Advancing Immune and Cell-Based Therapies Through Imaging
Advancing Immune and Cell-Based Therapies Through Imaging
Vladimir Ponomarev 0
0 Department of Radiology, Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center , 1275 York Ave Z-2063, Box 501, New York, NY, 10065 , USA
Immunotherapies include various approaches, ranging from stimulating effector mechanisms to counteracting inhibitory and suppressive mechanisms, and creating a forum for discussing the most effective means of advancing these therapies through imaging is the focus of the newly formed Imaging in Cellular and Immune Therapies (ICIT) interest group within the World Molecular Imaging Society. Efforts are being made in the identification and validation of predictive biomarkers for a number of immunotherapies. Without predictive biomarkers, a considerable number of patients may receive treatments that have no chance of offering a benefit. This will reflect poorly on the field of immunotherapy and will yield false hopes in patients while at the same time contributing to significant cost to the healthcare system. This review summarizes the main strategies in cancer immune and cell-based therapies and discusses recent advances in imaging strategies aimed to improve cancer immunotherapy outcomes.
Cell-based therapy; Imaging; Immunotherapy
Recently, immuno-based therapies have been found to provide
lasting and curative benefits to patients who have previously had
very few treatment options available to them. These
immunotherapeutic approaches thereby have the potential to revolutionize
cancer therapy and become an important part of comprehensive
therapeutic approaches for treating many diseases including
cancer. These therapies build on the primary function of the
immune system to rid the body of threats, both Bforeign^, such as
bacterial and viral pathogens and Bdomestic^, such as cancer cells.
Over the past several decades of cancer immunology research,
there has been evidence that tumor cells are recognized by the
native or genetically engineered adoptive immunity, but also that
tumors can modify these responses and escape immune
recognition . Immune modulation in cancer treatment, therefore, refers
to a range of approaches aimed at harnessing and enhancing the
patient’s immune system and overcoming immune escape, to
achieve tumor control, stabilization, and potential eradication of
disease. This has led to the development of therapies that permit
specific tumor destruction with minimal toxicity to normal tissue
[2–6]. Such strategies also have the potential to prevent tumor
recurrence because of the immune systems long-term memory.
Within the World Molecular Imaging Society, we have
constituted an interest group comprised of members of the society who
share the common interest of fostering the use of imaging to
advance and understand cellular and immune-based therapies.
This Interest Group is called Imaging in Cellular and Immune
Therapies (ICIT), and we present here a brief summary of the field
and our efforts in the society to support developments in this
important area of investigation.
Current Advances in Immune and Cell
The main categories of immunotherapies being developed
include monoclonal antibodies, recombinant cytokines,
cancerspecific, and other types of vaccines and adoptive immune cell
transfer [3, 7, 8]. Several immunotherapies have been approved
by the Food and Drug Administration (FDA), and others are
being evaluated in pre-clinical and clinical trials. The field of
immunotherapy for cancer has received a significant boost by
the approval of several immunotherapies. These include
immunostimulatory cytokines for the treatment of cancer, viral
hepatitis and osteopetrosis (e.g., IL-2 , interferons [10, 11]).
The autologous cellular vaccine, sipuleucel-T, has also recently
been approved for the treatment of prostate cancer . Perhaps
the immunotherapies that have received the most attention are the
immune checkpoint inhibitors that overcome immune escape.
These target the anti-cytotoxic T lymphocyte-associated protein 4
(anti-CTLA-4) and the anti-programmed cell death protein/protein
ligand 1 (anti-PD-1/PD-L1) with antibodies and are being used for
the treatment of melanoma, lung cancer, renal cell carcinoma and
head and neck tumors [13–16]. Other forms of immunotherapy
including administration of ex vivo expanded tumor infiltrating
lymphocytes (TILs), transgenic endogenous T cell receptor
(TCR)- or chimeric antigen receptor (CAR)-grafted T cells have
been successfully tested in clinical trials in patients with
melanoma, B cell malignancies, mesothelioma, ovarian and
prostate cancers and will likely get FDA approval in the near
future [17–23]. This emerging collection of immune-based
therapeutic approaches hold great promise for the treatment of
cancer, but are also be adopted for many non-malignant
conditions such as autoimmunity, infectious diseases, and
At the moment, immunotherapy with checkpoint inhibitors
provide a foundation for many of the combinatorial strategies 
as it allows for enhancing an immune response against multiple
cancers including tumors expressing weak antigens .
