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Habringer, S.* ; Lapa, C.* ; Herhaus, P.* ; Schottelius, M.* ; Istvanffy, R.* ; Steiger, K.* ; Slotta-Huspenina, J.* ; Schirbel, A.* ; Hänscheid, H.* ; Kircher, S.* ; Buck, A.K.* ; Götze, K.* ; Vick, B. ; Jeremias, I. ; Schwaiger, M.* ; Peschel, C.* ; Oostendorp, R.* ; Wester, H.J.* ; Grigoleit, G.U.* ; Keller, U.*

Dual targeting of acute leukemia and supporting niche by CXCR4-directed theranostics.

Theranostics 8, 369-383 (2018)
Publ. Version/Full Text DOI PMC
Open Access Gold
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C-X-C chemokine receptor 4 (CXCR4) is a transmembrane receptor with pivotal roles in cell homing and hematopoiesis. CXCR4 is also involved in survival, proliferation and dissemination of cancer, including acute lymphoblastic and myeloid leukemia (ALL, AML). Relapsed/refractory ALL and AML are frequently resistant to conventional therapy and novel highly active strategies are urgently needed to overcome resistance. Methods: We used patient-derived (PDX) and cell line-based xenograft mouse models of ALL and AML to evaluate the efficacy and toxicity of a CXCR4-targeted endoradiotherapy (ERT) theranostic approach. Results: The positron emission tomography (PET) tracer 68 Ga-Pentixafor enabled visualization of CXCR4 positive leukemic burden. In xenografts, CXCR4-directed ERT with 177 Lu-Pentixather distributed to leukemia harboring organs and resulted in efficient reduction of leukemia. Despite a substantial in vivo cross-fire effect to the leukemia microenvironment, mesenchymal stem cells (MSCs) subjected to ERT were viable and capable of supporting the growth and differentiation of non-targeted normal hematopoietic cells ex vivo. Finally, three patients with refractory AML after first allogeneic hematopoietic stem cell transplantation (alloSCT) underwent CXCR4-directed ERT resulting in leukemia clearance, second alloSCT, and successful hematopoietic engraftment. Conclusion: Targeting CXCR4 with ERT is feasible and provides a highly efficient means to reduce refractory acute leukemia for subsequent cellular therapies. Prospective clinical trials testing the incorporation of CXCR4 targeting into conditioning regimens for alloSCT are highly warranted.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Leukemia ; C-x-c Chemokine Receptor 4 ; In Vivo Molecular Imaging ; Microenvironment ; Theranostics; Acute Lymphoblastic-leukemia; Acute Myeloid-leukemia; Stem-cell Transplantation; Bone-marrow; Multiple-myeloma; Neuroendocrine Tumors; Conditioning Regimen; Kinase Inhibitors; Cxcr4 Expression; In-vitro
Language english
Publication Year 2018
HGF-reported in Year 2018
e-ISSN 1838-7640
Journal Theranostics
Quellenangaben Volume: 8, Issue: 2, Pages: 369-383 Article Number: , Supplement: ,
Publisher Ivyspring
Publishing Place Lake Haven
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Stem Cell and Neuroscience
PSP Element(s) G-506600-001
DOI 10.7150/thno.21397
WOS ID WOS:000417098700006
Scopus ID 85035081863
PubMed ID 29290814
Erfassungsdatum 2018-01-23
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