After identifying radiomic
biomarkers to predict lesion progression, the authors sought a biological basis for the biomarkers by comparing the CT biomarkers with matched array-based gene expression
data in an independent patient cohort. This analysis demonstrated that their radiomic signature was associated with cell cycle progression and mitosis, suggesting that there may be
a link between high tumor proliferation and improved response to anti-PD1 therapy.
The conclusion offers a rationale for immunotherapy in patients with aggressively
442 Thomas S.C. Ng and Miles A. Miller
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expanding tumors, and also suggests possible candidates for drug combinations. While
studies to date show promise, many of these studies were performed in small patient
cohorts and a retrospective manner. Future prospective studies in larger sets of patients
are needed to validate these techniques in the clinic. As shown by Trebeschi et al., integration of imaging data with other laboratory and clinical information will likely provide
the highest yield. Furthermore, an additional understanding of the robustness of these
techniques using imaging across different institutions, instruments, and software is necessary for clinical implementation.
4.1.4 Assessment of ICI toxicities by imaging
Immune-related adverse events (irAEs) are unique toxicities that have been associated with
ICI treatment [51, 99] (Fig. 6). Imaging findings of irAEs can occur before clinical manifestations, and early diagnosis can allow timely ICI dose titration and reduce irAE morbidity. Such findings can be seen on both anatomic imaging (CT/MRI) [51] and metabolic
imaging (FDG-PET) [99]. Several organ-specific irAEs commonly observed with imaging
include hypophysitis [100], pneumonitis [101], sarcoid-like lymphoid reactions [102],
colitis [103], pancreatitis [104], hepatitis [105], arthritis [106], and myocarditis [107].
5. Imaging of other immune targets
Imaging agents for several other immunotherapy targets are also currently being
explored [62]. Trastuzumab targets the human epidermal growth factor receptor 2
(HER2) in breast cancer and is a standard of care agent for HER2+ breast cancer [108].
Other agents based on this antibody, including immunodrug conjugates [109] and radioimmunotherapies [110], are also being explored for use in patients. Given the variability
in HER2 pathologic assessment, functional imaging of HER2 status may better identify
patients who would benefit from trastuzumab strategies. To this end, Mortimer et al. developed a 64Cu-DOTA-trastuzumab immunoPET agent to detect tumor uptake in patients
with HER2-positive metastatic breast cancer [111]. Patients with HER2+ disease demonstrated increased uptake of 64Cu-DOTA-trastuzumab, with greater interpatient variability
compared to the HER2- group, suggesting the utility of this agent for patient stratification.
Similarly, agents targeting lymphomas (CD20 [112], CD25 [113]), multiple myelomas [114], and in solid-tumors, CEA [115] and EGFR [116], can potentially better identify patients for companion treatment strategies.
6. Imaging immune cellular subsets
All immunotherapies enact therapeutic effects by stimulating one or more subsets
of the innate and adaptive immune system. Other modalities, such as chimeric antigen
receptor (CAR) T cells, redirect the immune cells themselves to better target tumor cells.
Fig. 6 Toxicities associated with immune checkpoint blockade. (A) Patient with colitis after ipilimumab
treatment. Left: Normal colon before ipilimumab. Middle: Diffuse colitis pattern. Colonic wall thickening and mucosal hyperenhancement (arrows). Right: Improvement after ipilimumab cessation and glucocorticoid treatment; (B) Patient with pancreatitis after pembrolizumab. Left: Normal pancreas before
pembrolizumab. Right: Pancreatitis with pancreatic enlargement and fat stranding (arrows);
(C) Pneumonitis after ipilimumab was given sequentially postpembrolizumab due to disease progression. i and ii, Pneumonitis with cryptogenic organizing pneumonia pattern, as depicted by mixed and
multifocal peripheral ground-glass opacities and consolidations. iii and iv, Improvement after
ipilimumab was stopped and steroids were given. Arrows show lung metastases; (C) Multifocal arthritis
(arrows) while on nivolumab; (D) Prominent mediastinal lymph nodes after immune checkpoint treatment (arrows, bottom), consistent with immune-related sarcoidosis. (Adapted from Widmann G, Nguyen
VA, Plaickner J, Jaschke W. Imaging features of toxicities by immune checkpoint inhibitors in cancer therapy. Curr Radiol Rep 2016;5(11):59.)
