Check for updates
CXCR4-targeted theranostics in oncology
Andreas K. Buck1 . Sebastian E. Serfling1 . Thomas Lindner1 . Heribert Hanscheid1 . 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 . [177 Lu]PentixaTher . [90Y] PentixaTher · Endoradiotherapy · Adrenocortical carcinoma · Multiple myeloma
This article is part of the Topical Collection on Theragnostic
☒ Andreas K. Buck buck_a@ukw.de
1 Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080 Wurzburg, Germany
2 Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital, University of Würzburg, Wurzburg, Germany
3 Department of Internal Medicine II, Hematology and Oncology, University Hospital Würzburg, Wurzburg, Germany
4 Division of Nuclear Medicine and Molecular Imaging, The Russell H Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins School of Medicine, Baltimore, MD, USA
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 spread, such as angiogenesis or further involvement lead- ing to therapeutic resistance [1]. Of note, ex vivo work-up revealed a large variety of solid cancers and hematological malignancies, which upregulate CXCR4 on the tumor cell surface, thereby rendering this G-protein coupled receptor as an attractive target for imaging and treatment [1]. Given its ability to precisely reflect sites of disease on a functional level, CXCR4-targeting radiotracers for single-photon emis- sion computed tomography and positron emission tomog- raphy (PET) have been introduced for clinical use [2-6]. For instance, [68 Ga]PentixaFor has been extensively applied to patients affected with various solid and hematological neoplasms [7-10]. Radiotracer accumulation did not only reveal substantial correlation with immunohistochemical ex- vivo CXCR4 expression derived from corresponding tissue
specimens [8], but was also more accurate in detecting meta- static sites, e.g., when compared to the current diagnostic work-up and standard imaging modalities in selected cases [11]. Of note, once [68Ga]PentixaFor has revealed substantial CXCR4 expression in vivo, the theranostic analogs [177 Lu]/ [9ºY]PentixaTher can also be administered (Fig. 1) [12]. As such, CXCR4-directed PET also serves as a “one-stop” solu- tion to determine the current status of disease spread and to identify patients eligible for a CXCR4-directed endoradio- therapy (ERT) using ß-emitters [13, 14]. In this regard, such treatment strategies have led to relevant anti-lymphoma/- tumor effect in selected cases and served as a conditioning regimen to enable for hematopoietic stem cell transplanta- tion (HSCT) [12, 15]. Over the last decades, the theranostic concept has been primarily used and established in the clinic for treating solid tumors, such as prostate cancer or neuroen- docrine neoplasms (NEN) [16, 17]. CXCR4-directed [68Ga] PentixaFor and [177 Lu]/[90Y]PentixaTher, however, meet the urgent need to provide this innovative treatment strategy to patients affected with advanced blood cancer. In the present review, we will provide an overview of CXCR4-directed molecular imaging for solid tumors and hematologic malig- nancies. We will also review current therapeutic applications for hematological malignancies, including pretherapeutic dosimetry.
CXCR4-directed molecular imaging
Solid cancers
CXCR4-targeted PET has been first applied to patients diagnosed with solid tumors. Vag and co-workers included 22 patients with pancreatic cancer, prostate carcinoma, small-cell lung cancer (SCLC), melanoma, breast cancer,
liver carcinoma, cancer of unknown primary, and glioblas- toma, reporting on an increased radiotracer accumulation with high tumor-to-background ratio in SCLC [9]. In 10 patients, in whom 2-deoxy-2-[18F]fluoro-D-glucose ([18F] FDG) PET was available, the latter radiotracer exhibited higher standardized uptake values [9]. Another cohort of treatment-naïve patients affected with various solid can- cers (including cholangiocarcinoma, ovarian cancer, and renal cell carcinoma) provided substantial correlation of tumor-derived specimens (defined as CXCR4-based immu- noreactive scores) and [68 Ga]PentixaFor accumulation in sites of disease [8]. Among those cancer entities, cholangio- carcinoma had the highest uptake, which was up to seven- fold higher when compared to background [8]. In addition, work-up of tissue samples derived from patients with neu- roendocrine neoplasms demonstrated that an increased pro- liferation index is linked to downregulation of somatostatin receptor (SSTR) 2 and 5, but upregulation of CXCR4 [18]. Those ex vivo findings were then further corroborated using SSTR-directed and [68 Ga]PentixaFor PET. In this regard, an increasing number of CXCR4(+)/SSTR(-) metastases were identified in patients with increasing tumor aggres- siveness [19]. Previous studies, however, have already reported on the usefulness of [18F]FDG PET in the con- text of highly malignant, dedifferentiated neuroendocrine tumors [20, 21]. A retrospective head-to-head comparison of the latter radiotracer with [68Ga]PentixaFor PET dem- onstrated equal or inferior diagnostic performance with CXCR4 molecular imaging [22]. Nonetheless, given the rather limited treatment options for neuroendocrine tumor patients with a high proliferation index, [68Ga]PentixaFor may still allow to select potential treatment candidates for [177 Lu] or [9ºY]PentixaTher. In this regard, bone mar- row ablation as a side effect would definitely occur and, thus, stem cell support would be needed [23]. Based on
[68Ga]PentixaFor
[177Lu]PentixaTher
[90Y]Pentixa Ther
preliminary findings of Vag and coworkers [9] and promis- ing ex vivo findings in lung cancer samples [24], Lapa et al. further investigated [68Ga]PentixaFor for treatment-naïve and pretreated SCLC and large-cell neuroendocrine carci- noma of the lung. In a comparison with SSTR-PET, the authors reported on an increased in-vivo CXCR4 expres- sion [25]. A recent preclinical study also demonstrated increased ex-vivo CXCR4 expression in tissue specimens of patients affected with adrenocortical carcinoma (ACC) [26]. As an orphan disease, ACC has a less favorable prog- nosis in the vast majority of patients and, thus, novel treat- ment options are urgently needed [27, 28]. Bluemel and coworkers therefore investigated the read-out capabilities of [68Ga]PentixaFor in those patients. Although no substantial differences relative to [18F]FDG could be established in a visual and quantitative assessment, a markedly high number of subjects (70%) were rendered suitable for ERT using the theranostic counterparts [177Lu] or [90Y ]PentixaTher [29]. In malignant pleural mesothelioma, human tissue samples also revealed robust CXCR4 expression in an ex-vivo set- ting [30], which then again provided a rationale to investi- gate [68Ga]PentixaFor in this disease [30]. Of note, ex-vivo findings were not confirmed by an in-vivo molecular imag- ing approach, as no substantial radiotracer accumulation was recorded [31], which further demonstrates that an ex- vivo proof of CXCR4 expression does not always lead to increased uptake on PET. Taken together, SCLC, cholan- giocarcinoma, highly dedifferentiated NEN, and ACC may be the most promising tumor entities for a CXCR4-directed PET (Fig. 2) [8, 19, 25, 29].
