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

PURPOSE 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 4CXCR4) is a useful target for imaging and radioligand therapy of MCL, using a novel pair of radioligands, [68Ga]Ga and [177Lu]Lu-BL02. EXPERIMENTAL DESIGN We performed a retrospective analysis of 146 MCL patients to evaluate CXCR4 expression and its correlation with outcomes. Guided by in silico methods, we designed BL02, a new radioligand labelled with 68Ga or 177Lu for positron emission tomography (PET) imaging and therapy, respectively. We performed imaging and biodistribution studies in xenograft models with varying CXCR4 expression. We evaluated [177Lu]Lu-BL02 in MCL models, and evaluated its potential for therapy in Z138 MCL xenografts. RESULTS Phosphorylated and non-phosphorylated CXCR4 expression were correlated with poor survival in MCL patients and characterized by unique underlying molecular signatures. [68Ga]Ga-BL02 uptake correlated with CXCR4 expression, and localized lesions in a metastatic xenograft model. [177Lu]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 to a control group. Upon regrowth, the treated mice experienced concurrent metastasis alongside localized xenograft regrowth, and recurrent lesions showed enhanced CXCR4 signaling. CONCLUSIONS CXCR4 is an independent factor of poor prognosis for MCL and a promising target for imaging and radioligand therapy. [68Ga]Ga-BL02 showed high contrast to visualize CXCR4-expressing xenografts for PET imaging and [177Lu]Lu-BL02 induced rapid tumor regression in a preclinical model of MCL.

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