443Image-guided cancer immunotherapy
Imaging approaches that can monitor immune cell populations, especially their trafficking to tumor sites over time and changes to their phenotype, would be especially helpful
to determine immunotherapy efficacy. Here, we outline imaging approaches that have
been used to image immune cell subsets in vivo.
6.1 Dendritic cells
Dendritic cells (DC) play an essential role as the link between the innate and adaptive
immune system by presenting antigens to T-cells for immune activation [117]. While
DCs have been engineered to identify tumor antigens in vitro, their efficacy in vivo relies
444 Thomas S.C. Ng and Miles A. Miller
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on understanding their pharmacokinetics, especially their migration into lymphoid tissue
to present antigen [118]. Preclinical assays using the sodium-iodide symporter and/or
firefly luciferase transfected into DCs have been developed, enabling 124I or 18Ftetrafluoroborate (18F-TFB) PET/CT and bioluminescence imaging in murine models
[119], enabling monitoring of DC migration into lymph nodes over two days. In another
study, multimodal DC tracking was achieved with gold nanoparticles labeled with radioiodine for both PET and Cerenkov luminescence imaging [120, 121]. DCs have also been
labeled with superparamagnetic iron oxide (SPIO) without significant toxicity [122] for
MRI in mice, showing migration of labeled cells to draining lymph nodes after leg injection [123]. Gene reporter technology has been applied to track DCs. Kim et al. transduced
human ferritin heavy chain and GFP (green fluorescent protein) genes into DC, allowing
T2*-weighted MRI and immunofluorescent evaluation in murine models [124].
Perfluorocarbon (PFC) labeling also enabled 19F MRI imaging of DC [125].Ina
first-in-human study, an autologous DC vaccine was labeled with a PFC nanoemulsion
and intradermally injected into patients with colorectal cancer and was able to be monitored over 24 h [14].
6.2 Monocytes/macrophages
TAM can be the most abundant immune cell type within solid tumors in some cases
[126]. They exist across a spectrum of phenotypes within the tumors but most often
present as immunosuppressive cells. Identifying the number and type of TAM is important for patient prognosis and administration of appropriate therapies, including immunomodulatory and nano-therapies [29, 127–132].
Several agents have been explored for TAM imaging. MRI of iron oxide
nanoparticles shows specificity for TAM via active endocytosis. To date, ferumoxytol
is the only nanoparticle that is widely clinically available for imaging in patients [129],
although multiple other iron oxide agents have been developed, including
ferumoxtran-10 [133] and Molday iron oxide [134] particles. Ferumoxytol is FDAapproved for iron supplementation in patients with iron deficiency but can be used
“off-label” for imaging. Ferumoxytol is phagocytosed by TAM over 24 h and has been
used to identify the presence of TAM using T2-weighted imaging to measure tumor
TAM load [135], including in patients with glioblastoma [136], osteosarcoma [137],
and lymphoma [138]. Recently, we demonstrated the ability of ferumoxytol-MRI to
identify context-dependent TAM infiltration in anaplastic thyroid cancer [76] (ATC,
Fig. 7). TAM uptake in a primary ATC tumor mouse model, as shown by MRI and ver-
ified by optical imaging, was significantly higher than uptake in metastatic ATC lung
lesions, which may have implications for prognosis and guiding TAM-modulating therapies. Similar findings have been seen in other tumor types, for example in breast cancer
models using 19F-PFC TAM imaging [139].
