European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:4133–4144

https://doi.org/10.1007/s00259-022-05849-y

REVIEW ARTICLE

CXCR4‑targeted theranostics in oncology

Andreas K. Buck1 · Sebastian E. Serfling1 · Thomas Lindner1 · Heribert Hänscheid1 · Andreas Schirbel1 ·
Stefanie Hahner2 · Martin Fassnacht2 · Hermann Einsele3 · Rudolf A. Werner1,4

Received: 23 March 2022 / Accepted: 21 May 2022 / Published online: 8 June 2022
© The Author(s) 2022

Abstract
A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of
cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting.
For instance, the CXCR4-targeting positron emission tomography (PET) agent [­ 68 Ga]PentixaFor has been proven useful
for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell
lung cancer. In addition, ­[68 Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as
multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities
in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent ­[177Lu]/[90Y]
PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem
cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly
sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely
performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The
present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce
the CXCR4-targeted theranostic concept for advanced hematological malignancies.

Keywords CXCR4 · Theranostics · C-X-C motif chemokine receptor 4 · [68Ga]PentixaFor · [177Lu]PentixaTher · [90Y]
PentixaTher · Endoradiotherapy · Adrenocortical carcinoma · Multiple myeloma

Introduction

The C-X-C motif chemokine receptor 4 (CXCR4) has

been recognized as a potential target for various applica-
tions in oncology and moderates crucial factors for cancer
This article is part of the Topical Collection on Theragnostic spread, such as angiogenesis or further involvement lead-
ing to therapeutic resistance [1]. Of note, ex vivo work-up
* Andreas K. Buck revealed a large variety of solid cancers and hematological
buck_a@ukw.de
malignancies, which upregulate CXCR4 on the tumor cell
1
Department of Nuclear Medicine, University Hospital surface, thereby rendering this G-protein coupled receptor
Würzburg, Oberdürrbacher Str. 6, 97080 Wurzburg, as an attractive target for imaging and treatment [1]. Given
Germany its ability to precisely reflect sites of disease on a functional
2
Division of Endocrinology and Diabetes, Department level, CXCR4-targeting radiotracers for single-photon emis-
of Medicine I, University Hospital, University of Würzburg, sion computed tomography and positron emission tomog-
Wurzburg, Germany
raphy (PET) have been introduced for clinical use [2–6].
3
Department of Internal Medicine II, Hematology For instance, ­[68 Ga]PentixaFor has been extensively applied
and Oncology, University Hospital Würzburg, Wurzburg,
Germany
to patients affected with various solid and hematological
4
neoplasms [7–10]. Radiotracer accumulation did not only
Division of Nuclear Medicine and Molecular Imaging,
The Russell H Morgan Department of Radiology
reveal substantial correlation with immunohistochemical ex-
and Radiological Sciences, The Johns Hopkins School vivo CXCR4 expression derived from corresponding tissue
of Medicine, Baltimore, MD, USA

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4134 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:4133–4144