A recent study comprised more than 145 solid tumor patients focusing on a potential predictive role of physi- ological splenic uptake and outcome [32]. In lung car- cinoma and NEN, the authors reported on a substantial interrelation between thrombocytes and white blood cell counts and radiotracer accumulation in the spleen as a hematopoetic reservoir involved in the immune response. As such, further studies are needed to elucidate the role of systemic inflammation detected by CXCR4 PET in those tumor subtypes [32]. Another recently published study investigated a potential tumor sink effect in the context of CXCR4-directed PET [33], as such a decrease of uptake in normal organs in subjects with increased tumor load has been reported for other theranostic agents, e.g., soma- tostatin receptor directed radiopharmaceuticals [34]. If such a tumor sink effect also occurs in patients injected with [68Ga]PentixaFor, this may have a relevant impact on “hot” and “cold” therapies targeting CXCR4, e.g., by safely increasing the amount of therapeutic activity but reducing side effects in organs with normal biodistribu- tion [33]. Investigating this effect on [68 Ga]PentixaFor in 90 patients with solid tumors, the authors did not report on decreasing radiotracer accumulation in patients with higher tumor burden, further supporting the hypothesis that doses in normal organs and sites of disease can rather not be estimated based on pretherapeutic PET. In this regard, those findings favor the use of treatment planning using dosimetry [33].
A
B
c
D
E
F
G
0
10
SUV
Advanced hematological malignancies
Multiple studies demonstrated that [68Ga]PentixaFor may be particularly useful for imaging various types of advanced blood cancers. As such, the first biodistribution study for this radiotracer was conducted in 5 subjects diag- nosed with multiple myeloma (MM) and reported on an effective of 2.3 mSv [3], which was comparable to other 68-Ga-labeled theranostic radiotracers [35]. MM has also been further investigated with [68 Ga]PentixaFor [36], demonstrating remarkable diagnostic accuracy for iden- tifying MM manifestations, which was superior relative to [18F]FDG in newly diagnosed subjects (positive rate almost twice for CXCR4 PET) [37]. Further demonstrating a tight interaction with disease state and in-vivo CXCR4 expression, uptake in bone marrow was associated with staging or relevant markers of disease activity, e.g., serum- free light chain or ß2-microglobulin [37]. Of note, the derived PET signal may also hold potential for outcome prediction, as a negative scan was linked to increased time- to-progression and overall survival [7]. Among hemato- logical malignancies, [68Ga]PentixaFor has also been first applied to patients affected with acute myeloid leukemia in a translational setup. Using flow cytometry, increased patient-derived high blast counts were linked to CXCR4 upregulation. In mice affected with either CXCR4( -) or CXCR4(+) leukemia xenografts, an increased [68Ga]Pen- tixaFor signal was observed in the latter animals. Last, in 10 patients with active disease, elevated radiotracer uptake was tightly linked to disease infiltration by magnetic reso- nance in half of the investigated subjects [38].
Moreover, CXCR4-directed imaging has also been applied to 22 treatment-naïve patients affected with mar- ginal zone lymphoma (MZL) [11]. When compared to routine clinical work-up (including endoscopy of the gas- trointestinal tract and bone marrow biopsy), [68Ga]Pentixa- For PET, but not standard procedures, classified all cases correctly [11]. Of interest, PET changed both staging and therapeutic management, further indicating that this radi- opharmaceutical could be applied to routine assessment in individuals affected with MZL (Fig. 3) [11]. Specimen of gastric mucosa-associated lymphoid tissue (MALT) lym- phoma also revealed CXCR4 overexpression in an ex-vivo setup [39] and those findings were further corroborated in an in-vivo setting, demonstrating an accuracy of 100% (with gastric biopsies serving as reference) in subjects after Helicobacter pylori eradication [10], thereby demonstrating that this radiotracer can assess residual disease activity [10]. The same research group also investigated [68Ga]PentixaFor PET for mantle cell lymphoma (MCL), as the diagnostic performance of the currently applied radiotracer [18F]FDG is hampered by increased uptake in the bone marrow [40]. Relative to the latter radiotracer, the CXCR4 agent demon- strated an increased sensitivity of up to 25% on a per region level [40]. A quantitative assessment also demonstrated higher target-to-background ratios, rendering [68Ga]Pen- tixaFor as a suitable alternative to [18F]FDG in MCL [40]. CXCR4-directed PET was also used in myeloproliferative neoplasms (including essential thrombocythemia and poly- cythemia vera) and all of the included 12 patients revealed positive findings [41]. Further corroborating the clinical relevance, the SUV reduction of a baseline and follow-up
A
B
C
D
E
F
G
0
10
SUV
also showed radiotracer accumulation in the cervical (E), abdominal (F), and in the inguinal region (G). Modified from Duell et al., Jour- nal of Nuclear Medicine, October 2021, 62 (10) 1415-1421 [11]. @ by the Society of Nuclear Medicine and Molecular Imaging, Inc
[68Ga]PentixaFor scan correlated with decrease of spleen volume, supporting the hypothesis that quantitative param- eters may be also applicable for response assessment [41]. As a relatively rare form of non-Hodgkin lymphoma, utility of [18F]FDG is also limited in Waldenström macroglobuline- mia/lymphoplasmacytic lymphoma (again, due to bone mar- row involvement leading to rather less specific uptake) [42]. Luo et al. reported on a substantial higher rate of positive findings after injection of [68Ga]PentixaFor when compared to [18F]FDG [42].
