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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5588_Библиотеки_им_академика_М_И_Перельмана
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431Image-guided cancer immunotherapy
Fig. 1 Approaches to imaging the immune system. (A) Imaging of the immune or cancer cells of interest can be performed by directly labeling the cells with radioactive or iron oxide probes. Alternatively,
specific receptors expressed by the cells of interest can be targeted with probes (e.g., antibodies, peptides) labeled with a radioisotope for imaging. (B) Imaging of cells can also be performed with reporter
gene systems. Proteins expressing a kinase of interest such as thymidine kinase can be transduced into
the cell’s DNA. Radiolabeled probes can be produced that are trapped in the cells upon phosphorylation by the expressed kinase. Alternatively, fluorescent proteins and luciferase can also be expressed
by cells, allowing for optical and bioluminescent imaging, respectively. Constructs can also be
expressed, resulting in nonnative cell surface receptors; probes targeting these receptors can then
be injected for imaging. (C) Metabolic pathways are amenable for imaging. Red denotes probes
imageable by PET or MR spectroscopy. Green denotes optical targets. (Reference from Momcilovic M,
Shackelford DB. Imaging cancer metabolism. Biomol Ther (Seoul) 2018;26(1):81–92.)
432 Thomas S.C. Ng and Miles A. Miller
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to be mediated by Fc receptors, highlighting the advantage of Fc-effectorless designs with
reduced binding to Fc receptors for non-TAM-targeting probe development. Several
preclinical studies have shown that the physical property of targeting probes, including
size, surface charge, shape, and binding affinity, can drastically impact appropriate labeling of the cells of interest within tumors and may potentially limit their efficacy as imaging agents [29].
3.2 Imaging metabolic pathways
Imaging of metabolic pathways offers several advantages beyond cell labeling [43].
Targeting metabolic pathways activated in immune cells in a particular state can offer
increased specificity for the physiological process or cellular subset wished to be monitored
[44]. Most agents developed for metabolic pathway monitoring are small molecules, which
have overall more favorable pharmacokinetic profiles. However, many leukocyte activating processes share similar metabolic pathways in vivo, resulting in lower specificity than
desired when applied in patients.
4. Imaging targets for immunotherapy
Imaging tools for the assessment of all facets of the immune system have been
explored, both for basic science understanding and clinical translation. Imaging targets
of both the innate and adaptive immune systems are outlined in Fig. 2. This section
describes progress in the development of clinically relevant imaging assays for these targets at both preclinical and clinical levels.
4.1 Immune checkpoint inhibition
The last decade has seen the emergence of immune-checkpoint inhibition (ICI) as a
highly promising and ubiquitous therapeutic class in oncology [45]. While the highest
impact of ICI has been seen in the treatment of metastatic melanoma [46], its use has been
expanded across multiple types of solid [47] and hematologic malignancies [48]. Indications for ICI are expanding, including in neo-adjuvant settings [49] and combination
with other targeted therapies [50]. Concordantly, there is a need to establish imaging
assays that guide ICI use in these contexts.
The two main classes of ICI currently used involve the targeting of the programmed
cell death protein 1 ligand-receptor interaction (PD1/PDL1) and cytotoxic
T-lymphocyte-associated protein 4 (CTLA4) receptor [51], among others [52]. Imaging
plays an important role in current standard clinical practice by monitoring ICI treatment
response and toxicity, identifying suitable candidates for ICI, and, at the preclinical level,
elucidating in vivo mechanisms of ICI action [53].
433Image-guided cancer immunotherapy
Fig. 2 Overview of the innate (bottom) and adaptive (top) immune system. Highlighted cell subsets
note common targets for immune cell imaging for immunotherapy applications. (PFC—perfluorocarbon, FLT—Fluorothymidine, FDG—Fluorodeoxyglucose). (Image adapted from OpenStax (https://
commons.wikimedia.org/wiki/File:0337_Hematopoiesis_new.jpg), https://creativecommons.org/licenses/
by/4.0/legalcode
.)