specimens [8], but was also more accurate in detecting meta- liver carcinoma, cancer of unknown primary, and glioblas-
static sites, e.g., when compared to the current diagnostic toma, reporting on an increased radiotracer accumulation
work-up and standard imaging modalities in selected cases with high tumor-to-background ratio in SCLC [9]. In 10
[11]. Of note, once [­ 68Ga]PentixaFor has revealed substantial patients, in whom 2-deoxy-2-[18F]fluoro-D-glucose ­([18F]
CXCR4 expression in vivo, the theranostic analogs ­[177Lu]/ FDG) PET was available, the latter radiotracer exhibited
[90Y]PentixaTher can also be administered (Fig. 1) [12]. As higher standardized uptake values [9]. Another cohort of
such, CXCR4-directed PET also serves as a “one-stop” solu- treatment-naïve patients affected with various solid can-
tion to determine the current status of disease spread and to cers (including cholangiocarcinoma, ovarian cancer, and
identify patients eligible for a CXCR4-directed endoradio- renal cell carcinoma) provided substantial correlation of
therapy (ERT) using ß-emitters [13, 14]. In this regard, such tumor-derived specimens (defined as CXCR4-based immu-
treatment strategies have led to relevant anti-lymphoma/- noreactive scores) and [­ 68 Ga]PentixaFor accumulation in
tumor effect in selected cases and served as a conditioning sites of disease [8]. Among those cancer entities, cholangio-
regimen to enable for hematopoietic stem cell transplanta- carcinoma had the highest uptake, which was up to seven-
tion (HSCT) [12, 15]. Over the last decades, the theranostic fold higher when compared to background [8]. In addition,
concept has been primarily used and established in the clinic work-up of tissue samples derived from patients with neu-
for treating solid tumors, such as prostate cancer or neuroen- roendocrine neoplasms demonstrated that an increased pro-
docrine neoplasms (NEN) [16, 17]. CXCR4-directed ­[68Ga] liferation index is linked to downregulation of somatostatin
PentixaFor and ­[177Lu]/[90Y]PentixaTher, however, meet the receptor (SSTR) 2 and 5, but upregulation of CXCR4 [18].
urgent need to provide this innovative treatment strategy to Those ex vivo findings were then further corroborated using
patients affected with advanced blood cancer. In the present SSTR-directed and ­[68 Ga]PentixaFor PET. In this regard,
review, we will provide an overview of CXCR4-directed an increasing number of CXCR4( +)/SSTR( −) metastases
molecular imaging for solid tumors and hematologic malig- were identified in patients with increasing tumor aggres-
nancies. We will also review current therapeutic applications siveness [19]. Previous studies, however, have already
for hematological malignancies, including pretherapeutic reported on the usefulness of ­[18F]FDG PET in the con-
dosimetry. text of highly malignant, dedifferentiated neuroendocrine
tumors [20, 21]. A retrospective head-to-head comparison
of the latter radiotracer with ­[68Ga]PentixaFor PET dem-
CXCR4‑directed molecular imaging onstrated equal or inferior diagnostic performance with
CXCR4 molecular imaging [22]. Nonetheless, given the
Solid cancers rather limited treatment options for neuroendocrine tumor
patients with a high proliferation index, ­[68Ga]PentixaFor
CXCR4-targeted PET has been first applied to patients may still allow to select potential treatment candidates
diagnosed with solid tumors. Vag and co-workers included for ­[177Lu] or ­[90Y]PentixaTher. In this regard, bone mar-
22 patients with pancreatic cancer, prostate carcinoma, row ablation as a side effect would definitely occur and,
small-cell lung cancer (SCLC), melanoma, breast cancer, thus, stem cell support would be needed [23]. Based on

Fig. 1  Chemical structures of ­[68Ga]PentixaFor, ­[90Y], and [.177Lu]PentixaTher

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European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:4133–4144 4135

preliminary findings of Vag and coworkers [9] and promis- A recent study comprised more than 145 solid tumor
ing ex vivo findings in lung cancer samples [24], Lapa et al. patients focusing on a potential predictive role of physi-
further investigated [­ 68Ga]PentixaFor for treatment-naïve ological splenic uptake and outcome [32]. In lung car-
and pretreated SCLC and large-cell neuroendocrine carci- cinoma and NEN, the authors reported on a substantial
noma of the lung. In a comparison with SSTR-PET, the interrelation between thrombocytes and white blood cell
authors reported on an increased in-vivo CXCR4 expres- counts and radiotracer accumulation in the spleen as a
sion [25]. A recent preclinical study also demonstrated hematopoetic reservoir involved in the immune response.
increased ex-vivo CXCR4 expression in tissue specimens As such, further studies are needed to elucidate the role of
of patients affected with adrenocortical carcinoma (ACC) systemic inflammation detected by CXCR4 PET in those
[26]. As an orphan disease, ACC has a less favorable prog- tumor subtypes [32]. Another recently published study
nosis in the vast majority of patients and, thus, novel treat- investigated a potential tumor sink effect in the context of
ment options are urgently needed [27, 28]. Bluemel and CXCR4-directed PET [33], as such a decrease of uptake
coworkers therefore investigated the read-out capabilities of in normal organs in subjects with increased tumor load
­[68Ga]PentixaFor in those patients. Although no substantial has been reported for other theranostic agents, e.g., soma-
differences relative to ­[18F]FDG could be established in a tostatin receptor directed radiopharmaceuticals [34]. If
visual and quantitative assessment, a markedly high number such a tumor sink effect also occurs in patients injected
of subjects (70%) were rendered suitable for ERT using the with ­[ 68Ga]PentixaFor, this may have a relevant impact
theranostic counterparts ­[177Lu] or ­[90Y]PentixaTher [29]. on “hot” and “cold” therapies targeting CXCR4, e.g., by
In malignant pleural mesothelioma, human tissue samples safely increasing the amount of therapeutic activity but
also revealed robust CXCR4 expression in an ex-vivo set- reducing side effects in organs with normal biodistribu-
ting [30], which then again provided a rationale to investi- tion [33]. Investigating this effect on ­[68 Ga]PentixaFor in
gate ­[68Ga]PentixaFor in this disease [30]. Of note, ex-vivo 90 patients with solid tumors, the authors did not report
findings were not confirmed by an in-vivo molecular imag- on decreasing radiotracer accumulation in patients with
ing approach, as no substantial radiotracer accumulation higher tumor burden, further supporting the hypothesis
was recorded [31], which further demonstrates that an ex- that doses in normal organs and sites of disease can rather
vivo proof of CXCR4 expression does not always lead to not be estimated based on pretherapeutic PET. In this
increased uptake on PET. Taken together, SCLC, cholan- regard, those findings favor the use of treatment planning
giocarcinoma, highly dedifferentiated NEN, and ACC may using dosimetry [33].
be the most promising tumor entities for a CXCR4-directed
PET (Fig. 2) [8, 19, 25, 29].