Ferumoxytol-MRI has also been used to evaluate TAM-dependent drug delivery
strategies and to monitor treatment response to TAM-targeting therapies. Recent studies
from our group showed that TAM is implicated as a tumor “drug-depot” for
nanotherapy delivery [140]. We and others demonstrated that ferumoxytol TAM uptake
could correlate with nanotherapy uptake and subsequent tumor treatment response using
a combination of imaging and mathematical modeling techniques [129]. TAM-depletion
445Image-guided cancer immunotherapy
Fig. 7 Ferumoxytol (FMX)-enhanced MRI shows lower tumor macrophage infiltration in pulmonary
compared with thyroid lesions of anaplastic thyroid cancer (ATC). (A) T2-weighted images, with R2
maps of an ATC tumor and multiple lung lesions in mice before and 24 h after intravenous injection
of FMX (scale bar, 5 mm). Tumor voxels that did not fit the monoexponential curve were excluded from
the analysis (black voxels). Baseline coronal images are shown at the right. (B) FMX-induced percent
change in R2 of tumors shows differential uptake in lungs vs thyroid lesions. (C) FMX uptake may be a
biomarker for tumor response to nanotherapy. Tumor lesions with high FMX uptake at 24 h showed
the statistically significant best change in lesion size as assessed by RECIST. (Panel (B) Adapted from Ng
TSC, Gunda V, Li R, Prytyskach M, Iwamoto Y, Kohler RH, et al. Detecting immune response to therapies
targeting PDL1 and BRAF by using ferumoxytol MRI and macrin in anaplastic thyroid cancer. Radiology.
2020;Accepted. Panel (C) Adapted from Ng TSC, Garlin MA, Weissleder R, Miller MA. Improving nanotherapy
delivery and action through image-guided systems pharmacology. Theranostics 2020;10(3):968–997.)
446 Thomas S.C. Ng and Miles A. Miller
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by CSF1/CSF1R inhibition can be monitored noninvasively with a significant decrease
in T2-weighted ferumoxytol signal in a preclinical model of breast cancer [141]. CD47
blockade has also been explored to polarize TAMs to a more M1-like inflammatory phenotype, with increased TAM-infiltration. This effect was monitored with ferumoxytol
MRI as an increase in ferumoxytol enhancement [137].
Interestingly, while iron oxide nanoparticles are being pursued as TAM imaging
agents, they can also have immunomodulatory effects on TAMs in some cases. Treatment
with high dose ferumoxytol could induce M1-polarization of TAMs in models of breast
and metastatic lung cancers [142]. Furthermore, in the presence of iron oxide,
M1-polarized TAM can induce a Fenton reaction and produce hydroxyl radicals leading
to cytotoxicity.
Other agents have been developed for tumor TAM imaging. We recently developed
the dextran-based nanoparticle Macrin that allows for both TAM optical and PET imaging, and which shows promise for guiding macrophage-targeted therapies [143] (Fig. 8).
For example, Macrin has been used to confirm the enhanced tumor-targeting efficacy of
immunomodulating therapies in vivo, including nanoencapsulated TLR7/8 agonists in
murine colon cancer models [132], and the augmentation of nanomedicine delivery as
a function of combined BRAF-targeted kinase inhibition and anti-PDL1 treatment in
anaplastic thyroid cancer [76]. 64Cu-Macrin is currently being translated for human
use. 89Zr-labeled high-density lipoprotein nanoparticles have also shown the ability
for preferential TAM PET imaging [144].
Pan-macrophage targeting agents complement agents that target macrophage subsets,
allowing identification of protumorigenic and antitumorigenic TAMs. Several TAM targets have been explored for imaging. The macrophage mannose receptor (CD206) is
preferentially expressed in M2-like immunosuppressive macrophages. Intact antibodies
and nanobodies have been developed for SPECT (99mTc) and PET (18F) TAM
Fig. 8 Polyglucose nanoparticle, Macrin, uptake in a mouse model of lung cancer identifies tumorassociated macrophage (TAM) populations. 64Cu-Macrin PET/CT showing segmented lung adenocarcinomas in C57BL/6 mice (blue and cyan) and Macrin (orange). Representative tumors with high Macrin
uptake (cyan tumors with arrows) were further highlighted in transverse sections. (Adapted from Kim
HY, Li R, Ng TSC, Courties G, Rodell CB, Prytyskach M, et al. Quantitative imaging of tumor-associated macrophages and their response to therapy using (64)Cu-labeled macrin. ACS Nano 2018;12
(12):12015–12029.)
