Targeting Refractory Mantle Cell Lymphoma for Imaging and Therapy Using C-X-C Chemokine Receptor Type 4 Radioligands
Daniel Kwon1, Katsuyoshi Takata2,3, Zhengxing Zhang1
1Molecular Oncology, British Columbia Cancer, Vancouver, British Columbia, Canada.
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 4 (CXCR4) 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 patients with MCL 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 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 nonphosphorylated CXCR4 expression were correlated with poor survival in patients with MCL 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 with 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.
Insights
C-X-C chemokine receptor type 4 (CXCR4) is a poor prognostic factor in mantle cell lymphoma (MCL). Novel radioligands [68Ga]Ga-BL02 and [177Lu]Lu-BL02 show promise for CXCR4-targeted PET imaging and radioligand therapy in MCL.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with poor patient survival rates.
- C-X-C chemokine receptor type 4 (CXCR4) expression is implicated in MCL pathogenesis and patient outcomes.
- Effective imaging and therapeutic strategies targeting CXCR4 are needed for MCL management.
Purpose of the Study:
- To evaluate C-X-C chemokine receptor type 4 (CXCR4) as a therapeutic and imaging target in mantle cell lymphoma (MCL).
- To assess the utility of novel radioligands, [68Ga]Ga-BL02 for PET imaging and [177Lu]Lu-BL02 for radioligand therapy, in MCL models.
Main Methods:
- Retrospective analysis of 146 MCL patients to correlate CXCR4 expression with outcomes.
- Development and in vitro/in vivo evaluation of BL02 radioligands ([68Ga]Ga-BL02 and [177Lu]Lu-BL02).
- Imaging, biodistribution, and therapeutic efficacy studies in MCL xenograft models.
Main Results:
- CXCR4 expression, both phosphorylated and nonphosphorylated, correlated with poor survival in MCL patients.
- [68Ga]Ga-BL02 demonstrated high contrast uptake in CXCR4-expressing xenografts, enabling lesion visualization.
- [177Lu]Lu-BL02 showed significant tumor regression and improved survival in preclinical MCL models, with enhanced CXCR4 signaling upon recurrence.
Conclusions:
- CXCR4 is an independent prognostic factor in MCL, representing a promising target for imaging and therapy.
- [68Ga]Ga-BL02 is effective for PET imaging of CXCR4-expressing MCL xenografts.
- [177Lu]Lu-BL02 demonstrated potent therapeutic effects in a preclinical MCL model, warranting further investigation.
