Immune Checkpoint Inhibitors
Immune checkpoint inhibitors release T-cell suppression by blocking PD-1, PD-L1, or CTLA-4, unleashing durable antitumor immunity.
## Overview
Cancer cells exploit immune checkpoint pathways to evade immune destruction. Checkpoint inhibitors are monoclonal antibodies that block inhibitory signals on T cells, restoring antitumor immunity. They have transformed outcomes in melanoma, NSCLC, bladder, renal, and many other cancers, producing durable responses in a subset of patients.
## CTLA-4 Pathway
CTLA-4 (cytotoxic T-lymphocyte antigen 4) competes with CD28 for CD80/CD86 ligands on antigen-presenting cells. CTLA-4 engagement dampens T-cell activation in lymph nodes. **Ipilimumab** blocks CTLA-4, enhancing T-cell priming. It was first approved for unresectable melanoma (2011) and improved long-term survival. High-dose ipilimumab (3 mg/kg) is more toxic than lower doses; combination with nivolumab increases both efficacy and immune-related adverse events.
## PD-1/PD-L1 Pathway
PD-1 (programmed death 1) on T cells binds PD-L1/PD-L2 on tumor cells and APCs, inhibiting T-cell effector function in peripheral tissues. Tumor PD-L1 expression represents an adaptive immune resistance mechanism.
**Anti-PD-1**: Pembrolizumab and nivolumab are approved across many tumor types including melanoma, NSCLC, MSI-H tumors (tumor-agnostic), Hodgkin lymphoma, urothelial, head/neck, gastric cancers.
**Anti-PD-L1**: Atezolizumab, durvalumab, and avelumab. Slightly different efficacy and toxicity profiles; atezolizumab preserves PD-L2 signaling on lung tissue, potentially reducing pneumonitis.
## Biomarkers of Response
- **PD-L1 expression (TPS/CPS)**: Predictive in NSCLC, head/neck, gastric cancers; not universally predictive
- **TMB (tumor mutational burden)**: High TMB tumors have more neoantigens; pembrolizumab is approved for TMB-high tumors (≥10 mut/Mb)
- **MSI-H/dMMR**: Strong predictor; pembrolizumab approved for all MSI-H solid tumors (tumor-agnostic)
## Immune-Related Adverse Events (irAEs)
irAEs result from immune activation in normal tissues: colitis, pneumonitis, hepatitis, endocrinopathies (thyroiditis, adrenal insufficiency, diabetes), dermatitis. Management involves withholding checkpoint inhibitor and administering corticosteroids (prednisone 1-2 mg/kg for grade 3-4). Endocrinopathies often require permanent hormone replacement.
## Key Takeaways
- CTLA-4 inhibitors enhance T-cell priming; PD-1/PD-L1 inhibitors restore effector function in tumors
- MSI-H/dMMR is a strong, tumor-agnostic predictor of checkpoint inhibitor benefit
- irAEs are immune-mediated; managed with immunosuppression (corticosteroids, infliximab for refractory colitis)
- Combination ipilimumab + nivolumab increases efficacy and irAE frequency in melanoma and NSCLC