What are immune checkpoint inhibitors?

What Are Immune Checkpoint Inhibitors

Immune checkpoint inhibitors are monoclonal antibodies that block regulatory immune checkpoint molecules (primarily CTLA-4, PD-1, and PD-L1) to restore and enhance the antitumor immune response of cytotoxic T cells. 1

Mechanism of Action

Immune checkpoint inhibitors work by removing the "brakes" on the immune system that cancer cells exploit to evade immune destruction 1:

• CTLA-4 inhibitors (such as ipilimumab) block the interaction between CTLA-4 and its ligands, interfering at the interface between T cells and antigen-presenting dendritic cells, thereby preventing inhibitory signaling cascades that suppress T cell activation 2

• PD-1/PD-L1 inhibitors (such as nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab) prevent the binding of PD-1 to its ligands PD-L1/PD-L2, restoring T cell-mediated cytotoxicity and allowing the immune system to identify and destroy malignant cells 1

FDA-Approved Agents

Currently, seven immune checkpoint inhibitors are approved for clinical use 3:

• Anti-CTLA-4: Ipilimumab (first approved in 2011 for metastatic melanoma) 1, 2
• Anti-PD-1: Nivolumab and pembrolizumab (approved in 2014 for melanoma, with subsequent expansion to multiple cancer types) 1, 4
• Anti-PD-L1: Atezolizumab, durvalumab, and avelumab (approved for various malignancies including urothelial carcinoma and NSCLC) 1, 5

Clinical Applications

These agents have demonstrated significant survival benefits across multiple malignancies 1, 3:

• Melanoma (both advanced and adjuvant settings) 1, 2
• Non-small cell lung cancer (as monotherapy and combined with chemotherapy) 1, 4
• Renal cell carcinoma 1, 4
• Hodgkin lymphoma 1, 4
• Head and neck cancer 1, 4
• Urothelial carcinoma 5
• Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancers (tissue-agnostic approval) 1

Immune-Related Adverse Events (irAEs)

A critical distinguishing feature of immune checkpoint inhibitors is their unique toxicity profile 1:

• Common irAEs affect skin, gastrointestinal tract, endocrine organs, lungs, and musculoskeletal system 1
• Less common but serious irAEs include cardiovascular, hematologic, renal, neurologic, and ophthalmologic toxicities 1
• Toxicity varies by agent: Anti-CTLA-4 therapy (ipilimumab) causes irAEs of any grade in up to 90% of patients, while anti-PD-1 agents have an incidence ≤30% for any grade 3
• Combination therapy (anti-CTLA-4 plus anti-PD-1) produces higher rates of grade 3-5 adverse events than either agent alone 1
• Treatment-related deaths occur in up to 2% of patients, varying by specific ICI 1

Management Principles

Early recognition and prompt intervention with immunosuppression are essential for managing irAEs 1:

• Delayed onset: irAEs typically have delayed onset and prolonged duration compared to chemotherapy adverse events 1
• Corticosteroids: High-dose systemic corticosteroids (1-2 mg/kg/day prednisone equivalent) are the mainstay of treatment for grade 3-4 toxicities 1, 3
• Additional immunosuppression: Steroid-sparing agents may be required for corticosteroid-refractory cases 1, 3
• Treatment interruption: Grade 2 toxicities typically require withholding therapy, while grade 3-4 toxicities often necessitate permanent discontinuation 6

Important Clinical Caveats

Several critical warnings apply to immune checkpoint inhibitor use 7, 6:

• Allogeneic HSCT complications: Fatal and serious complications including hyperacute GVHD can occur in patients who receive allogeneic hematopoietic stem cell transplantation before or after PD-1 blockade 7
• Multiple myeloma contraindication: Addition of PD-1 blocking antibodies to thalidomide analogues plus dexamethasone results in increased mortality and is not recommended outside controlled trials 7
• Embryo-fetal toxicity: These agents can cause fetal harm; females of reproductive potential require effective contraception during treatment and for 5 months after the last dose 7