Fig. 2  Patient after resection of adrenocortical carcinoma imaged and PET/CT (D) demonstrated intense uptake in a retroperitoneal
with ­[68 Ga]PentixaFor. The right-sided primary was resected earlier. lesion. Further CXCR4 positive sites of disease included liver lesions
Maximum intensity projection in A revealed multiple sites of disease (E and G). Additional discernible uptake in the left adrenal gland (F)
after administration of ­[68Ga]PentixaFor. Transaxial CT (B), PET (C),

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4136 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:4133–4144

Advanced hematological malignancies Moreover, CXCR4-directed imaging has also been

applied to 22 treatment-naïve patients affected with mar-
Multiple studies demonstrated that [­68 Ga]PentixaFor ginal zone lymphoma (MZL) [11]. When compared to
may be particularly useful for imaging various types of routine clinical work-up (including endoscopy of the gas-
advanced blood cancers. As such, the first biodistribution trointestinal tract and bone marrow biopsy), ­[68Ga]Pentixa-
study for this radiotracer was conducted in 5 subjects diag- For PET, but not standard procedures, classified all cases
nosed with multiple myeloma (MM) and reported on an correctly [11]. Of interest, PET changed both staging and
effective of 2.3 mSv [3], which was comparable to other therapeutic management, further indicating that this radi-
68-Ga-labeled theranostic radiotracers [35]. MM has also opharmaceutical could be applied to routine assessment in
been further investigated with ­[ 68 Ga]PentixaFor [36], individuals affected with MZL (Fig. 3) [11]. Specimen of
demonstrating remarkable diagnostic accuracy for iden- gastric mucosa-associated lymphoid tissue (MALT) lym-
tifying MM manifestations, which was superior relative phoma also revealed CXCR4 overexpression in an ex-vivo
to ­[ 18F]FDG in newly diagnosed subjects (positive rate setup [39] and those findings were further corroborated
almost twice for CXCR4 PET) [37]. Further demonstrating in an in-vivo setting, demonstrating an accuracy of 100%
a tight interaction with disease state and in-vivo CXCR4 (with gastric biopsies serving as reference) in subjects after
expression, uptake in bone marrow was associated with Helicobacter pylori eradication [10], thereby demonstrating
staging or relevant markers of disease activity, e.g., serum- that this radiotracer can assess residual disease activity [10].
free light chain or ß2-microglobulin [37]. Of note, the The same research group also investigated [­ 68Ga]PentixaFor
derived PET signal may also hold potential for outcome PET for mantle cell lymphoma (MCL), as the diagnostic
prediction, as a negative scan was linked to increased time- performance of the currently applied radiotracer [­ 18F]FDG
to-progression and overall survival [7]. Among hemato- is hampered by increased uptake in the bone marrow [40].
logical malignancies, [­ 68Ga]PentixaFor has also been first Relative to the latter radiotracer, the CXCR4 agent demon-
applied to patients affected with acute myeloid leukemia strated an increased sensitivity of up to 25% on a per region
in a translational setup. Using flow cytometry, increased level [40]. A quantitative assessment also demonstrated
patient-derived high blast counts were linked to CXCR4 higher target-to-background ratios, rendering ­[68Ga]Pen-
upregulation. In mice affected with either CXCR4( −) or tixaFor as a suitable alternative to ­[18F]FDG in MCL [40].
CXCR4( +) leukemia xenografts, an increased [­ 68Ga]Pen- CXCR4-directed PET was also used in myeloproliferative
tixaFor signal was observed in the latter animals. Last, in neoplasms (including essential thrombocythemia and poly-
10 patients with active disease, elevated radiotracer uptake cythemia vera) and all of the included 12 patients revealed
was tightly linked to disease infiltration by magnetic reso- positive findings [41]. Further corroborating the clinical
nance in half of the investigated subjects [38]. relevance, the SUV reduction of a baseline and follow-up