imaging. Devoogdt, van Ginderacter, and colleagues developed camelid antibody fragments with high-affinity cross-reactivity for both mouse and human CD206 [145], facil-
itating direct clinical translation [146]. Iron oxide particles functionalized to target
CD206 have also been developed with the potential for MRI imaging [147]. The macrophage scavenger receptor (CD163) is another marker for M2-like polarized macrophages; a 68Ga-antibody for CD163 has been tested for PET imaging in a rat model
of arthritis [148], but not to date in cancer models. An 18F-PEG-folate PET agent
targeting folate receptor β expression in macrophages was recently evaluated in patients
with arthritis [149]. Other targets that have been explored for noninvasive imaging
include F4/80 [150] and MHC class II [59]. However, these agents may be challenging
to translate to humans. The F4/80 antigen is mouse-specific, and its human homologue
EMR1 is expressed in eosinophils. While nanobodies developed for MHC class II
targeted M1-like TAMs, MHC class II can be expressed on B-cells and antigenpresenting cells such as dendritic cells, potentially decreasing specificity. Macrophage
gene reporter systems have been reported [30, 151]. For example, Aalipour et al. transduced the secreted luciferase Glue under an arginase-1 promoter in macrophages and
demonstrated that these cells were imageable by BLI upon infiltrating the tumor and
adopting an M2-like phenotype. Furthermore, luciferase secretion was also assayable
in blood samples, providing a laboratory readout of tumor macrophage profile at an earlier timepoint than imaging can provide [30].
Given the increasing appreciation of the significant role of TAMs in tumorigenesis
and the development of several TAM-targeting agents in the clinical pipeline, continued
evaluation of TAM-imaging agents will be highly desired.
447Image-guided cancer immunotherapy
6.3 Natural killer cells
Natural killer (NK) cells are a critical component of the innate immune system that is
being increasingly investigated for targeted cancer immunotherapy [152]. NK cells are
the predominant cell population responsible for antibody-dependent cellular cytotoxicity (ADCC) [153]. They do not require prior sensitization, such as needed by T-cells.
Approaches to label adoptive NK cell transfer therapies, including using ex vivo labeling
with near-infrared agents [154, 155], iron oxide particles (for MRI) [154, 156–159], 19FPFC (for 19F MRI) [160, 161], 11C-methyl iodide [162], 111In-oxine (for SPECT)
[163], 89Zr-oxine (for PET), or using PET reporter gene methods have been tried,
showing promise for NK-cell tracking [164]. Multiple studies evaluated the use of
111In-oxine-NK cells in patients [165], showing variable tumor targeting, and
suggesting better tumor targeting with intra-arterial NK cell infusion [166].
Endogenous NK-cell labeling approaches have also been pursued. 99mTc-anti-CD56
has been used to image NK cells [167], but lacks specificity, since CD56 is expressed on
multiple cell types, including T cells, dendritic cells, and cancer cells of glioma, renal cell
448 Thomas S.C. Ng and Miles A. Miller
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carcinoma, and pancreatic cancer. Recently, Shaffer et al. developed an immunoPET
agent targeting the natural cytotoxicity receptor NKp30, showing good NK-cell targeting
for up to 120 h postinjection in xenograft models using an 89Zr-NKp30 targeting
antibody [168].
6.4 B-cells
Immunotherapies directed at B-cells have been developed as clinically approved
approaches for the treatment of non-Hodgkin’s lymphoma. Furthermore, recent studies
implicate B-cell tumor infiltration as facilitating response to tumor immunotherapy
[169]. Thus, several efforts have been devoted to tracking B-cell populations. Rituximab
is an anti-CD20 monoclonal antibody that targets B cells and has been used in mono and
combination chemotherapies (R-CHOP) [170]. The radiolabeled anti-CD20 antibody
has also been FDA-approved for radioimmunotherapy in lymphoma [171]. Complementary B-cell labeling techniques have been developed to monitor treatment response.