4.1.1 Imaged-guided stratification of patients for ICI treatment
Precision oncology, the notion of molecular profiling individual patient tumors to identify appropriate treatment targets, can be valuable for delivering more efficacious and
individualized treatment. Currently, the identification of patients who are likely to
respond to ICI treatment is based on pathologic immuno-histochemical (IHC) biomarkers and genetic readouts of tumor antigenicity, for instance via tumor mutational
burden [51]. The presence of PDL1 expression in tumors has been associated with better
434 Thomas S.C. Ng and Miles A. Miller
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response to anti-PD1/PDL1 treatment in some cases. However, PDL1 expression can be
spatially and temporally heterogeneous both in tumors across different patients and
among tumors within individual patients. This information can be challenging for tissue
biopsies to provide alone, as suggested by clinical results showing that patients with
tumors staining negative for PDL1 can benefit from ICI. Thus, extensive work has
focused on developing noninvasive imaging assays that quantify PDL1 tumor expression
at a whole-body scale.
Given its exquisite sensitivity, most research efforts to date have focused on developing
radiolabeled agents for PET and SPECT imaging of the PD1/PDL1 axis [54].Mostofthese
agentsare based on antibodyagents and are radiolabeled using isotopes with radioactive halflives commensurate with antibody pharmacokinetics (89Zr: 3.3 days, 64Cu: 12.7 h) [55].
Preclinical studies have demonstrated the ability of radiolabeled anti-PDL1 antibodies to
quantify varying levelsof tumorPDL1 expression in animal models [19, 56] and demonstrate
dynamic PDL1 expression as a function of ICI or other types of treatment.
Antibodies have inherent limitations given their pharmacokinetic profiles, which may
curtail their suitability for clinical imaging, including prolonged blood half-life and low
tumor penetration leading to a high background-to-tumor ratio. Consequently, other
types of targeting agents have been explored, including antibody fragments to reduce
nonspecific Fc binding [57], nanobodies [58], single-domain antigen-binding fragments
of camelid heavy-chain antibodies [59], affibody molecules [60], and adnectins [52]. The
decreased circulating half-lives of these smaller agents allow other isotopes with shorter
decay half-lives to be used (18F: 110 min, 68Ga: 68 min) and may allow for better tumor
penetration. Other strategies have also been explored to improve the tumor to background ratio. For example, Chatterjee et al. reported a pre-dosing strategy with unlabeled
antibody decreased nonspecific liver and splenic uptake [61].
Several anti-PDL1/PDL1 imaging agents have been tested in patients with promising
results (Table 2) [62, 63]. Bensch et al. reported the first-in-human administration of
89Zr-atezolizumab, an Fc-effectorless PDL1-targeted antibody [64]. 22 patients with
advanced bladder cancer, nonsmall cell lung cancer, or triple-negative breast cancer
underwent immuno PET/CT before atezolizumab treatment. Interestingly,
intratumoral and intrapatient heterogeneity of uptake was observed. Furthermore, lesion
89Zr-atezolizumab uptake was correlated to tumor response, progression-free survival,
and overall survival. Niemeijer et al. also demonstrated promising results in patients with
nonsmall cell lung cancer using both 18F-BMS-986192 and 89Zr-nivolumab agents [65]
(Fig. 3).
While MRI is an important clinical modality for tumor evaluation, targeted PDL1
imaging using MRI agents is less pursued [66], likely because of the lower sensitivity and
potential toxiceffects of Gadoliniumagents. For instance, Du et al. developed a dual-labeled
PDL1 targeting nanoparticle functionalized with Gd-DOTA and a near-infrared fluorescence dye, showing increased signal intensity in PDL1 expressing 4T1 tumors [67].
Table 2 Immune checkpoint targeted imaging in clinical trials.