Fig. 3  Patient with marginal zone lymphoma after injection of ­[68 Ga] also showed radiotracer accumulation in the cervical (E), abdominal
PentixaFor. Multiple disease sites are visualized on maximum inten- (F), and in the inguinal region (G). Modified from Duell et al., Jour-
sity projection in A. Transaxial CT (B), PET (C), and PET/CT (D) nal of Nuclear Medicine, October 2021, 62 (10) 1415–1421 [11]. ©
revealed intense lymph node manifestations in the thorax. PET/CT by the Society of Nuclear Medicine and Molecular Imaging, Inc

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European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:4133–4144 4137

­[68Ga]PentixaFor scan correlated with decrease of spleen blood cancers, including MM, MCL, and acute lymphoblas-
volume, supporting the hypothesis that quantitative param- toid leukemia (Fig. 4B) [43]. Moreover, lower specific activ-
eters may be also applicable for response assessment [41]. ity is characterized by higher amounts of cold mass, thereby
As a relatively rare form of non-Hodgkin lymphoma, utility having a relevant impact on image interpretation [44]. The
of ­[18F]FDG is also limited in Waldenström macroglobuline- authors did not record any relevant significant associations
mia/lymphoplasmacytic lymphoma (again, due to bone mar- with semiquantitative parameters and specific activity, sup-
row involvement leading to rather less specific uptake) [42]. porting the hypothesis that read-out capabilities are not ham-
Luo et al. reported on a substantial higher rate of positive pered, regardless of the amount of specific activities [43].
findings after injection of ­[68Ga]PentixaFor when compared
to ­[18F]FDG [42].
CXCR4‑targeted endoradiotherapy
Roadmap of relevant in‑vivo CXCR4 expression
Biokinetics and pretherapeutic dosimetry
Aiming to provide a roadmap among a broad spectrum of
neoplasms, a recent bicentric study of our group and col- After intravenous administration, [­ 177Lu]PentixaTher binds
leagues from Vienna Medical University assessed ­[68Ga] to plasma proteins with high metabolic stability, and only
PentixaFor uptake and image contrast among the largest a small fraction of about 4% is attached to leukocytes and
cohort of subjects imaged with CXCR4-directed PET to platelets via CXCR4 binding [45]. Scintigraphically detect-
date, thereby determining the most relevant clinical applica- able activity accumulations are found in kidney, liver,
tions. Investigating 690 patients affected with various solid spleen, and bone marrow, as well as in CXCR4-expressing
tumors and hematological neoplasms scheduled for 777 malignant tissues. An example of measured time functions
scans, 68.9% demonstrated uptake in sites of disease [43]. of activity retention in organs and tissues in a patient with
The highest tracer uptake was recorded in MM (maximum MM is shown in Fig. 5. The figure, like the results sum-
SUV > 12). The second highest uptake was then found in marized below unless otherwise specified, is taken from a
ACC, MCL, adrenocortical adenoma, and SCL. Osteosar- recently published study on ­[177Lu]PentixaTher biokinetics
coma, bladder cancer, head and neck cancer, and Ewing sar- and dosimetry [46].
coma, on the other hand, exhibited the lowest average SUV The total body 177Lu activity typically decays bi-exponen-
(< 6; Fig. 4A) [43]. Comparable findings were recorded for tially. About half of the activity is eliminated with a median
target-to-background ratio (TBR), thereby reflecting image effective half-life of about 10 h mainly by renal excretion;
contrast. Again, the highest TBR was found in advanced the remainder decays with a mean effective half-life of about