Roadmap of relevant in-vivo CXCR4 expression
Aiming to provide a roadmap among a broad spectrum of neoplasms, a recent bicentric study of our group and col- leagues from Vienna Medical University assessed [68Ga] PentixaFor uptake and image contrast among the largest cohort of subjects imaged with CXCR4-directed PET to date, thereby determining the most relevant clinical applica- tions. Investigating 690 patients affected with various solid tumors and hematological neoplasms scheduled for 777 scans, 68.9% demonstrated uptake in sites of disease [43]. The highest tracer uptake was recorded in MM (maximum SUV> 12). The second highest uptake was then found in ACC, MCL, adrenocortical adenoma, and SCL. Osteosar- coma, bladder cancer, head and neck cancer, and Ewing sar- coma, on the other hand, exhibited the lowest average SUV (<6; Fig. 4A) [43]. Comparable findings were recorded for target-to-background ratio (TBR), thereby reflecting image contrast. Again, the highest TBR was found in advanced
blood cancers, including MM, MCL, and acute lymphoblas- toid leukemia (Fig. 4B) [43]. Moreover, lower specific activ- ity is characterized by higher amounts of cold mass, thereby having a relevant impact on image interpretation [44]. The authors did not record any relevant significant associations with semiquantitative parameters and specific activity, sup- porting the hypothesis that read-out capabilities are not ham- pered, regardless of the amount of specific activities [43].
CXCR4-targeted endoradiotherapy
Biokinetics and pretherapeutic dosimetry
After intravenous administration, [177Lu]PentixaTher binds to plasma proteins with high metabolic stability, and only a small fraction of about 4% is attached to leukocytes and platelets via CXCR4 binding [45]. Scintigraphically detect- able activity accumulations are found in kidney, liver, spleen, and bone marrow, as well as in CXCR4-expressing malignant tissues. An example of measured time functions of activity retention in organs and tissues in a patient with MM is shown in Fig. 5. The figure, like the results sum- marized below unless otherwise specified, is taken from a recently published study on [177Lu]PentixaTher biokinetics and dosimetry [46].
The total body 177 Lu activity typically decays bi-exponen- tially. About half of the activity is eliminated with a median effective half-life of about 10 h mainly by renal excretion; the remainder decays with a mean effective half-life of about
A
BP
Ewing sarcoma (n = 1)
Head and neck cancer (n = 2)
Mediastinal tumor (n = 1)
Bladder cancer (n = 1)
Osteosarcoma (n = 1)
Renal cell carcinoma (n = 1)
Pleural mesothelioma (n = 1)
Pancreas carcinoma (n = 8)
T-cell lymphoma (n = 3)
Colorectal cancer (n = 1)
AML (n = 9)
CCC (n = 3)
NSCLC (n = 7)
NEN (n = 30)
Myeloid disorders (n = 13)
Liver carcinoma (n = 4)-
Ovarian cancer (n = 1)-
B-cell lymphoma (n = 10)-
DSRCT (n = 14)
ALL (n = 6)-
CLL (n = 50)
MZL (n = 187)
SCLC (n = 12)
Adrenocortical adenoma (n = 6).
Mantle cell lymphoma (n = 20)
Adrenocortical carcinoma (n = 30)
MM (n = 113)
0
10
20
30
40
SUV
max
B
Mediastinal tumor (n = 1)
Renal cell carcinoma (n = 1
Bladder cancer (n = 1)
Ewing sarcoma (n = 1)
Osteosarcoma (n = 1)
Colorectal cancer (n = 1)
Head and neck cancer (n = 2)
Pancreas carcinoma (n = 8)
Pleural mesothelioma (n = 1)
NSCLC (n = 7)
NEN (n = 30)
AML (n = 9)
Ovarian cancer (n = 1)
T-cell lymphoma (n = 3)
Liver carcinoma (n = 4)
B-cell lymphoma (n = 10)
Myeloid disorders (n = 13)-
Adrenocortical adenoma (n = 6).
CCC (n = 3)
CLL (n = 50)
MZL (n = 187)
DSRCT (n = 14)-
SCLC (n = 12)
Adrenocortical carcinoma (n = 30)
ALL (n = 6)
Mantle cell lymphoma (n = 20)
MM (n = 113)
0
5
10
15
20
45
50
TBR
CLL chronic lymphocytic leukemia, MZL marginal zone lymphoma, SCLC small-cell lung carcinoma, MM multiple myeloma. Adreno- cortical adenoma: aldosteron-producing adrenocortical adenoma. Modified from Buck et al., Journal of Nuclear Medicine, 2022 Mar 3; jnumed.121.263693 [43]. @ by the Society of Nuclear Medicine and Molecular Imaging, Inc
100 %
10 %
Activity retention
1 %
0.1%
0
24
48
72
96
8 %
4 %
2 %
10
8
1 %
6
0.5%
4
2
0.025%
0
24
48
72
96
0
Time (h)
counts
pixel
4 days. Activity concentration in blood typically shows three components with about 10%, 2.5%, and 0.2% of the admin- istered activity per liter of blood decaying with half-lives of 0.23 h, 7 h, and 40 h, respectively.
[177 Lu]PentixaTher accumulates in the bone marrow and remains there with a half-life of several days, making the bone marrow the critical organ where acute toxicity is fore- most expected. The calculated specific bone marrow doses were heterogeneous, ranging from 0.14 to 2.3 (median value, 0.5) Gy/GBq 177Lu. Given high individual variability and the uncertainties of bone marrow dosimetry, therapeutic use of PentixaTher may be confined to myeloablative therapies. However, it must be considered in myeloablative treatment that the long residence time of the activity in the bone mar- row requires a long decay time before a stem cell transplan- tation can be safely performed. Therefore, in order to reduce the duration of the phase of aplasia and the associated risk of threatening complications, therapy is usually performed with the nuclide 90Y instead of 177 Lu [46].