Agent Target Cancer type Clinical trials
18F-PD-L1 Adnectin PET PD-L1 Melanoma NCT03520634
Tracer (BMS-986192) Oral cancer NCT03843515
89Zr-atezolizumab PD-L1 Esophageal and
rectal cancer
Lobular Breast
Cancer
Diffuse large
B-cell
lymphoma
89Zr-durvalumab PD-1 Head and neck
squamous cell
carcinoma
18F-WL12 or 68Ga-WL12 PD-L1 Primary and
metastatic
solid tumors
89Zr-KN035 PD-L1 Advanced solid
tumors
89Zr-avelumab PD-L1 Nonsmall cell
lung cancer
89Zr-MPDL3280A PD-L1 Primary and
metastatic
solid tumors
89Zr-M7824 Bifunctional fusion of
PD-L1 antibody and
TGF beta ligand trap
89Zr-DFO-REGN3504 PD-L1 Advanced solid
99mTc-NM01 PD-L1 Nonsmall cell
89Zr-Pembrolizumab PD-1 Melanoma NCT02760225
89Zr-ipilimumab CTLA-4 Melanoma NCT03313323
Nonsmall cell
lung cancer
tumors
lung cancer
Nonsmall cell
lung cancer
NCT04564482
NCT04222426
NCT03850028
NCT03829007
NCT04304066
NCT03638804
NCT03514719
NCT02453984
NCT02478099
NCT04297748
NCT03746704
NCT04436406
NCT03065764
435Image-guided cancer immunotherapy
Anti-CTLA4 therapy aims to potentiate the stimulatory interaction between CD28
on T cells and CD80/CD86 on antigen-presenting cells [52]. The CTLA4 inhibitor
ipilimumab is FDA-approved and shows efficacy in multiple cancer models. Given
the costs and treatment-related toxicities involved, precise identification of patients that
will benefit from CTLA4 blockade is ideal. While less explored than the PD1/PDL1 axis,
several imaging probes targeting the CTLA4 axis have been developed, including a
g
p
g
g
436 Thomas S.C. Ng and Miles A. Miller
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A
B
20
15
10
F-BMS-986192
18
5
peak
SUV
0
Non-respondin
p = 0.03
Res
ondin
Zr-nivolumab
89
peak
SUV
20
15
p = 0.019
10
5
0
Non-respondingRespondin
Fig. 3 Identifying PD1/PDL1 tumor uptake with imaging. (A) Low uptake of the PDL1-targeted18F-BMS-
986192 in untreated brain metastasis in a patient. This may be due to low CNS tracer penetration or
PD-L1 expression heterogeneity. (B) 18F-BMS-986192 tracer uptake is higher in responding lesions as
compared to nonresponding lesions (left). The uptake of a companion PD1-targeted 89Zr-nivolumab
tracer is higher in responding lesions. For boxplots, the lower edge of the box represents the first quartile,
and the upper edge represents the third quartile. The horizontal line inside the box indicates the median.
Whiskers identify the minimum and the maximum value. (Adapted from Niemeijer AN, Leung D, Huisman
MC, Bahce I, Hoekstra OS, van Dongen G, et al. Whole body PD-1 and PD-L1 positronemission tomography in
patients with non-small-cell lung cancer. Nat Commun 2018;9(1):4664.)
64Cu-anti-murine CTLA4 antibody demonstrated to visualize CTLA4 in CT26 tumorbearing mice [68], 64Cu-ipilimumab used to visualize human nonsmall cell lung cancer
xenografts [52], and a 64Cu-IdeS protease fragmented ipilimumab F(ab
0
)2tracer that
visualized CTLA4-positive T-cells in humanized mouse models. Ingram et al. developed
18F- and 89Zr- alpaca heavy chain-only antibody fragments, showing increased tumor to
background uptake in a murine model of melanoma, which was augmented by a
GM-CSF-secreting autologous irradiated tumor vaccine (GVAX) [69].
CD80 (B7.1) and CD86 (B7.2) are found on B cells, monocytes, and antigenpresenting cells and serve as ligands for CTLA4 and CD28. Adoptive T-cell therapy is
also being developed that targets these ligands (NCT03060343). Thus, CD80 and
CD86 may serve as biomarkers to identify patients amenable to anti-CTLA4 therapy.
Meletta et al. developed 111-Ind-belatacept, a fusion protein comprising a human
IgG1 Fc fragment linked to the extracellular domain of CTLA-4 [70]. This tracer showed
increased uptake in a CD80 +/CD86+ Burkitt’s lymphoma model. In a subsequent
study, the same group reported the development of 11C-AM7 and 18F-AC74,
pyrazolocinnoline derivatives that target CD80+ cells. This agent was better able to
demonstrate the presence of CD80+ atherosclerotic plaques [71].
Other promising immune checkpoint targets for which imaging agents are being
developed include CD276 (B7-H3), which is an immune checkpoint target implicated in
T-cell function inhibition [72], and which is targeted by the antibody 89Zr-DS-5573a
[73]; the adenosine2a receptor(A2aR) [52], which has been implicated in immune function
suppression [74]; and the costimulatory receptor OX40 (CD134). Using a lymphoma
mouse model, Alam et al. showed that a 64Cu-AbOX40 murine antibody could exhibit
increased uptake in the draining lymph nodes of tumors treated intratumorally with the
immune stimulant CpG-ODN (cytosine phosphodiester guanine-oligodeoxynucleotide),
suggesting OX40 imaging as a potential readout of T-cell activation [75].
437Image-guided cancer immunotherapy
4.1.2 Understanding ICI interactions with the tumor microenvironment
In vivo optical imaging using fluorescently labeled ICI can link IHC findings with clinical
approaches described above. Optical readout of PDL1 expression is a versatile preclinical
tool to evaluate therapeutic strategies and can be combined with multiphoton imaging to
garner mechanistic insights at the cellular level. For example, multiphoton intravital
microscopy has been used to visualize the interactions of anti-PD1 antibodies with
immune cells within MC38 colorectal cancer tumors, showing that TAM can capture
anti-PD1 antibodies away from CD8+ T cells within minutes, via an Fcγ receptor interaction [42] (Fig. 4). Furthermore, blocking this interaction prolongs anti-PD1 binding to
CD8+ cells and enhances tumor ICI response in mice. Using a high-affinity alpaca heavy
chain-only antibody fragment (VHH) against CTLA-4, Ingram et al. demonstrated the
presence of the Fc domain is required for anti-CTLA4 antibody efficacy [69]. These findings have the potential to guide designs of newer imaging and therapeutic agents.
Recently, using optically labeled anti-PDL1 antibodies [76], we demonstrated the heterogeneous penetration of these antibodies in metastatic and primary anaplastic thyroid
cancer, which may be drastically different from the patterns of nanomedicine delivery and
small molecule drugs. Such comparisons of the uptake patterns of different agents may
inform future designs of combination therapies [77].
438 Thomas S.C. Ng and Miles A. Miller
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A
Tumor cellsaPD-1 •
15 min24 h
Tumor cellsaPD-1 •
T cells TAM•
B
T cells T cellsTAM TAMaPD-1
••
15 min
24 h
Fig. 4 Intravital imaging of PD-1 antibodies shows accumulation in tumor-associated macrophages
(TAM). DPE-GFP mice bearing GFP + T cells and MC38-H2B-mApple tumor cells were imaged with intravital imaging. TAM was labeled with ferumoxytol–pacific blue, and anti-PD1 antibodies with Alex Fluor
647 (AF647–aPD-1). (A) Z-projections of an MC38– H2B-mApple tumor in a DPE-GFP mouse injected
intravenously with AF647–aPD-1 after 15 min (top)or24h(bottom). (B) Images of T cells (magenta
outline) identified as GFP
+
cells and TAMs (yellow outline) identified by Pacific Blue signal. Outlines
are overlaid on microscopy images of the corresponding AF647–aPD-1 channel. Early timepoint imaging shows aPD-1 to be associated mainly with T-cells, but most of the antibodies were associated with
TAMs by 24 h postinjection. Scale bars, 30 μm. (Adapted from Arlauckas SP, Garris CS, Kohler RH, Kitaoka
M, Cuccarese MF, Yang KS, et al. In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med. 2017;9(389).)
4.1.3 Image-guided assessment of ICI treatment response
Clinical imaging is most influential in oncology for its ability to provide a direct readout of
anatomic and functional response to therapy [51]. Standardized anatomic (based on MRI
and CT; Response evaluation criteria in solid tumors, RESIST) and functional (based on
FDG-PET, PET response criteria in solid tumors, PERCIST) tumor response assessment
guidelines were developed to allow robust comparisons across clinical trials and sites [51].