Fig. 4  Bar chart showing A average S ­ UVmax and B target-to-back- CLL chronic lymphocytic leukemia, MZL marginal zone lymphoma,
ground ratio (TBR). For A, black dotted lines indicate S
­ UVmax cut- SCLC small-cell lung carcinoma, MM multiple myeloma. Adreno-
offs of 6 and 12, and for B, those lines show TBR cutoffs of 4 and cortical adenoma: aldosteron-producing adrenocortical adenoma.
8, respectively. BP blood pool (red dotted line), AML acute myeloid Modified from Buck et al., Journal of Nuclear Medicine, 2022 Mar 3;
leukemia, CCC​ cholangiocarcinoma, NSCLC non-small-cell lung jnumed.121.263693 [43]. © by the Society of Nuclear Medicine and
carcinoma, NEN neuroendocrine neoplasm, DSRCT​ Desmoplas- Molecular Imaging, Inc
tic Small Round Cell Tumor, ALL acute lymphoblastoid leukemia,

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4138 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:4133–4144

approximately 18 h after administration [46]. The mean

effective half-life of the activity elimination from kidneys
by degradation of the compound and physical decay is
41 ± 10 h [46]. In the kidneys as well, large heterogeneity
of specific absorbed doses have been observed with values
between 0.4 and 3.5 (median: 0.9) Gy/GBq 177Lu [46]. It
has been reported that the accumulation of PenixaTher in
the kidneys was reduced to 64% ± 13% by the concomitant
administration of amino acids [48]; however, this value
was determined using data from only six patients receiving
­[177Lu]PentixaTher, showing reduction factors ranging from
50 to 80% [48].
Liver and spleen show delayed kinetics compared to
kidneys. Specific absorbed doses are often high but never
restrict the administrable activity. High splenic doses are
often observed and therapeutically desirable in patients
with hematologic disease with malignant infiltration of the
spleen, often associated with splenomegaly [46].
A long half-life of ­[177Lu]PentixaTher of 122 ± 32 h is
Fig. 5  Example of activity time functions in a patient with multiple also found in tumors and extramedullary lesions in hemato-
myeloma. Activity retention measurements as well as fit functions are logical diseases. The absorbed doses are typically twice as
shown for the whole body (black), per liter of whole blood (grey), red high as in the critical organ, the kidneys. Since myeloabla-
bone marrow (red), liver (green), kidneys (purple), and spleen (blue).
Modified from Hänscheid et al., Journal of Nuclear Medicine 2021 tive therapy cannot be repeated several times, therapy with
Aug 19; jnumed.121.262295, https://​doi.​org/​10.​2967/​jnumed.​121.​ PentixaTher is primarily promising for tissues that are very
262295 [46]. © by the Society of Nuclear Medicine and Molecular sensitive to radiation, such as the hematological system [46].
Imaging, Inc In order to plan therapy with radioactively labeled Pen-
tixaTher and to estimate the activity that can be safely
4 days. Activity concentration in blood typically shows three administered, the kinetics of at least kidneys and, if pos-
components with about 10%, 2.5%, and 0.2% of the admin- sible, the target tissue, should be measured. A sufficiently
istered activity per liter of blood decaying with half-lives of reliable pretherapeutic dosimetry is possible with 200 MBq
0.23 h, 7 h, and 40 h, respectively. ­[177Lu]PentixaTher [46]. Due to the short half-life in the kid-
[177Lu]PentixaTher accumulates in the bone marrow and neys, daily measurements over 4 days are usually sufficient
remains there with a half-life of several days, making the for treatment with 177Lu and measurements over 3 days for
bone marrow the critical organ where acute toxicity is fore- therapy with 90Y. The relative time course of the activity
most expected. The calculated specific bone marrow doses in tissues of interest is determined by identically executed
were heterogeneous, ranging from 0.14 to 2.3 (median value, planar scans or SPECT. Bi-exponential functions are usu-
0.5) Gy/GBq 177Lu. Given high individual variability and ally adequate for fitting activity-time functions to the meas-
the uncertainties of bone marrow dosimetry, therapeutic use ured count rates. At least one SPECT/CT with correction
of PentixaTher may be confined to myeloablative therapies. for attenuation and scatter in the reconstruction is required
However, it must be considered in myeloablative treatment to assess absolute activity concentrations used to normalize
that the long residence time of the activity in the bone mar- the activity time functions [46, 47].
row requires a long decay time before a stem cell transplan-
tation can be safely performed. Therefore, in order to reduce Efficacy
the duration of the phase of aplasia and the associated risk
of threatening complications, therapy is usually performed After having visualized CXCR4 expression of tumor lesions
with the nuclide 90Y instead of 177Lu [46]. in an in vivo setting, patients can be scheduled for CXCR4-
In myeloablative treatment, therapeutic activity is limited directed ERT using the ß-emitting theranostic twin ­[177Lu]/
by the absorbed dose to the kidneys. As with other radi- [90Y]PentixaTher (Fig. 1). Using human cell lines and a
olabelled peptides such as ­[177Lu]DOTA-TOC/TATE [47], tumor-bearing murine lymphoma model, Schottelius et al.
a fraction of the active compound filtered by the kidneys reported on increased radiotracer accumulation over time
is retained in renal tubules, leading to an initial increase in tumor sites [45]. In a translational approach, those pre-
of the retention per kidney up to a mean maximum uptake clinical investigations paved the way for the injection of
of 2.2% of the administered ­[177Lu]PentixaTher activity, ­[177Lu]PentixaTher in a patient affected with MM, leading