In myeloablative treatment, therapeutic activity is limited by the absorbed dose to the kidneys. As with other radi- olabelled peptides such as [177Lu]DOTA-TOC/TATE [47], a fraction of the active compound filtered by the kidneys is retained in renal tubules, leading to an initial increase of the retention per kidney up to a mean maximum uptake of 2.2% of the administered [177Lu]PentixaTher activity,
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 also found in tumors and extramedullary lesions in hemato- logical diseases. The absorbed doses are typically twice as high as in the critical organ, the kidneys. Since myeloabla- tive therapy cannot be repeated several times, therapy with PentixaTher is primarily promising for tissues that are very sensitive to radiation, such as the hematological system [46].
In order to plan therapy with radioactively labeled Pen- tixaTher and to estimate the activity that can be safely administered, the kinetics of at least kidneys and, if pos- sible, the target tissue, should be measured. A sufficiently reliable pretherapeutic dosimetry is possible with 200 MBq [177 Lu]PentixaTher [46]. Due to the short half-life in the kid- neys, daily measurements over 4 days are usually sufficient for treatment with 177Lu and measurements over 3 days for therapy with 90Y. The relative time course of the activity in tissues of interest is determined by identically executed planar scans or SPECT. Bi-exponential functions are usu- ally adequate for fitting activity-time functions to the meas- ured count rates. At least one SPECT/CT with correction for attenuation and scatter in the reconstruction is required to assess absolute activity concentrations used to normalize the activity time functions [46, 47].
Efficacy
After having visualized CXCR4 expression of tumor lesions in an in vivo setting, patients can be scheduled for CXCR4- directed ERT using the ß-emitting theranostic twin [177Lu]/ [9ºY]PentixaTher (Fig. 1). Using human cell lines and a tumor-bearing murine lymphoma model, Schottelius et al. reported on increased radiotracer accumulation over time in tumor sites [45]. In a translational approach, those pre- clinical investigations paved the way for the injection of [177 Lu]PentixaTher in a patient affected with MM, leading
to successful bone marrow ablation [45]. Herrmann and coworkers also reported on three MM patients, which under- went CXCR4-directed ERT, followed by chemotherapy and autologous HSCT [48]. During follow-up, a remarkable response was noted with two patients achieving either par- tial (PMR) or complete metabolic response (CMR) [48]. Based on these promising results, another study reported on 8 advanced, extensively pretreated MM patients sched- uled for CXCR4 ERT, also reporting on PMR and CMR in 6/8 cases [49]. Despite such remarkable anti-myeloma activity, one subject succumbed to sepsis and another patient with extremely high tumor burden to tumor lysis syndrome [49]. Further increasing the safety margin, protocols to pre- vent such syndromes can be employed, preferably starting prior to on-set of CXCR4 ERT [50]. The same group also reported on CXCR4-targeted ERT in acute lymphoblastic and myeloid leukemia. After having assessed the target capacities in vivo by PET, PentixaTher was administered to three subjects with refractory disease. After successful myelosuppression, all patients underwent allogeneic hemat- opoietic stem cell transplantation, thereby paving the way for successful engraftment [12]. The concept of CXCR4 ERT 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 [9ºY]PentixaTher ERT and radioimmunotherapy, PR was achieved (Fig. 6) [15].
Toxicity profile
Investigating the safety profile, 22 patients with advanced blood cancer treated with [177 Lu] or [9ºY ]PentixaTher and subsequent chemotherapy followed by HSCT were inves- tigated [23]. As expected, all patients developed cytope- nia (including hemoglobin, leukocytes, granulocytes, and platelets; Fig. 7A) [23]. One patient developed tumor lysis syndrome, followed by grade 3 acute kidney failure, while all other adverse effects were manageable and did not cause any delay for further treatment [23]. In this regard, time interval between CXCR4 ERT and conditioning therapy was significantly longer with [177Lu]PentixaTher, which can be explained by the longer half-life of 6.7 days when compared to [90Y]PentixaTher (2.7 days; Fig. 7B) [23]. The ongoing COLPRIT trial is a prospective phase I/II study which will further elucidate the therapeutic efficacy and safety of this theranostic strategy in patients with advanced blood cancer (Eudra-CT 2015-001817-28).
Table 1 provides an overview of conducted CXCR4 thera- pies to date, including maximum achieved tumor doses and responses.
Before 90Y-pentixather
After 90Y-pentixather
adrenals (arrows), lung, and nodal disease manifestations. Note that diffuse radiotracer accumulation in the lung on [18F]FDG maximum intensity projection on the right was due to pneumonia. Modified from Lapa et al., Journal of Nuclear Medicine Jan 2019, 60 (1) 60-64 [15], @ by the Society of Nuclear Medicine and Molecular Imaging, Inc
A
Hemoglobin
Leukocytes
Granulocytes
Platelets
B
P = 0.007
% reduction from baseline
0
25
-25
P = 0.116
P = 0.891
P = 0.465
20
Time (d)
-50
15
P = 0.051
10
-75
5
-100
0
177
Lu
90Y
177
7Lu
90Y
177Lu
90Y
177
Lu
90Y
177Lu
90Y
| Study | Type of blood cancer | No. of patients | Used radionu- clide | Administered activity (GBq) | Achieved Gy to tumor sites (maximum) | Outcome | |
|---|---|---|---|---|---|---|---|
| SAE | Best response | ||||||
| Herrmann et al. [48] | MM | 3 | [177 Lu]/[90Y] PentixaTher | 6.3-23.5 | 84 | Death (1/3, sepsis) | PR (1/3), CMR (1/3) |
| Habringer et al. [12] | AML | 3 | [9ºY [PentixaTher | 2.7-4.72 | 53 | Death (1/3, sepsis) | CMR (1/3), NA in 1/3 |
| Lapa et al. [49] | MM | 8* | [177Lu]/[90Y] PentixaTher | 2.6-23.5 | >70 | 2/8 death (sepsis, lethal TLS) | 5/8 PR, 1/8 CMR |
| Lapa et al. [15] | DLBCL | 6 | [9ºY [PentixaTher | 2.8-6.5 | 96.5 | Death (2/6, sep- sis and CNS aspergillosis) | 2/6 PR$, MR in 2/6 |
| Maurer et al. | AML, MM, DLBCL, MCL, T-PLL | 22 | [177 Lu]/[90Y] PentixaTher# | 7.6-23.5 | NA | TLS with grade 3 kidney fail- ure (1/22) | NA (investigation of side effects) |
| [23] |
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
Expanding CXCR4-targeted theranostics to solid tumors
To date, [177Lu]/[90Y]PentixaTher has been applied to patients affected with various types of blood cancers [12, 15, 48, 49], not only to achieve an anti-tumor effect, but also as a conditioning regimen followed by allogenic or autologous HSCT. Although such a stem cell backup is
mandatory due to bone marrow ablation, CXCR4-directed ERT could also be applied to solid tumor patients exhibit- ing increased CXCR4 expression on PET [43]. Such an approach, however, would be restricted to refractory end- stage disease patients having exhausted all other treatment lines. For instance, in ACC patients, treatment options are limited [51] and, thus, administration of [9ºY ]PentixaTher may be feasible as a salvage approach, e.g., after having harvested stem cells during previous chemotherapeutic protocols [52].