Thorek et al. labeled B cells with SPIO and near-infrared dye and were able to monitor
dynamic changes of B-cell populations in vivo in response to B-cell depleting anti-CD79
therapy enabling MRI and optical monitoring [172]. Dias et al. directly labeled rituximab
with 99mTc and 188Re for use as a theranostic [173]. Monitoring of cellular proliferation
(using FLT [174]), and metabolism using FDG has also been pursued in malignant lymphoma as a treatment response marker for immunotherapies [175], including for CD-40
targeted immunotherapy [176].
6.5 T-cells
Many immunotherapies currently in development and use, including ICI, aim to take
advantage of the anti-tumor activity of cytotoxic T-cells [177]. Furthermore, other types
of therapy, for example, radiotherapy [178], can significantly alter the tumor immune
landscape and subsequent treatment response. Thus, several approaches have been
explored to monitor T-cell infiltration and response as a function of these therapies.
6.5.1 Monitoring T-cell via surface markers
Several cell surface markers expressed on T-cells have been explored as imaging markers
of immune subsets, many of which are based on antibodies, antibody fragments, or minibodies conjugated to radioisotopes [32]. A number of these are being tested in active
clinical trials (Table 3). CD3 is a global marker of T cells and can serve as a marker of
total T-cell infiltration. Larimer et al. developed a 89Zr-p-isothiocyanatobenzyldeferoxamine-CD3 probe for PET imaging, demonstrating its ability to differentiate
responders and nonresponders to anti-CTLA4 treatment in a syngeneic colon cancer
model as a function of T-cell infiltration [179]. While CD3 provides an overview of
global T-cell dynamics, it does not provide information about immune subsets
Table 3 T-cell targeted imaging in clinical trials.
Agent Cancer type Clinical trials Cellular/molecular target
89Zr-Df-IAB22M2C Metastatic solid tumors NCT03802123 CD8
NCT03802123
18F-AraG Solid tumors NCT03129061 deoxycytidine kinase (dCK)
Nonsmall cell lung cancer NCT04186988
Nonsmall cell lung cancer NCT04052412
Melanoma NCT04401995
89Zr-ZED88082A Metastatic cancer NCT04029181 CD8
(i.e., CD4 vs CD8) as well as their activation states. Agents targeting the CD4 and CD8
coreceptors have been developed, with an 89Zr-labeled human CD8 targeted minibody
currently in multiple clinical trials [180]. The T-cell receptor itself has also been used as a
potential probe target. Imaging of activated T-cells has also been pursued. CD134 is a
member of the tumor necrosis receptor superfamily of receptors expressed on T-cells
24–72 h after activation. A 64Cu-conjugated murine antibody targeting CD134 was
shown to increase activated T-cell infiltration in tumors and draining lymph nodes in
a mouse model of lymphoma over 24-h [75]. CD8 + T-cells mediate their specific recognition of antigens expressed on antigen-presenting cells (APC) through the interaction
of the alpha-beta T-cell receptor with a major histocompatibility complex (MHC)encoded product and its peptide-bound ligand (pMHC) on APCs [181]. Woodham
et al leveraged this interaction as a strategy to imaging antigen-specific CD8 + T-cells.
They developed a radiolabeled Fc-based covalent pMHC dimer that targeted specific
epitopes (synapse for T-cell activation, synTac). In a proof-of-concept study, synTac
PET identified human papillomavirus-specific CD8 + T-cells in a murine model of cervical cancer, as well as influenza A virus-specific CD8+ T-cells in the lungs of influenza
A virus-infected mice [182]. Cytokines play an integral role in immune signaling, with
interleukin 2 being extensively examined as a T-cell activating agent, and complementary imaging agents have been developed [183, 184]. In a phase I study, Markovic et al.
evaluated 99mTc-HYNIC-IL2 to detect T-cell infiltration as a function of ICI [185],
showing a correlation between uptake and size of lesions.