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European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:4133–4144 4139

to successful bone marrow ablation [45]. Herrmann and Toxicity profile

coworkers also reported on three MM patients, which under-
went CXCR4-directed ERT, followed by chemotherapy and Investigating the safety profile, 22 patients with advanced
autologous HSCT [48]. During follow-up, a remarkable blood cancer treated with ­[177Lu] or ­[90Y]PentixaTher and
response was noted with two patients achieving either par- subsequent chemotherapy followed by HSCT were inves-
tial (PMR) or complete metabolic response (CMR) [48]. tigated [23]. As expected, all patients developed cytope-
Based on these promising results, another study reported nia (including hemoglobin, leukocytes, granulocytes, and
on 8 advanced, extensively pretreated MM patients sched- platelets; Fig. 7A) [23]. One patient developed tumor lysis
uled for CXCR4 ERT, also reporting on PMR and CMR syndrome, followed by grade 3 acute kidney failure, while
in 6/8 cases [49]. Despite such remarkable anti-myeloma all other adverse effects were manageable and did not cause
activity, one subject succumbed to sepsis and another patient any delay for further treatment [23]. In this regard, time
with extremely high tumor burden to tumor lysis syndrome interval between CXCR4 ERT and conditioning therapy was
[49]. Further increasing the safety margin, protocols to pre- significantly longer with ­[177Lu]PentixaTher, which can be
vent such syndromes can be employed, preferably starting explained by the longer half-life of 6.7 days when compared
prior to on-set of CXCR4 ERT [50]. The same group also to ­[90Y]PentixaTher (2.7 days; Fig. 7B) [23]. The ongoing
reported on CXCR4-targeted ERT in acute lymphoblastic COLPRIT trial is a prospective phase I/II study which will
and myeloid leukemia. After having assessed the target further elucidate the therapeutic efficacy and safety of this
capacities in vivo by PET, PentixaTher was administered theranostic strategy in patients with advanced blood cancer
to three subjects with refractory disease. After successful (Eudra‐CT 2015‐001817‐28).
myelosuppression, all patients underwent allogeneic hemat- Table 1 provides an overview of conducted CXCR4 thera-
opoietic stem cell transplantation, thereby paving the way for pies to date, including maximum achieved tumor doses and
successful engraftment [12]. The concept of CXCR4 ERT responses.
has also been applied to patients affected with diffuse large
B cell lymphoma, which were treated with [­ 90Y]PentixaTher
in combination with CD20/CD66 radioimmunotherapy, also
followed by chemotherapy and allogeneic HSCT [15]. In
patients treated with combined ­[90Y]PentixaTher ERT and
radioimmunotherapy, PR was achieved (Fig. 6) [15].

