Abstract
Introduction:
The G-protein coupled CXC-motif Chemokine Receptor 4 (CXCR4) and its ligand CXCL12 are master regulators of cell migration, organogenesis and maintenance of the hematopoietic stem/progenitor cell (HSPC) niche. However, CXCR4 also drives survival, proliferation and metastasis of cancer cells and its expression is associated with adverse prognosis in a broad range of malignancies, including acute myeloid and lymphoblastic leukemia (AML, ALL). Despite of high rates of complete remissions after induction chemotherapy, AML, and to a lesser extend ALL, frequently relapse with a more aggressive phenotype and require highly active therapies to reduce leukemic burden before allogeneic stem cell transplantation (alloSCT). We recently showed that CXCR4-directed PET imaging with 68Ga-Pentixafor is feasible in AML patients, providing first evidence for the potential of CXCR4-directed theranostics (Herhaus, Habringer et al., Haematologica 2016).
Methods:
We used patient-derived xenograft (PDX) and cell line xenograft mouse models of AML and ALL to evaluate the efficacy and toxicity of a CXCR4-targeted peptide receptor radiotherapy (PRRT) theranostic approach with the CXCR4-binding PET tracer 68Ga-Pentixafor and its b-emitting therapeutic counterpart 177Lu-Pentixather. We analyzed bone marrow (BM), spleen, blood (PB) and liver of treated PDX mice by flow cytometry, immunohistochemistry and radioactive biodistribution assays. The toxicity to the murine BM HSPC and the hematopoietic niche was assessed via flow cytometry, colony forming unit assays, isolation and differentiation of BM mesenchymal stem cells (MSCs) and co-culture experiments. We provide first evidence for this highly innovative CXCR4-directed theranostic approach in patients with AML who relapsed after alloSCT and had no other established treatment options.
Results:
We generated PDX models of acute leukemia patients in NSG mice that required intact CXCR4 signaling for disease initiation and progressively infiltrated spleen, BM and PB. 68Ga-Pentixafor PET imaging enabled visualization of CXCR4-positive leukemic burden in spleen and BM of acute leukemia PDX and cell line xenografts. In ALL PDX, CXCR4-directed PRRT with 177Lu-Pentixather rapidly distributed to leukemia-harboring organs, which lead to significant accumulation of radioactivity in spleen and BM. 177Lu-Pentixather therapy resulted in efficient eradication or significant reduction of leukemic infiltration in PB, spleen and BM. Spleen size was reduced dramatically as early as 24hr after initiation of PRRT. Treated mice suffered severe suppression of BM function as evidenced by therapy-induced severe cytopenia affecting mature CD45+ blood cells and colony-forming unit potential of progenitors in the BM. To assess the damage to the BM niche, we isolated MSCs of 177Lu-Pentixather treated mice compared to control. We found that MSCs from 177Lu-Pentixather-treated mice were still viable and proliferated in vitro. Importantly, treated MSCs were still capable of supporting normal lineage-marker negative murine HSPC and induced their differentiation into mature leukocytes in co-culture. Finally, we treated patients with refractory AML after alloSCT and multiple failed treatment regimens, who had no further established treatment options with CXCR4 PRRT followed by a conventional conditioning regimen and second alloSCT. Our data indicate that CXCR4 targeting and the inevitable and desired cross-fire effect of 177Lu-Pentixather PRRT could be a highly efficient means to eradicate leukemia and to induce myeloablation. This approach could serve as a valuable addition to conditioning protocols in alloSCT.
Conclusion:
In conclusion, our work provides first evidence for the efficacy of the novel CXCR4-directed agent 177Lu-Pentixather in acute leukemia PDX models and in a proof-of-concept individual treatment approach in one patient relapsed after standard alloSCT. Importantly, these findings can directly be translated into clinical studies in patients and provide crucial information regarding efficacy and toxicity. A phase I/II study to integrate CXCR-directed PRRT into conditioning regimens is planned.
Disclosures
Peschel: MophoSys: Honoraria. Wester:Scintomics GmbH: Employment, Other: CEO.
Rotation osteotomy of the distal femur influences coronal femoral alignment and the ischiofemoral space