However, one of the main obstacles to the development of a successful
immunotherapeutic approach is in identification and in vivo
assessment of the most suitable antigen(s) to use. Molecular
imaging reagents that target specific cancer antigens can help
selecting patients that will likely respond to antigen-directed
immunotherapies and will allow for early response assessment and
prediction of treatment outcome by visualizing antigen distribution
preceding tumor targeting with radioimmunotherapy,
drugimmunoconjugates, or antigen-specific T lymphocytes [29–33].
Imaging as an Outcome Measure
A vital component of any cancer treatment is the objective
assessment and monitoring of tumor response to anticancer
therapy using imaging and specific response evaluation criteria.
The response evaluation criteria in solid tumors (RECIST) was
proposed in 2000, and this criterion is anatomic in nature and
specifies the number of disease sites and their dynamics as the
imaging metric for determining response (e.g., complete response
(CR), partial response (PR), stable disease (SD), and progressive
disease (PD)) . However, clinical experience suggests that
RECIST may be inadequate to cover the spectrum of imaging
responses to immunotherapy since the determinants of increase in
tumor size and/or the appearance of new lesions that often suggest
treatment failure, might not be entirely applicable here. As
observed in multiple studies, immunotherapy often demonstrates
initial anatomical imaging changes that would be classified as
disease progression, followed by radiological and clinical
response suggesting therapeutic response [35, 36].
As immunotherapies continue to be developed and undergo
testing in clinical trials, consideration needs to be given to the
unique appearance of images that predict tumor responses. Such
studies have found four distinct response patterns on imaging, all
of which were associated with favorable survival: (a) shrinkage of
baseline lesions without new lesions, which is consistent with
RECIST; (b) durable SD followed by a slow, steady decline in
total tumor burden in some patients; (c) response after initial
increase in total tumor burden; and (d) response in the presence of
new lesions [37–39]. These updated immune-related response
criteria (IrRC) are defined as a way to incorporate imaging
patterns observed with immunotherapy into the response
assessment criteria including metabolic response to treatment assessed
by 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and positron
emission tomography (PET) . One of the aims of the ICIT
Interest Group is to verify and validate these measures over a
range of immune-based therapies, and to continue to develop new
measures as new tools and technologies are developed for both
treating and imaging cancer.
One of the challenges of immunotherapy is that accurate and
reproducible biomarkers that would allow treating physicians to
select the patients most likely to respond have yet to be identified,
vetted, and deployed. The potential of molecular imaging to detect
these biomarkers and better stratify the patients for targeted
therapies and interpreting their response to this novel treatment
option cannot be overestimated. Currently, there is no single
robust biomarker to identify the patients who will most likely
benefit from these treatments, and as we advance precision
medicine, it is likely that panels of biomarkers will be required for
guiding therapy and assessing outcome. For example, PD-L1
expression levels have been suggested as a positive prognostic
biomarker for patients undergoing immune checkpoint blockade
therapy . Following pathology-derived data, a number of
PDL1-specific radiotracers were developed that allowed for
noninvasive assessment of tumor PD-L1 status in murine models,
with the intent of predicting the efficacy of PD-1 checkpoint
blockade [42–45]. However, studies have demonstrated the lack
of clinical benefit in some patients treated with anti-PD-1
antibodies despite positive PD-L1 status of their tumors [46, 47].
Therefore, the levels of PD-L1 within the tumor
microenvironment cannot, at present, be considered an optimal biomarker for
patient selection until we can better reveal and understand the
basic biology and mechanisms of action of check-point blockade.
