Theranostics 2018; 8(2):369-383. doi:10.7150/thno.21397
Dual Targeting of Acute Leukemia and Supporting Niche by CXCR4-Directed Theranostics
1. Internal Medicine III, Hematology and Medical Oncology, Technische Universität München, Munich, Germany;
2. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany;
3. Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany;
4. Institute of Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany;
5. Institute of Pathology, Technische Universität München, Munich, Germany;
6. Research Unit Gene Vectors, Helmholtz Center Munich, Germany;
7. Institute for Pathology, University of Würzburg, Würzburg, Germany;
8. Department of Nuclear Medicine, Technische Universität München, Munich, Germany;
9. Department of Internal Medicine II, Hematology and Medical Oncology, University Hospital Würzburg, Würzburg, Germany.
# These authors contributed equally.
* These authors contributed equally.
Habringer S, Lapa C, Herhaus P, Schottelius M, Istvanffy R, Steiger K, Slotta-Huspenina J, Schirbel A, Hänscheid H, Kircher S, Buck AK, Götze K, Vick B, Jeremias I, Schwaiger M, Peschel C, Oostendorp R, Wester HJ, Grigoleit GU, Keller U. Dual Targeting of Acute Leukemia and Supporting Niche by CXCR4-Directed Theranostics. Theranostics 2018; 8(2):369-383. doi:10.7150/thno.21397. Available from http://www.thno.org/v08p0369.htm
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 68Ga-Pentixafor enabled visualization of CXCR4 positive leukemic burden. In xenografts, CXCR4-directed ERT with 177Lu-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.
Keywords: acute leukemia, microenvironment, C-X-C chemokine receptor 4, in vivo molecular imaging, theranostics