Fig. 6  Partial response in a patient affected with diffuse large B cell adrenals (arrows), lung, and nodal disease manifestations. Note that
lymphoma treated with CXCR4-targeted endoradiotherapy and addi- diffuse radiotracer accumulation in the lung on ­[18F]FDG maximum
tional radioimmunotherapy. Pretherapeutic ­ [68Ga]PentixaFor (left) intensity projection on the right was due to pneumonia. Modified
and posttherapeutic ­[18F]FDG PET/CT (right) after tandem treatment from Lapa et al., Journal of Nuclear Medicine Jan 2019, 60 (1) 60–64
using ­[90Y]PentixaTher and ­ [90Y]Ibritumomab-Tiuxetan (Zevalin). [15], © by the Society of Nuclear Medicine and Molecular Imaging,
Posttherapy scans demonstrated reduction of lesions in the kidneys, Inc

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4140 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:4133–4144

Fig. 7  A Reduction of blood values relative to baseline after CXCR4- interval until start of conditioning therapy was significantly shorter,
directed endoradiotherapy. B Time interval between CXCR4-directed which can be explained by the longer half-life of 2.7 days (177Lu,
endoradiotherapy and start of conventional conditioning therapy. 6.7 days) (B). Modified from Maurer et al., 2019 Oct; 60(10): 1399–
Desired cytopenia was achieved for both [­90Y]PentixaTher and 1405 [23], © by the Society of Nuclear Medicine and Molecular
­[177Lu]PentixaTher (A). For ­ [90Y]PentixaTher, however, the time Imaging, Inc

Table 1  Overview of CXCR4-directed endoradiotherapies in advanced hematological malignancies

Study Type of blood No. of patients Used radionu- Administered Achieved Gy Outcome
cancer clide activity (GBq) to tumor sites
(maximum) SAE Best response

Herrmann et al. MM 3 [177Lu]/[90Y] 6.3–23.5 84 Death (1/3, PR (1/3), CMR

[48] PentixaTher sepsis) (1/3)
Habringer et al. AML 3 [90Y[PentixaTher 2.7–4.72 53 Death (1/3, CMR (1/3), NA
[12] sepsis) in 1/3
Lapa et al. [49] MM 8* [177Lu]/[90Y] 2.6–23.5 > 70 2/8 death 5/8 PR, 1/8 CMR
PentixaTher (sepsis, lethal
TLS)
Lapa et al. [15] DLBCL 6 [90Y[PentixaTher 2.8–6.5 96.5 Death (2/6, sep- 2/6 ­PR§, MR in
sis and CNS 2/6
aspergillosis)
Maurer et al. AML, MM, 22 [177Lu]/[90Y] 7.6–23.5 NA TLS with grade NA (investigation
[23] DLBCL, PentixaTher# 3 kidney fail- of side effects)
MCL, T-PLL ure (1/22)

SAE severe adverse event, MM multiple myeloma, PR partial response, CMR complete metabolic response, AML acute myeloid leukemia, NA
not available, TLS tumor lysis syndrome, DLBCL diffuse large B cell lymphoma, CNS central nervous system, MR mixed response, MCL mantle
cell lymphoma, T-PLL T-cell prolymphocytic leukemia
*One patient treated with three cycles
§
Treated with additional radioimmunotherapy
#
8/22 treated with additional radioimmunotherapy

Future aspects mandatory due to bone marrow ablation, CXCR4-directed

ERT could also be applied to solid tumor patients exhibit-
Expanding CXCR4‑targeted theranostics to solid ing increased CXCR4 expression on PET [43]. Such an
tumors approach, however, would be restricted to refractory end-
stage disease patients having exhausted all other treatment
To date, ­[ 177Lu]/[ 90Y]PentixaTher has been applied to lines. For instance, in ACC patients, treatment options are
patients affected with various types of blood cancers [12, limited [51] and, thus, administration of ­[90Y]PentixaTher
15, 48, 49], not only to achieve an anti-tumor effect, but may be feasible as a salvage approach, e.g., after having
also as a conditioning regimen followed by allogenic or harvested stem cells during previous chemotherapeutic
autologous HSCT. Although such a stem cell backup is protocols [52].

