How do checkpoint inhibitors (CTLA‑4 (cytotoxic T‑lymphocyte‑associated protein 4) and PD‑1 (programmed death‑1 receptor)/PD‑L1 (programmed death‑ligand 1) blockers) work in treating malignancy?

Mechanism of Checkpoint Inhibitors in Cancer Treatment

Core Mechanism of Action

Checkpoint inhibitors are monoclonal antibodies that block inhibitory immune checkpoint molecules (CTLA-4 and PD-1/PD-L1), thereby releasing the "brakes" on T-cell activation and restoring the immune system's ability to recognize and destroy cancer cells. 1, 2, 3

Two Distinct Checkpoint Pathways

CTLA-4 Blockade (Ipilimumab)

• CTLA-4 is a negative regulator of T-cell activity that normally limits immune responses to prevent autoimmunity. 2

• Ipilimumab blocks the interaction between CTLA-4 and its ligands (CD80/CD86), preventing inhibitory signaling that suppresses T-cell activation. 1, 2

• This blockade primarily interferes at the interface between T cells and antigen-presenting dendritic cells in lymphoid tissues, occurring early in the immune response. 4, 5

• The mechanism augments T-cell activation and proliferation, reduces T-regulatory cell function, and contributes to a general increase in T-cell responsiveness including anti-tumor immunity. 2

PD-1/PD-L1 Blockade (Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab)

• PD-1 is a cell surface receptor on activated T cells that, when bound by its ligands PD-L1 or PD-L2, inhibits T-cell proliferation and cytokine production. 3, 6

• Cancer cells evade immune surveillance by overexpressing PD-L1, which binds to PD-1 on tumor-infiltrating T cells and shuts down their cytotoxic function. 7, 6

• Anti-PD-1 antibodies (nivolumab, pembrolizumab) and anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab) prevent this interaction, releasing PD-1 pathway-mediated inhibition of the immune response. 3, 6

• This blockade primarily occurs later in the immune response at the interface between T cells and tumor cells in peripheral tissues, restoring T-cell-mediated cytotoxicity against cancer. 7, 5

Temporal and Spatial Differences

• CTLA-4 regulates T-cell proliferation early in immune responses, primarily in lymph nodes, while PD-1 suppresses T cells later in immune responses, primarily in peripheral tumor tissues. 5

• These mechanistic differences explain why combining both pathways produces enhanced anti-tumor activity greater than either antibody alone. 8, 9

Combination Therapy Rationale

• Combined CTLA-4 and PD-1 blockade (ipilimumab plus nivolumab) results in enhanced T-cell function and improved anti-tumor responses compared to monotherapy. 3, 8

• The dual blockade addresses both early T-cell priming (CTLA-4) and effector function at the tumor site (PD-1), providing complementary mechanisms of immune activation. 9, 10

• However, combination therapy causes substantially more immune-related adverse events (55-60% high-grade) compared to PD-1 monotherapy (10-20%), with treatment discontinuation rates of 39% versus 12%. 6

Clinical Implications

• Seven checkpoint inhibitors are currently FDA-approved: ipilimumab (anti-CTLA-4), nivolumab and pembrolizumab (anti-PD-1), and atezolizumab, avelumab, and durvalumab (anti-PD-L1). 1

• These agents have demonstrated significant survival improvements across multiple malignancies including melanoma, non-small cell lung cancer, renal cell carcinoma, and others. 1, 7

• The immune stimulation triggered by checkpoint blockade can cause immune-related adverse events affecting virtually any organ system, requiring prompt recognition and immunosuppressive management. 7, 1

Important Safety Consideration

• Both PD-1 and CTLA-4 blockade may reactivate latent tuberculosis and other opportunistic infections by disrupting immune control of these pathogens, necessitating screening in high-risk patients before treatment initiation. 7, 6