There are certain challenges with [18F]FDG and [18F]FLT
PET avidity as biomarkers in assessment of the efficacy of
immunotherapy that include the difficulty of discriminating
between viable tumor and the infectious or inflammatory
processes associated with novel therapies [48, 49]. A
number of new radiopharmaceuticals have been proposed
and evaluated in pre-clinical and clinical studies aiming to
distinguish rapidly proliferating immune cells invading the
Fig. 1 Anti-CD8 immuno-PET in subcutaneous colorectal
immunotherapy model. CT26 murine colon cancer-grafted
mice were treated with CD137-agonistic Abs:
CD137treated, CD137-treated/CD8-blocked mice, and control mice
(no anti-CD137 therapy) were injected with
89Zr-malDFO169 cDb and immuno-PET images were acquired at 22 h
postinjection. Note the presence of increased CD8+
tumorinfiltrating lymphocytes within the tumor in CD137-treated
animal (white arrow, adapted from ).
tumor or involved in any type of immune response. Several
18F–labeled nucleoside analogs, including
1-(2′-Deoxy-2′[18F]fluoroarabinofuranosylcytosine (aka [18F]FAC) [50, 51],
2-chloro-2′-deoxy-2′-[(18)F]fluoro-9-β-d-arabinofuranosyl-adenine (aka [18F]CFA) [52, 53], and
2′-deoxy-2′-[18F]fluoro-9β-D-arabinofuranosylguanine (aka [18F]AraG)  that are
specific for key enzymes involved in T lymphocyte and other
immune cell activation and proliferation, have been used for
detecting location of activated T cells, monitoring transplant
rejection, and graft–versus–host–disease and diagnosis and staging
of auto–immune disorders. These new radiotracers can be early
Immune cell compartment/function
predictors of response and adverse reactions to immunotherapy
measuring functional status of immune cells involved.
Another imaging approach that can directly visualize immune
cells behavior is immuno-PET. In this approach, antibodies or
antibody fragments are used to direct PET radionuclides to
immune cells for detection, localization and typing. Immuno-PET
has the potential to detect T cell subsets within tumors or lymphoid
tissues and noninvasively monitor distribution and temporal
dynamics of CD8 cytotoxic and CD4 helper T lymphocytes that
participate in the inflammation and cytotoxic attack within tumors.
Anti-CD8 full size antibodies and mini-bodies labeled with Cu-64,
Zr-89, F-18, or I-124 showed excellent PET imaging and target
specificity and importantly did not deplete CD8 T cells due to the
absence of Fc function (Fig. 1) [55, 56]. Other targets include
markers of immunostimulatory dendritic cells (MHC II, IDO1),
chemokine ligands, and receptors (CXCR3,-4, CXCL9,-12
CCR5) as well as immunosuppressive neutrophils and
macrophages (CD11b, CD47), which may downregulate T cell
responses within tumors [57–61]. Examples of immuno-imaging
targets and agents are summarized in Table 1.
Imaging of Immune Cells
Recent advances in the field of adoptive immunotherapy require
the ability to monitor the trafficking, targeting, and activation/
proliferation of the administered cells. The application of labeling
molecules and genetic reporter systems (gene/probe combinations)
together with non-invasive imaging modalities, such as PET,
SPECT, and MRI, has shown the potential for monitoring T cells
in clinical settings [67–69]. In-111, in particular, found a wide
clinical application in oncology as an imaging agent for
monitoring immunotherapy with tumor-infiltrating lymphocytes
and granulocytes administration [70, 71]. However, imaging
approaches that require ex vivo cell labeling encompass a number
of limitations such as radiotoxicity and limited period of
monitoring as a result of cell division, biological clearance and
radiolabel decay [72, 73].
