Data from Targeting Refractory Mantle Cell Lymphoma for Imaging and Therapy Using C-X-C Chemokine Receptor Type 4 Radioligands

Abstract

<div>AbstractPurpose:<p>Mantle cell lymphoma (MCL) is associated with poor survival. The purpose of this study was to assess whether the C-X-C chemokine receptor type 4 (CXCR4) is a useful target for imaging and radioligand therapy of MCL, using a novel pair of radioligands, [<sup>68</sup>Ga]Ga and [<sup>177</sup>Lu]Lu-BL02.</p>Experimental Design:<p>We performed a retrospective analysis of 146 patients with MCL to evaluate CXCR4 expression and its correlation with outcomes. Guided by <i>in silico</i> methods, we designed BL02, a new radioligand labelled with <sup>68</sup>Ga or <sup>177</sup>Lu for PET imaging and therapy, respectively. We performed imaging and biodistribution studies in xenograft models with varying CXCR4 expression. We evaluated [<sup>177</sup>Lu]Lu-BL02 in MCL models, and evaluated its potential for therapy in Z138 MCL xenografts.</p>Results:<p>Phosphorylated and nonphosphorylated CXCR4 expression were correlated with poor survival in patients with MCL and characterized by unique underlying molecular signatures. [<sup>68</sup>Ga]Ga-BL02 uptake correlated with CXCR4 expression, and localized lesions in a metastatic xenograft model. [<sup>177</sup>Lu]Lu-BL02 showed high uptake in MCL xenografts. Therapy studies with a single dose in the Z138 model showed tumor regression and improved survival compared with a control group. Upon regrowth, the treated mice experienced concurrent metastasis alongside localized xenograft regrowth, and recurrent lesions showed enhanced CXCR4 signaling.</p>Conclusions:<p>CXCR4 is an independent factor of poor prognosis for MCL and a promising target for imaging and radioligand therapy. [<sup>68</sup>Ga]Ga-BL02 showed high contrast to visualize CXCR4-expressing xenografts for PET imaging and [<sup>177</sup>Lu]Lu-BL02 induced rapid tumor regression in a preclinical model of MCL.</p></div>