Image-guided therapy for non-radioactive CXCR4-directed drugs
Despite treatment with hot CXCR4-directed radiotrac- ers, [68Ga]PentixaFor could also be applied to patients scheduled for treatment with cold drugs also interacting with this chemokine receptor. Among others, those medi- cations include small molecule (AMD3100/plerixafor), molecules targeting CXC12 (NOX-12, CX-01), peptide- based molecules (BL-8040, LYS2510924, POL5551), or antibodies (ulocuplumab). Such agents have been par- tially investigated in humans as chemosensitizing agents, e.g., for acute myeloid leukemia and ALL, but with rather disappointing results [53]. Pretherapeutic [68Ga]Pentixa- For PET could assess the current status quo of the target and may provide guidance towards better patient selec- tion. In addition, ex-vivo CXCR4 overexpression has been advocated to be tightly linked to worse prognosis in those patients, e.g., in ALL [54, 55] and CXCR4 may be also involved in chemotherapeutic resistance [56]. As such, in vivo molecular imaging may then also be useful to identify such high risks prone to chemotherapy failure or as a prognostic tool for further clinical outcome.
Systemic networking on CXCR4-PET to assess cardiovascular toxicity as an adverse effect of anti-tumor treatment
A recent study enrolling oncology patients revealed increased in-vivo expression of fibroblast activation protein not only in metastases, but also in the myocar- dium [57]. Such a complex interplay between tumor 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- ity of CXCR4-directed PET in patients after myocardial infarction [58-60]. Cardio-oncology studies investigat- ing interactions between the heart, vessels, and tumor sites may allow to detect subjects developing relevant off-target effects caused by their anti-tumor therapeutic regimen [61]. Such studies demonstrating a potential inflammatory activity in large arteries have already been conducted using a retrospective cohort of mela- noma patients imaged with [18F]FDG and treated with immune checkpoint inhibitors, which are known to cause myocarditis and potential life-threating cardiovascular events [62, 63]. Relative to [18F]FDG, however, CXCR4 PET has already identified a higher number of athero- sclerotic lesions in the vessel wall in oncology patients and, thus, may even provide a more reliable read-out of ongoing inflammatory activities under tumor-specific treatment [64].
Conclusions
CXCR4 is upregulated on various cancer cells, rendering this receptor as a potential target for tumor read-out and treatment strategies [1]. The CXCR4-targeted PET agent [68Ga]PentixaFor has been successfully applied to patients with solid and advanced blood cancers, demonstrating substantially increased radiotracer accumulation in ACC, SCLC, MM, MZL, MCL, or gastric MALT [10, 11, 25, 29, 37, 40]. In addition to assessment of widespread dis- ease, such a functional imaging approach allows to assess the capacities of the target in-vivo. Thus, quantification of [68Ga]PentixaFor accumulation may then allow to estimate the efficacy of non-radioactive CXCR4 inhibitory treatments (e.g., with anti-human CXCR4 IgG monoclonal antibodies for MM patients) [65] or to identify patients that would be eligible for treatment with hot CXCR4-directed theranostic radiotracers, such as [177 Lu]/[90Y ]PentixaTher [46]. The lat- ter concept has already been applied to hematological malig- nancies known to be sensitive to radiation, e.g., in advanced MM, ALL, or diffuse large B cell lymphoma [12, 15, 49]. In this context, pretherapeutic dosimetry can determine the 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 been incorporated in the therapeutic algorithm of advanced blood cancer patients (allogenic/autologous HSCT following CXCR4 ERT along with successful engraftment) [12, 15, 49]. Therapeutic efficacy of those treatment regimens led to remarkable outcome benefits in those heavily pretreated patients [12, 15, 23, 49]. Given substantial high doses in the tumor, some patients experienced tumor lysis syndrome and thus, those individuals should be closely monitored [23].
Funding Open Access funding enabled and organized by Projekt DEAL.
Declarations
Research involving human participants or animals This article does not contain any studies with human participants or animals performed by any of the authors.
Conflict of interest The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
References
1. Chatterjee S, Behnam Azad B, Nimmagadda S. The intricate role of CXCR4 in cancer. Adv Cancer Res. 2014;124:31-82. https://doi.org/10.1016/B978-0-12-411638-2.00002-1.
2. Demmer O, Gourni E, Schumacher U, Kessler H, Wester HJ. PET imaging of CXCR4 receptors in cancer by a new optimized ligand. ChemMedChem. 2011;6:1789-91. https://doi.org/10. 1002/cmdc.201100320.
3. Herrmann K, Lapa C, Wester HJ, Schottelius M, Schiepers C, Eberlein U, et al. Biodistribution and radiation dosimetry for the chemokine receptor CXCR4-targeting probe 68Ga-pentixafor. J Nucl Med. 2015;56:410-6. https://doi.org/10.2967/jnumed.114. 151647.
4. Hartimath SV, Domanska UM, Walenkamp AM, Rudi AJOD, de Vries EF. [(9)(9)mTc]O(2)-AMD3100 as a SPECT tracer for CXCR4 receptor imaging. Nucl Med Biol. 2013;40:507-17. https://doi.org/10.1016/j.nucmedbio.2013.02.003.