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European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:4133–4144 4141

Image‑guided therapy for non‑radioactive Conclusions

CXCR4‑directed drugs
CXCR4 is upregulated on various cancer cells, rendering
Despite treatment with hot CXCR4-directed radiotrac- this receptor as a potential target for tumor read-out and
ers, ­[ 68Ga]PentixaFor could also be applied to patients treatment strategies [1]. The CXCR4-targeted PET agent
scheduled for treatment with cold drugs also interacting ­[68Ga]PentixaFor has been successfully applied to patients
with this chemokine receptor. Among others, those medi- with solid and advanced blood cancers, demonstrating
cations include small molecule (AMD3100/plerixafor), substantially increased radiotracer accumulation in ACC,
molecules targeting CXC12 (NOX-12, CX-01), peptide- SCLC, MM, MZL, MCL, or gastric MALT [10, 11, 25,
based molecules (BL-8040, LYS2510924, POL5551), or 29, 37, 40]. In addition to assessment of widespread dis-
antibodies (ulocuplumab). Such agents have been par- ease, such a functional imaging approach allows to assess
tially investigated in humans as chemosensitizing agents, the capacities of the target in-vivo. Thus, quantification of
e.g., for acute myeloid leukemia and ALL, but with rather ­[68Ga]PentixaFor accumulation may then allow to estimate
disappointing results [53]. Pretherapeutic [­ 68Ga]Pentixa- the efficacy of non-radioactive CXCR4 inhibitory treatments
For PET could assess the current status quo of the target (e.g., with anti-human CXCR4 IgG monoclonal antibodies
and may provide guidance towards better patient selec- for MM patients) [65] or to identify patients that would be
tion. In addition, ex-vivo CXCR4 overexpression has been eligible for treatment with hot CXCR4-directed theranostic
advocated to be tightly linked to worse prognosis in those radiotracers, such as ­[177Lu]/[90Y]PentixaTher [46]. The lat-
patients, e.g., in ALL [54, 55] and CXCR4 may be also ter concept has already been applied to hematological malig-
involved in chemotherapeutic resistance [56]. As such, nancies known to be sensitive to radiation, e.g., in advanced
in vivo molecular imaging may then also be useful to MM, ALL, or diffuse large B cell lymphoma [12, 15, 49].
identify such high risks prone to chemotherapy failure or In this context, pretherapeutic dosimetry can determine the
as a prognostic tool for further clinical outcome. appropriate amount of activity to achieve anti-tumor effects
and to minimize off-target effects [46]. CXCR4 ERT also
caused desired bone marrow ablation and has therefore
Systemic networking on CXCR4‑PET to assess been incorporated in the therapeutic algorithm of advanced
cardiovascular toxicity as an adverse effect blood cancer patients (allogenic/autologous HSCT following
of anti‑tumor treatment CXCR4 ERT along with successful engraftment) [12, 15,
49]. Therapeutic efficacy of those treatment regimens led
A recent study enrolling oncology patients revealed to remarkable outcome benefits in those heavily pretreated
increased in-vivo expression of fibroblast activation patients [12, 15, 23, 49]. Given substantial high doses in the
protein not only in metastases, but also in the myocar- tumor, some patients experienced tumor lysis syndrome and
dium [57]. Such a complex interplay between tumor thus, those individuals should be closely monitored [23].
and the cardiovascular system could also be assessed
in future studies using [­ 68Ga]PentixaFor. In this regard,
numerous studies have already reported on the feasibil- Funding Open Access funding enabled and organized by Projekt
DEAL.
ity of CXCR4-directed PET in patients after myocardial
infarction [58–60]. Cardio-oncology studies investigat-
ing interactions between the heart, vessels, and tumor Declarations
sites may allow to detect subjects developing relevant
Research involving human participants or animals This article does
off-target effects caused by their anti-tumor therapeutic not contain any studies with human participants or animals performed
regimen [61]. Such studies demonstrating a potential by any of the authors.
inflammatory activity in large arteries have already
been conducted using a retrospective cohort of mela- Conflict of interest The authors declare no competing interests.
noma patients imaged with [­ 18F]FDG and treated with
immune checkpoint inhibitors, which are known to cause Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
myocarditis and potential life-threating cardiovascular
tion, distribution and reproduction in any medium or format, as long
events [62, 63]. Relative to ­[ 18F]FDG, however, CXCR4 as you give appropriate credit to the original author(s) and the source,
PET has already identified a higher number of athero- provide a link to the Creative Commons licence, and indicate if changes
sclerotic lesions in the vessel wall in oncology patients were made. The images or other third party material in this article are
included in the article's Creative Commons licence, unless indicated
and, thus, may even provide a more reliable read-out of
otherwise in a credit line to the material. If material is not included in
ongoing inflammatory activities under tumor-specific the article's Creative Commons licence and your intended use is not
treatment [64]. permitted by statutory regulation or exceeds the permitted use, you will

13
4142 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:4133–4144

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