Stable genetic labeling of adoptively transferred cells with
reporter genes (genes encoding easily detectable proteins not
normally expressed by the cells) has been used to circumvent
the temporal limitations of ex vivo radiolabeling. Several
reporter gene/reporter probe combinations have been used in
the majority of the seminal studies on imaging immune cell
trafficking including ex vivo expanded cytotoxic lymphocytes
(CTLs) and CAR-grafted Tcells by optical and nuclear
techniques (e.g., luciferases, fluorescent proteins, HSV1tk,
respectively [67, 68, 74–79]) including imaging in humans
(Fig. 2) . In addition, reporter gene imaging allows for
visualization of T lymphocyte functional status following T
cell receptor engagement by using inducible reporter systems
sensitive to T cell activation . This circumstance makes this
imaging approach clinically valuable, as it allows for
monitoring functional status of adoptively transferred immune cells in
cancer patients as well as in bone marrow and stem cell
recipients. The major impediment to the translation of
viraland bacterial-derived reporter gene imaging approaches into
clinical practice is the immunogenicity of these non-human
derived reporter proteins. However, there has been a recent
focus on human reporter systems to avoid the potential risk of
generating an immunological reaction to xenogeneic
(nonhuman) reporter proteins thus allowing for long-term repetitive
Fig. 2 Tumor-directed CAR-T cell PET imaging with
[18F]FHBG. [18F]FHBG PET imaging was performed in a
patient with a recurrent right frontoparietal glioblastoma a
before and b 1 week after tumor-specific CAR-T cell
infusions. Allogeneic CAR-T cells and IL-2 were injected
intratumorally (red arrows). Tumor recurrence was monitored
by T1-weighted (T1W) MRI (top panels). [18F]FHBG PET
images were fused with MR images (bottom panels), and
three-dimensional (3D) volumes of interest were drawn using
a 50 % [18F]FHBG SUVmaxthreshold, outlined in yellow
(adapted from ).
visualization of adoptively transferred immune cells. These
include human-derived sodium iodide symporter (hNIS),
norepinephrine transporter (hNET), somatostatin receptor 2
(hSSTR2), truncated, and mutated mitochondrial thymidine
kinase type 2 (hΔTK2, hΔTK2DM) and deoxycytidine kinase
(hdCKDM, hdCK3M), ferritin reporter, and transferrin
receptor [82–89]. Some reporter genes may have the added benefit of
suicide gene potential. This provides a mechanism for
elimination of rogue reporter gene-expressing immune cells
with clinically approved chemo- and radiotherapeutics (e.g.,
HSV1tk/ganciclovir, hdCKDM/gemcitabine, hNIS/I-131,
Principles of immuno-PET can be applied to imaging
adoptively transferred cells by administrating
anti-antigenspecific transgenic TCR radiolabeled antibodies.
Antigenspecific TCR transgenic T cells were successfully visualized
with PET using 89Zr-89 labeled anti–TCRmu-F(ab')2 fragment
 and [64Cu]DOTA–modified cOVA-TCR–specific mAbs
The potential of imaging for quantifying cell signals in a region
of anatomical interest (ROI) provides a unique opportunity to
estimate the absolute number of injected labeled cells at the target
site. Several studies determined the correlation of PET signal to
cell number and characterized the cellular limit of detection for
PET imaging using human and mouse T cells transduced with
different human and non-human reporters with a limit of detection
below 105 cells in a region of interest of 0.1 ml volume [85, 87,
94]. This level of sensitivity enables effective assessment of cell
localization at target sites and assessment of off target homing
in vivo and will be useful in guiding development of novel
As immunotherapies continue to be developed and undergo
testing in clinical trials, consideration needs to be given to the
differences observed in response following immunotherapy, and
as a community, we need to standardize these measures and
ensure uniformity among studies. While optimal combinations of
treatment schemas still need to be determined, significant efforts
have to be made in the identification and validation of predictive
biomarkers that can be used alone or in combination in imaging,
but also in conjunction with blood and tissue markers ex vivo. It is
imperative that we as a community of imaging scientists interested
in immunotherapy be proactive in advancing this field.
Compliance with Ethical Standards
Conflict of Interest
The author declares that he has no conflict of interest.
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