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Dual targeting of acute leukemia and supporting niche by CXCR4-directed theranostics.
Theranostics 8, 369-383 (2018)
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
e-ISSN
1838-7640
Journal
Theranostics
Quellenangaben
Volume: 8,
Issue: 2,
Pages: 369-383
Publisher
Ivyspring
Publishing Place
Lake Haven
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)