5. Nimmagadda S, Pullambhatla M, Pomper MG. Immunoimaging of CXCR4 expression in brain tumor xenografts using SPECT/CT. J Nucl Med. 2009;50:1124-30. https://doi.org/10.2967/jnumed. 108.061325.
6. Woodard LE, Nimmagadda S. CXCR4-based imaging agents. J Nucl Med. 2011;52:1665-9. https://doi.org/10.2967/jnumed.111. 097733.
7. Lapa C, Schreder M, Schirbel A, Samnick S, Kortum KM, Herrmann K, et al. [(68)Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - comparison to [(18)F]FDG and laboratory values. Theranostics. 2017;7:205-12. https://doi.org/10.7150/thno.16576.
8. Werner RA, Kircher S, Higuchi T, Kircher M, Schirbel A, Wester HJ, et al. CXCR4-directed imaging in solid tumors. Front Oncol. 2019;9:770. https://doi.org/10.3389/fonc.2019.00770.
9. Vag T, Gerngross C, Herhaus P, Eiber M, Philipp-Abbrederis K, Graner FP, et al. First experience with chemokine receptor CXCR4-targeted PET imaging of patients with solid cancers. J Nucl Med. 2016;57:741-6. https://doi.org/10.2967/jnumed.115. 161034.
10. Mayerhoefer ME, Raderer M, Lamm W, Weber M, Kiesewetter B, Rohrbeck J, et al. CXCR4 PET/MRI for follow-up of gastric mucosa-associated lymphoid tissue lymphoma after first-line Heli- cobacter pylori eradication. Blood. 2022;139:240-4. https://doi. org/10.1182/blood.2021013239.
11. Duell J, Krummenast F, Schirbel A, Klassen P, Samnick S, Rauert- Wunderlich H, et al. Improved primary staging of marginal-zone lymphoma by addition of CXCR4-directed PET/CT. J Nucl Med. 2021;62:1415-21. https://doi.org/10.2967/jnumed.120.257279.
12. Habringer S, Lapa C, Herhaus P, Schottelius M, Istvanffy R, Steiger K, et al. Dual targeting of acute leukemia and supporting niche by CXCR4-directed theranostics. Theranostics. 2018;8:369- 83. https://doi.org/10.7150/thno.21397.
13. Walenkamp AME, Lapa C, Herrmann K, Wester HJ. CXCR4 ligands: the next big hit? J Nucl Med. 2017;58:77S-82S. https:// doi.org/10.2967/jnumed.116.186874.
14. Buck AK, Stolzenburg A, Hanscheid H, Schirbel A, Luckerath K, Schottelius M, et al. Chemokine receptor - directed imaging and therapy. Methods. 2017;130:63-71. https://doi.org/10.1016/j. ymeth.2017.09.002.
15. Lapa C, Hanscheid H, Kircher M, Schirbel A, Wunderlich G, Werner RA, et al. Feasibility of CXCR4-directed radioligand therapy in advanced diffuse large B-cell lymphoma. J Nucl Med. 2019;60:60-4. https://doi.org/10.2967/jnumed.118.210997.
16. Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385:1091-103. https://doi. org/10.1056/NEJMoa2107322.
17. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376:125-35. https://doi.org/10.1056/ NEJMoa1607427.
18. Kaemmerer D, Trager T, Hoffmeister M, Sipos B, Hommann M, Sanger J, et al. Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy. Oncotarget. 2015;6:27566-79. https://doi.org/10.18632/oncotarget.4491.
19. Werner RA, Weich A, Higuchi T, Schmid JS, Schirbel A, Lass- mann M, et al. Imaging of chemokine receptor 4 expression in neuroendocrine tumors - a triple tracer comparative approach. Theranostics. 2017;7:1489-98. https://doi.org/10.7150/thno. 18754.
20. Panagiotidis E, Alshammari A, Michopoulou S, Skoura E, Naik K, Maragkoudakis E, et al. Comparison of the impact of 68Ga- DOTATATE and 18F-FDG PET/CT on clinical management in patients with neuroendocrine tumors. J Nucl Med. 2017;58:91- 6. https://doi.org/10.2967/jnumed.116.178095.
21. Hayes AR, Furtado O’Mahony L, Quigley AM, Gnanasegaran G, Caplin ME, Navalkissoor S, et al. The combined interpre- tation of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT in metastatic gastroenteropancreatic neuroendocrine tumors: a classification system with prognostic impact. Clin Nucl Med. 2022;47:26-35. https://doi.org/10.1097/RLU.0000000000 003937.
22. Weich A, Werner RA, Buck AK, Hartrampf PE, Serfling SE, Scheurlen M, et al. CXCR4-directed PET/CT in patients with newly diagnosed neuroendocrine carcinomas. Diagnostics (Basel). 2021;11. https://doi.org/10.3390/diagnostics11040605.
23. Maurer S, Herhaus P, Lippenmeyer R, Hanscheid H, Kircher M, Schirbel A, et al. Side effects of CXC-chemokine receptor 4-directed endoradiotherapy with pentixather before hematopoi- etic stem cell transplantation. J Nucl Med. 2019;60:1399-405. https://doi.org/10.2967/jnumed.118.223420.
24. Burger M, Glodek A, Hartmann T, Schmitt-Graff A, Silberstein LE, Fujii N, et al. Functional expression of CXCR4 (CD184) on small-cell lung cancer cells mediates migration, integrin activa- tion, and adhesion to stromal cells. Oncogene. 2003;22:8093-101. https://doi.org/10.1038/sj.onc.1207097.
25. Lapa C, Luckerath K, Rudelius M, Schmid JS, Schoene A, Schir- bel A, et al. [68Ga]Pentixafor-PET/CT for imaging of chemokine receptor 4 expression in small cell lung cancer-initial experi- ence. Oncotarget. 2016;7:9288-95. https://doi.org/10.18632/oncot arget. 7063.
