Selzentry (maraviroc)

Our findings identify the CCL5/CCR5 axis as a key mediator of tumor-stromal crosstalk driving cisplatin resistance in NEPC. Mechanistically, CAF-derived CCL5 activates AKT signaling in tumor cells by promoting the formation of the CCR5/β-arrestin1/p85 complex. Targeting this pathway with maraviroc in combination with cisplatin offers a promising therapeutic strategy for overcoming drug resistance in NEPC.

Translational techniques employing CCR5 antagonists such as Maraviroc, GAG-binding modulators, glycoengineered CCL5 variants, delivery systems, and their integration with immune checkpoint inhibitors (ICIs) and targeted therapies are highlighted for their considerable therapeutic promise. Critical research priorities, encompassing single-cell phenotyping, CRISPR-mediated screening of chemokine pathways, and structural-functional mapping, are outlined to facilitate precise modulation of the CCL5/CCR5 axis in targeted cancer therapy. This review addresses structural biology and tumor immunology to identify the CCL5/CCR5 axis as a multifaceted yet promising biological target for innovative cancer therapeutics.

Therapeutic targeting of CCL4-CCR5 signaling with maraviroc, an FDA-approved antiviral drug, significantly reduced brain metastasis progression without exerting direct cytotoxic effects on tumor cells. These findings highlight a promising therapeutic strategy that focuses on modulating glial communication within the tumor microenvironment. By disrupting the supportive glial niche rather than targeting tumor cells directly, this represents a distinct and potentially less toxic approach for managing brain metastases.

P2, N=70, Not yet recruiting, Federal University of São Paulo | Phase classification: P=N/A --> P2

With therapeutic inhibition of CCR5 gaining attention, Maraviroc is approved for HIV treatment, while monoclonal antibodies such as leronlimab, genetic strategies (CRISPR), and dual CCR2/CCR5 antagonists such as cenicriviroc are under investigation for broader applications. Blocking CCR5 has shown efficacy in reducing metastasis and improving chemotherapy outcomes, reinforcing its therapeutic potential. Along with CCR5's role in disease pathogenesis, emphasizing its involvement in immune regulation and inflammatory processes, this review explores the multifaceted role of CCR5 in immunity, its contribution to disease pathogenesis, and innovative therapeutic interventions targeting CCR5 to modulate immune responses and treat diseases.

Finally, CCR5 blockade with the FDA-approved inhibitor Maraviroc during neoantigen vaccination improved tumor control by preventing the migration of immunosuppressive, antigen-presenting recMacs (moDCs). These findings support the development of macrophage-targeted therapies by identifying pro-tumorigenic subsets and recMac trafficking as actionable targets, while preserving macrophage populations that sustain anti-tumor immunity.

Antagonizing chemokine receptor 5 (CCR5) using a European Medicines Agency-approved drug, maraviroc, reduced immune cell infiltration, alleviated demyelination, and attenuated EAE progression. We found an OPC-orchestrated immune cellular network that instigates early demyelination, provides insight into MS pathophysiology, and suggests avenues for early interventions.

P2, N=120, Not yet recruiting, University of California, San Francisco

MVC reduced macrophage polarization and enhanced Bortezomib sensitivity in MM cells.

Although only the CCR5 antagonist maraviroc is US Food and Drug Administration-approved (for HIV), we curated data on CCR3, CCR4, and CCR5 antagonists from ChEMBL to develop and validate machine learning models. Using these models, we identified lapatinib as a potent inhibitor of CCR3, CCR4, and CCR5. Our study illustrates the potential of machine learning in identifying molecules for repurposing as antagonists for G protein-coupled receptors, including CCR3, CCR4, and CCR5, which have various therapeutic applications.

P2, N=90, Recruiting, Icahn School of Medicine at Mount Sinai | Not yet recruiting --> Recruiting

Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.