Leronlimab and Immune Checkpoint Inhibitor (ICI) Synergy: An Overview
Background
- Leronlimab (PRO 140): A humanized monoclonal antibody targeting CCR5, a chemokine receptor involved in tumor metastasis, immune cell trafficking, and HIV entry into cells.
- Immune Checkpoint Inhibitors (ICIs): Drugs like anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies that restore T-cell activity by removing inhibitory signals in the tumor microenvironment (TME).
Potential Synergy Mechanisms
1. Modulation of Tumor Microenvironment (TME)
- CCR5 is upregulated on Tregs, MDSCs, and TAMs—key immunosuppressive cells.
- Leronlimab blocks CCR5, reducing these cells in the TME.
- This "unmasks" tumors and allows ICIs to work more effectively by shifting the TME from immunosuppressive to immunostimulatory.
2. Enhanced T-Cell Trafficking and Activation
- ICIs activate exhausted T cells, but infiltration into tumors is often limited.
- CCR5 blockade may enhance trafficking of effector T cells into tumors, improving ICI efficacy.
3. Reduction in Metastatic Spread
- CCR5 signaling is implicated in tumor cell migration and metastasis.
- Leronlimab could reduce metastatic burden, giving ICIs a more favorable context to operate.
4. PD-L1 Expression and CCR5 Crosstalk
- Some preclinical studies suggest CCR5+ macrophages and T cells promote PD-L1 expression in tumors.
- Targeting CCR5 may downregulate PD-L1, enhancing the response to anti-PD-1/PD-L1 therapies.
Preclinical & Clinical Evidence (as of mid-2024)
- Preclinical models (e.g., breast cancer, prostate cancer, melanoma) showed enhanced tumor regression when CCR5 inhibitors were combined with ICIs.
- Leronlimab clinical trials (monotherapy and in combination, e.g., with chemotherapy) are ongoing or completed in HIV, metastatic triple-negative breast cancer (mTNBC), and COVID-19. Limited published data on ICI combinations.
- A notable preclinical study from 2020 demonstrated that CCR5 knockout or inhibition improved anti-PD-1 efficacy in murine tumor models.
Challenges and Considerations
- Patient selection: Synergy may depend on CCR5 expression in tumors and immune cells.
- Timing and sequencing: The best order of administration (simultaneous vs. sequential) isn't established.
- Toxicity: Combination therapy may increase immune-related adverse events (irAEs).
Conclusion
There is strong theoretical and preclinical rationale for combining Leronlimab with ICIs, particularly in tumors with immunosuppressive microenvironments where CCR5+ cells dominate. However, clinical validation is lacking as of now, and more combination trials are needed to assess safety, efficacy, and patient stratification biomarkers.