26. Chifu I, Heinze B, Fuss CT, Lang K, Kroiss M, Kircher S, et al. Impact of the chemokine receptors CXCR4 and CXCR7 on clinical outcome in adrenocortical carcinoma. Front Endocrinol (Lausanne). 2020;11: 597878. https://doi.org/10.3389/fendo.2020. 597878.
27. Altieri B, Ronchi CL, Kroiss M, Fassnacht M. Next-generation therapies for adrenocortical carcinoma. Best Pract Res Clin Endo- crinol Metab. 2020;34: 101434. https://doi.org/10.1016/j.beem. 2020.101434.
28. Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, de Kri- jger R, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study
of Adrenal Tumors. Eur J Endocrinol. 2018;179:G1-46. https:// doi.org/10.1530/EJE-18-0608.
29. Bluemel C, Hahner S, Heinze B, Fassnacht M, Kroiss M, Bley TA, et al. Investigating the chemokine receptor 4 as potential theranostic target in adrenocortical cancer patients. Clin Nucl Med. 2017;42:e29-34. https://doi.org/10.1097/RLU.0000000000 001435.
30. Li T, Li H, Wang Y, Harvard C, Tan JL, Au A, et al. The expres- sion of CXCR4, CXCL12 and CXCR7 in malignant pleural mes- othelioma. J Pathol. 2011;223:519-30. https://doi.org/10.1002/ path.2829.
31. Lapa C, Kircher S, Schirbel A, Rosenwald A, Kropf S, Pelzer T, et al. Targeting CXCR4 with [(68)Ga]Pentixafor: a suit- able theranostic approach in pleural mesothelioma? Oncotarget. 2017;8:96732-7. https://doi.org/10.18632/oncotarget.18235.
32. Lewis R, Habringer S, Kircher M, Hefter M, Peuker CA, Werner R, et al. Investigation of spleen CXCR4 expression by [(68)Ga] Pentixafor PET in a cohort of 145 solid cancer patients. EJNMMI Res. 2021;11:77. https://doi.org/10.1186/s13550-021-00822-6.
33. Serfling SE, Lapa C, Dreher N, Hartrampf PE, Rowe SP, Higuchi T, et al. Impact of tumor burden on normal organ distribution in patients imaged with CXCR4-targeted [68Ga]Ga-PentixaFor PET/ CT. Mol Imaging Biol. 2022.
34. Beauregard JM, Hofman MS, Kong G, Hicks RJ. The tumour sink effect on the biodistribution of 68Ga-DOTA-octreotate: implications for peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2012;39:50-6. https://doi.org/10.1007/ s00259-011-1937-3.
35. Sandstrom M, Velikyan I, Garske-Roman U, Sorensen J, Eriksson B, Granberg D, et al. Comparative biodistribution and radiation dosimetry of 68Ga-DOTATOC and 68Ga-DOTATATE in patients with neuroendocrine tumors. J Nucl Med. 2013;54:1755-9. https://doi.org/10.2967/jnumed.113.120600.
36. Philipp-Abbrederis K, Herrmann K, Knop S, Schottelius M, Eiber M, Luckerath K, et al. In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma. EMBO Mol Med. 2015;7:477-87. https://doi.org/10. 15252/emmm.201404698.
37. Pan Q, Cao X, Luo Y, Li J, Feng J, Li F. Chemokine receptor-4 targeted PET/CT with (68)Ga-Pentixafor in assessment of newly diagnosed multiple myeloma: comparison to (18)F-FDG PET/CT. Eur J Nucl Med Mol Imaging. 2020;47:537-46. https://doi.org/ 10.1007/s00259-019-04605-z.
38. Herhaus P, Habringer S, Philipp-Abbrederis K, Vag T, Gerngross C, Schottelius M, et al. Targeted positron emission tomography imaging of CXCR4 expression in patients with acute myeloid leu- kemia. Haematologica. 2016;101:932-40. https://doi.org/10.3324/ haematol.2016.142976.
39. Deutsch AJ, Steinbauer E, Hofmann NA, Strunk D, Gerlza T, Beham-Schmid C, et al. Chemokine receptors in gastric MALT lymphoma: loss of CXCR4 and upregulation of CXCR7 is asso- ciated with progression to diffuse large B-cell lymphoma. Mod Pathol. 2013;26:182-94. https://doi.org/10.1038/modpathol.2012. 134.
40. Mayerhoefer ME, Raderer M, Lamm W, Pichler V, Pfaff S, Weber M, et al. CXCR4 PET imaging of mantle cell lymphoma using [(68)Ga]Pentixafor: comparison with [(18)F]FDG-PET. Thera- nostics. 2021;11:567-78. https://doi.org/10.7150/thno.48620.
41. Kraus S, Dierks A, Rasche L, Kertels O, Kircher M, Schirbel A, et al. (68)Ga-Pentixafor PET/CT for detection of chemokine receptor CXCR4 expression in myeloproliferative neoplasms. J Nucl Med. 2022;63:96-9. https://doi.org/10.2967/jnumed.121. 262206.
42. Luo Y, Cao X, Pan Q, Li J, Feng J, Li F. (68)Ga-Pentixafor PET/ CT for imaging of chemokine receptor 4 expression in Wal- denstrom macroglobulinemia/lymphoplasmacytic lymphoma:
comparison to (18)F-FDG PET/CT. J Nucl Med. 2019;60:1724-9. https://doi.org/10.2967/jnumed.119.226134.
43. Buck AK, Haug A, Dreher N, Lambertini A, Higuchi T, Lapa C, et al. Imaging of C-X-C motif chemokine receptor 4 expression in 690 patients with solid or hematologic neoplasms using (68) Ga-PentixaFor PET. J Nucl Med. 2022. https://doi.org/10.2967/ jnumed. 121.263693.
44. Keller T, Lopez-Picon FR, Krzyczmonik A, Forsback S, Takkinen JS, Rajander J, et al. Comparison of high and low molar activity TSPO tracer [(18)F]F-DPA in a mouse model of Alzheimer’s dis- ease. J Cereb Blood Flow Metab. 2020;40:1012-20. https://doi. org/10.1177/0271678X19853117.
