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Theranostics 2018; 8(2):369-383. doi:10.7150/thno.21397

Research Paper

Dual Targeting of Acute Leukemia and Supporting Niche by CXCR4-Directed Theranostics

Stefan Habringer^1,2#, Constantin Lapa^3#, Peter Herhaus¹, Margret Schottelius⁴, Rouzanna Istvanffy¹, Katja Steiger⁵, Julia Slotta-Huspenina⁵, Andreas Schirbel³, Heribert Hänscheid³, Stefan Kircher⁷, Andreas K. Buck³, Katharina Götze^1,2, Binje Vick^2,6, Irmela Jeremias^2,6, Markus Schwaiger^2,8, Christian Peschel^1,2, Robert Oostendorp¹, Hans-Jürgen Wester⁴, Götz-Ulrich Grigoleit^9*, Ulrich Keller^1,2*✉

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.

Abstract

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