However, given the different ICI mechanisms of action compared to traditional chemo- or
targeted therapies, correspondingly distinct tumor response patterns using ICI have been
noted. In particular, the immune-related phenomenon of “pseudoprogression” has been
observed in patients on ICI treatment, which describes the pattern that shows either initial
growth or appearance of new lesions and/or increased FDG metabolism of lesions preceding tumor response [78] (Fig. 5). Using previously set guidelines, such as RESIST/
PERCIST, these imaging findings would be characterized as disease progression. As a
result, modifications to these guidelines have been described that account for this
439Image-guided cancer immunotherapy
Fig. 5 Pseudoprogression with immune checkpoint inhibition. Comparison of RECIST 1.1 and iRECIST
criteria in a patient with metastatic melanoma treated with ipilimumab (anti-CTLA-4) and nivolumab
(anti-PD-1). Baseline CT image shows a 13-mm lung metastasis (upper panel, arrow ) and a 10-mm shortaxis axillary lymph node (lower panel, arrow). 3-month follow-up imaging showed enlargement of both
lesions, denoting progressive disease and treatment cessation according to RECIST 1.1, and
unconfirmed progressive disease with treatment continuation according to iRECIST. The two following
CT examinations (March and June 2018) showed decreased size in lung metastasis, but stable axillary
lymph node (unconfirmed PD) but still enlarged compared with the baseline (according to iRECIST, still
unconfirmed progressive disease). In August 2018, CT imaging demonstrated decreases in size of both
lesions of up to 70%, confirming pseudoprogression, and leading to a partial response classification
according to iRECIST criteria. (Adapted from Dromain C, Beigelman C, Pozzessere C, Duran R, Digklia A.
Imaging of tumour response to immunotherapy. Eur Radiol Exp 2020;4(1):2.)
440 Thomas S.C. Ng and Miles A. Miller
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phenomenon, and imaging agents are being developed to provide less ambiguous readouts
of treatment response.
4.1.3.1 Anatomic IC assessment
Multiple criteria have been developed to evaluate patients specifically treated with
immunotherapy [79]. These include the immune-related response criteria (irRC)
[80], which require progression to be delineated in two studies spaced at least 4 weeks
apart and for new lesion measurements to be incorporated into the summation of total
tumor burden, instead of being definitive for progressive disease. Hodi et al. demonstrated that patients with progressive melanoma using RESIST 1.1, but nonprogression
with irRC had overall longer survival than patients deemed to have progressive disease
using both criteria [81]. Nishino et al. optimized a set of criteria based on RESIST [82],
based on single diameter lesion measurements, reduction in the number of target lesions,
and short axis measurements in lymph nodes, providing the basis of immune-related
RESIST (irRECIST). A subsequent set of criteria, iRECIST, has also been introduced
for immunotherapy trials, albeit not yet validated prospectively [83].
4.1.3.2 Functional IC assessment
FDG-PET/CT While less validated for use in ICI, FDG-PET/CT is a useful tool for
assessing functional tumor response in a variety of treatment settings and has been applied
for multiple types of solid malignancies [55]. Like anatomic imaging, FDG-PET/CT
assessment can be confounded by pseudoprogression, especially since infiltrative immune
cells can also show increased FDG metabolism. Several groups have sought to build upon
PERCIST for immunotherapy assessment. For example, iPERCIST replaces the progressive metabolic disease category with either unconfirmed progressive metabolic disease
(UPMD) and confirmed progressive metabolic disease (CPMD) [84]. The Lugano criteria
were also modified to introduce an “indeterminate response” for lymphoma assessment.
These criteria generally rely on multi-timepoint assessment, usually spaced at least 4 weeks
apart, to differentiate between pseudo-progression and true progression [85].
FLT-PET/CT 3-deoxy-3-18F-fluorothymidine (FLT) PET is a promising biomarker
for evaluating cellular proliferation. Ribas et al. evaluated the ability of FDG-PET and
FLT-PET to assess the downstream effects of CTLA4 blockade [86]. While FDG and
FLT-PET tumor uptake within 3 months of treatment onset did not show significant
ability to predict treatment response, FLT uptake in the spleen increased posttreatment,
suggestive of lymphoid activation.
Functional MRI Multimodal MRI may complement the approaches outlined above to
monitor treatment response. For example, motion-robust dynamic contrast-enhanced
MRI (DCE-MRI) can monitor changes in tumor perfusion and vessel permeability posttreatment [87, 88]. Relative cerebral blood volume ratios in dynamic susceptibility
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