45. Schottelius M, Osl T, Poschenrieder A, Hoffmann F, Beykan S, Hanscheid H, et al. [(177)Lu]pentixather: comprehensive preclini- cal characterization of a first CXCR4-directed endoradiotherapeu- tic agent. Theranostics. 2017;7:2350-62. https://doi.org/10.7150/ thno.19119.
46. Hanscheid H, Schirbel A, Hartrampf P, Kraus S, Werner RA, Einsele H, et al. Biokinetics and dosimetry of [(177)Lu]Lu- Pentixather. J Nucl Med. 2021. https://doi.org/10.2967/jnumed. 121.262295.
47. Hanscheid H, Lapa C, Buck AK, Lassmann M, Werner RA. Dose mapping after endoradiotherapy with (177)Lu-DOTA- TATE/DOTATOC by a single measurement after 4 days. J Nucl Med. 2018;59:75-81. https://doi.org/10.2967/jnumed. 117.193706.
48. 3. Herrmann K, Schottelius M, Lapa C, Osl T, Poschenrieder A, Hanscheid H, et al. First-in-human experience of CXCR4-directed endoradiotherapy with 177Lu- and 90Y-labeled pentixather in advanced-stage multiple myeloma with extensive intra- and extramedullary disease. J Nucl Med. 2016;57:248-51. https://doi. org/10.2967/jnumed.115.167361.
49. Lapa C, Herrmann K, Schirbel A, Hanscheid H, Luckerath K, Schottelius M, et al. CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed multiple myeloma. Theranostics. 2017;7:1589-97. https://doi.org/10.7150/thno. 19050.
50. Sarno J. Prevention and management of tumor lysis syndrome in adults with malignancy. J Adv Pract Oncol. 2013;4:101-6.
51. Fassnacht M, Assie G, Baudin E, Eisenhofer G, de la Fouchar- diere C, Haak HR, et al. Adrenocortical carcinomas and malig- nant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31:1476-90. https://doi.org/10.1016/j.annonc.2020.08.2099.
52. Werner RA, Schirbel A, Buck AK, Fassnacht M, Hahner S. Adre- nal functional imaging. Presse Med. 2022;51: 104114. https://doi. org/10.1016/j.lpm.2022.104114.
53. Cancilla D, Rettig MP, DiPersio JF. Targeting CXCR4 in AML and ALL. Front Oncol. 2020;10:1672. https://doi.org/10.3389/ fonc.2020.01672.
54. Crazzolara R, Kreczy A, Mann G, Heitger A, Eibl G, Fink FM, et al. High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia. Br J Haematol. 2001;115:545-53. https://doi.org/10. 1046/j.1365-2141.2001.03164.x.
55. Ko SY, Park CJ, Park SH, Cho YU, Jang S, Seo EJ, et al. High CXCR4 and low VLA-4 expression predicts poor survival in adults with acute lymphoblastic leukemia. Leuk Res. 2014;38:65- 70. https://doi.org/10.1016/j.leukres.2013.10.016.
56. Sison EA, McIntyre E, Magoon D, Brown P. Dynamic chemo- therapy-induced upregulation of CXCR4 expression: a mecha- nism of therapeutic resistance in pediatric AML. Mol Cancer Res. 2013;11:1004-16. https://doi.org/10.1158/1541-7786. MCR-13-0114.
57. Heckmann MB, Reinhardt F, Finke D, Katus HA, Haberkorn U, Leuschner F, et al. Relationship between cardiac fibroblast
activation protein activity by positron emission tomography and cardiovascular disease. Circ Cardiovasc Imaging. 2020;13: e010628. https://doi.org/10.1161/CIRCIMAGING.120.010628.
58. Werner RA, Koenig T, Diekmann J, Haghikia A, Derlin T, Thack- eray JT, et al. CXCR4-targeted imaging of post-infarct myocardial tissue inflammation: prognostic value after reperfused myocardial infarction. JACC Cardiovasc Imaging. 2022;15:372-4. https://doi. org/10.1016/j.jcmg.2021.08.013.
59. Hess A, Derlin T, Koenig T, Diekmann J, Wittneben A, Wang Y, et al. Molecular imaging-guided repair after acute myocardial infarction by targeting the chemokine receptor CXCR4. Eur Heart J. 2020;41:3564-75. https://doi.org/10.1093/eurheartj/ehaa598.
60. Reiter T, Kircher M, Schirbel A, Werner RA, Kropf S, Ertl G, et al. Imaging of C-X-C motif chemokine receptor CXCR4 expres- sion after myocardial infarction with [(68)Ga]Pentixafor-PET/ CT in correlation with cardiac MRI. JACC Cardiovasc Imaging. 2018;11:1541-3. https://doi.org/10.1016/j.jcmg.2018.01.001.
61. Werner RA, Thackeray JT, Diekmann J, Weiberg D, Bauersachs J, Bengel FM. The changing face of nuclear cardiology: guid- ing cardiovascular care toward molecular medicine. J Nucl Med. 2020;61:951-61. https://doi.org/10.2967/jnumed.119.240440.
62. Calabretta R, Hoeller C, Pichler V, Mitterhauser M, Kara- nikas G, Haug A, et al. Immune checkpoint inhibitor therapy induces inflammatory activity in large arteries. Circulation.
2020;142:2396-8. https://doi.org/10.1161/CIRCULATIONAHA. 120.048708.
63. Escudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J, et al. Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation. 2017;136:2085-7. https://doi.org/10.1161/CIRCULATIONAHA. 117.030571.
64. Kircher M, Tran-Gia J, Kemmer L, Zhang X, Schirbel A, Werner RA, et al. Imaging inflammation in atherosclerosis with CXCR4- directed (68)Ga-Pentixafor PET/CT: correlation with (18)F-FDG PET/CT. J Nucl Med. 2020;61:751-6. https://doi.org/10.2967/ jnumed. 119.234484.
65. Kuhne MR, Mulvey T, Belanger B, Chen S, Pan C, Chong C, et al. BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies. Clin Cancer Res. 2013;19:357-66. https://doi.org/10.1158/1078-0432.CCR-12-2333.
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.