Chemokine receptor - Directed imaging and therapy

Abstract

The C-X-C chemokine receptor 4 (CXCR4) and its natural ligand CXCL12 are key factors in the process of cell migration, homing of hematopoietic stem cells to the bone marrow, and represent important mediators of angiogenesis and cell proliferation. The CXCR4/CXCL12 interplay can be disrupted by CXCR4 antagonists such as Plerixafor which are already in daily clinical use, i.e. for mobilization and subsequent harvesting of hematopoietic progenitor cells and stem cell transplantation. In a pathological condition, involvement in the process of metastasis and homing of cancer cells to a protective niche has been described, making CXCR4 an attractive target for imaging and treatment of malignant diseases. Recently, radiolabeled analogs of CXCR4 antagonists (e.g., [⁶⁸Ga]Pentixafor) have been introduced which can be used for non-invasive imaging of CXCR4 expression in animal models and humans using positron emission tomography. In addition, beta emitter-labeled antagonists (i.e., [¹⁷⁷Lu]/[⁹⁰Y]Pentixather) have been used in small patient cohorts for treatment of hematological neoplasms such as lymphoma, multiple myeloma and acute myeloid leukemia. This review reports on current imaging protocols for CXCR4-directed positron emission tomography in preclinical models and in humans. Furthermore, a theranostic approach using beta emitter-labeled antagonists is highlighted. Molecular imaging of the CXCR4/CXCL12 axis can contribute to further understand the process of metastatic spread and the intra-/interindividual heterogeneity of tumors. In addition, CXCR4 directed imaging allows tracking of activated, CXCR4⁺ immune cells. This allows for watching inflammatory processes, thus contributing to enlighten the role of the immune system in a variety of cardiovascular and neurological diseases.

Keywords: Acute myeloid leukemia; C-X-C chemokine receptors; Lymphoma; Microenvironment; Multiple myeloma; Positron emission tomography; Theranostics.