No abstract

C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM).Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival.ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive.CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted.

Given its prominent role in inflammation and cancer biology, the C-X-C motif chemokine receptor 4 (CXCR4) has gained a lot of attention in the recent years. This review gives a short overview of the physiology and pathology of chemokines and chemokine receptors and then focuses on the current experience of targeting CXCR4, using radiolabeled receptor ligands suitable for positron emission tomography (PET) imaging, in both hematologic and solid malignancy as well as in inflammatory conditions. Additionally, CXCR4-directed endoradiotherapy (ERT) as a new treatment option is discussed.

We have recently reported on our experience with C-X-C-motif chemokine receptor 4- (CXCR4-) directed radioligand therapy (RLT) in multiple myeloma and acute leukemia. Six patients with heavily pre-treated relapsed diffuse large B cell lymphoma (DLBCL) (3 males, 3 females; aged, 54±8 years) underwent CXCR4-directed RLT in combination with conditioning chemotherapy and allogeneic stem cell transplantation (SCT). In 2 patients, radioimmunotherapy (RIT) targeting CD20 or CD66 was added to enhance anti-lymphoma activity. Endpoints were incidence and severity of adverse events, progression-free and overall survival. RLT as well as additional RIT were well-tolerated without any acute adverse events or changes in vital signs. Successful engraftment was recorded after a median of 11 days (range, 9-13 d). In the 4 patients who were available for follow-up (one patient died of CNS aspergillosis 29 days, another of sepsis in aplasia 34 days after after RLT), CXCR4-directed RLT resulted in partial response in 2/4 cases (both treated with additional RIT) and mixed response in the remaining 2 subjects. Response duration was rather short-lived with median progression-free survival of 62 days (range, 29-110 d) and median overall survival of 76 days (range, 29-313 d). CXCR4-directed RLT (in combination with additional RIT) as a conditioning regimen prior to allogeneic SCT in DLBCL is feasible.

Purpose While [18F]-fluorodeoxyglucose ([18F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT. Methods Ten consecutive, treatment-naïve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [18F]FDG and [68Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUVmax) and peak (SUVpeak) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference. Results [18F]FDG and FAP-directed PET/CT detected all primary tumors with a SUVmax of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUVpeak of 16.1 ± 10.3 ([18F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3% vs. 87.5%; P = 0.32) and specificity (93.3% vs. 81.3%; P = 0.16) to [18F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples. Conclusion FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted.