Immune checkpoints (CTLA-4, PD-1, PD-L1, LAG3) have revolutionized oncology, enabling durable remissions in advanced cancer.
Mechanisms of action:
- CTLA-4 (Ipilimumab): Tumor-specific Treg depletion mediated by FcγR.
- PD-1/PD-L1: Pure receptor blockade, though some antibodies (e.g., Avelumab) retain Fc functions (ADCC).
- LAG3 (Relatlimab): Combination with Nivolumab improves PFS in metastatic melanoma.
Efficacy vs. Toxicity:
- Direct dose-toxicity relationship for anti-CTLA-4.
- Fixed, spaced doses (e.g., 480 mg Q4W for Nivolumab) improve quality of life.
Hyperprogression: Seen in up to 20% of patients, linked to FcγRIIb in immunosuppressive macrophages.
Innovation: Fc-enhanced antibodies (e.g., botensilimab) show greater efficacy and Treg depletion in solid tumors.
Takeaway: Fc affinity and genetic polymorphisms shape clinical outcomes. New frontiers in immunological precision!”