Immunocytokines are a promising class of agents that couple tumor-targeting antibodies or antibody fragments with the immune-activating cytokines [186]. Imaging
has also played a vital role in developing these agents, characterizing the ability of these
immunoconjugates to target the tumor in a dose-dependent manner [187].
449Image-guided cancer immunotherapy
6.5.2 Identifying T-cells via imaging effector pathways
An alternative approach to monitori ng T-cells is to image the expression of activated
effector pathways. ICIs targeting the CTLA4andthePD1/PDL1axesarebeingextensively explored for treatment and imaging, as d escribed above. Activated CD8 + T cells
450 Thomas S.C. Ng and Miles A. Miller
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(and natural killer cells) secrete t he serine-protease Granzyme B, which affects
immune-related cell death [188].Larimeret al. developed peptides labeled with
68Ga targeting both human and murine isoforms of granzyme B and showed good
targeting of this agent in murine tumors treated with ICI and granzyme targeting in
tissue samples of melanoma patients treated with ICI [189]. First-in-human trials of
this agent are shortly anticipated.
6.5.3 Metabolic imaging of activated T-cells
The upregulation of multiple metabolic pathways is observed upon T-cell activation and
can be monitored by imaging. 18F-FDG is the most oft-used clinical marker to date for
monitoring treatment response to ICI and shows increased uptake in activated T-cells.
However, while FDG is a sensitive imaging biomarker, it is challenging to differentiate
FDG signal from tumor cells themselves vs infiltration of inflammatory cells, making early
response assessment challenging. 18F-Fluciclovine is a synthetic amino acid currently
FDA-approved for imaging in the setting of biochemically recurrent prostate cancer.
Preclinical studies in rats suggested increased uptake of this agent in stimulated
T-cells, but this increase was less than that seen with FDG [190, 191].
Extracellular tryptopha n levels and their metabolites modulate T and NK cell proliferation and activation; expression of tryptophan degrading enzyme s including
indoleamine 2,3-dioxygenase (IDO1 and IDO2) and tryptophan 2,3-dioxygenase
(TDO) have been exploited as targets for immunotherapy [192]. 11C- and 18F-agents
targeting these enzymes have been developed, most of which are tryptophan analogs
[52, 193].Thusfar,onlytheIDO1tracerα-11C-methyl-
L-tryptophan (11 C- AMT)
has been explored in clinical studies, showing increased uptake in gliomas [194],nonsmall cell lung cancer [195], breast cancer [196], a nd meningiomas [197].Alkonyiet al.
reported that 11C-AMT distinguished recurrent glioma with radiation necrosis [198].
Substrates for deoxyribonucleoside salvage pathway enzymes have been explored as
imaging targets. 1-(2
0
-deoxy-20-18F-fluoroarabinofuranosyl) cytosine (18F-FAC) is a
deoxycytidine analog metabolized by deoxyctidine kinase (dCK), which showed fourfold higher uptake in CD62low/CD44high effector CD8+ T-cells compared to naı¨ve
T-cells, and enabled visualization of immune activation in mice with virally-induced
sarcomas [199]. 18F-labeled clofarabine (18F-CFA) is a purine analog metabolized by
dCK and studied in me lanoma patients [200].2
0
-deoxy-20-[18F]fluoro-9-β-D-
arabinofuranosylguanine (18F-AraG) has been shown to accumulate in activated
T-cells via the dGK pathway and has been able to visualize a ctivated T-cells in models
of Graft vs Host Disease [201], inflammatory arthritis [202], and most recent ly, in a
modelofrhabdomyosarcoma[203]. Multiple clinical trials are underway with this
agent (NCT03311672, NCT03142204). While imaging activated metabolic pathways
may allow insights into specific activation states, there can be extensive lymphocyte
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