How does immunotherapy work in cancer treatment?

How Immunotherapy Works in Cancer Treatment

Immunotherapy works by targeting the host's immune system and tumor microenvironment rather than directly attacking cancer cells, primarily through blocking inhibitory immune checkpoint molecules that suppress T-cell activation, thereby "releasing the brake" on the body's natural anti-tumor immune response. 1, 2

Core Mechanism of Action

Immune Checkpoint Blockade

The primary mechanism involves disrupting inhibitory signals that cancer cells exploit to evade immune destruction:

• CTLA-4 inhibitors (such as ipilimumab) block the interaction between CTLA-4 receptors on T-cells and their ligands on antigen-presenting cells, preventing the inhibitory signaling cascade that normally suppresses T-cell activation at the interface between T-cells and dendritic cells 1, 3

• PD-1/PD-L1 inhibitors (such as nivolumab, pembrolizumab, atezolizumab) prevent the binding of PD-1 receptors on T-cells to PD-L1/PD-L2 ligands expressed on tumor cells and tumor-infiltrating immune cells, which releases PD-L1/PD-1 mediated inhibition of cytotoxic T-cell activity, T-cell proliferation, and cytokine production 1, 4, 5

Restoration of Immune Surveillance

Once checkpoint inhibition occurs, the immune system regains its ability to recognize and destroy malignant cells through natural immunosurveillance mechanisms:

• Enhanced T-cell activation allows cytotoxic CD8+ T-cells to identify tumor neoantigens and mount an effective anti-tumor response 1, 2
• The process activates both CD8+ killer T-cells and CD4+ helper T-cells to attack cancer cells without inducing antibody-dependent cellular cytotoxicity 5, 6

Synergy with Chemotherapy

Contrary to historical assumptions that chemotherapy is purely immunosuppressive, modern understanding reveals complex immune-enhancing mechanisms:

• Immunogenic cell death: Chemotherapy agents like anthracyclines trigger tumor cell death that increases antigen cross-presentation to CD8+ T-cells 1
• Tumor load reduction: Cytotoxic agents decrease overall tumor burden, making remaining cancer cells more vulnerable to immune attack 1
• Depletion of immunosuppressive cells: Agents like cyclophosphamide selectively deplete regulatory T-cells while maintaining cytotoxic immunity 1
• Increased tumor antigenicity: Chemotherapy can enhance the expression of tumor antigens, making cancer cells more recognizable to the immune system 1

Clinical Implementation Considerations

Timing and Response Patterns

A critical distinction from traditional chemotherapy is the delayed and prolonged nature of immunotherapy responses:

• Tumor regression may occur over extended periods, requiring immune-related response criteria rather than traditional RECIST criteria for assessment 2
• Steady-state drug levels are achieved after 6-9 weeks of treatment, with systemic accumulation occurring over multiple doses 5

Toxicity Profile

The mechanism of action creates a unique adverse event profile distinct from chemotherapy:

• Immune-related adverse events (irAEs) result from the same mechanisms responsible for therapeutic efficacy—namely, removal of inhibitory controls on the immune system 1
• Anti-CTLA-4 therapy (ipilimumab) causes irAEs in up to 90% of patients at any grade, while anti-PD-1 agents have ≤30% incidence 4, 3
• These autoimmune-mediated toxicities can affect any organ system and require fundamentally different management than chemotherapy side effects, typically involving immunosuppression with corticosteroids rather than supportive care alone 1

Management Algorithm for Toxicities

The severity-based approach differs markedly from chemotherapy toxicity management:

• Grade 1 toxicities: Continue immunotherapy with close monitoring (except neurologic, hematologic, and cardiac toxicities which require immediate intervention) 1
• Grade 2 toxicities: Suspend immunotherapy temporarily; consider corticosteroids; resume when symptoms revert to grade 1 1
• Grade 3 toxicities: Suspend immunotherapy and initiate high-dose corticosteroids with taper over at least 4-6 weeks 1
• Grade 4 toxicities: Permanently discontinue immunotherapy (except endocrinopathies controlled by hormone replacement) 1

Common Pitfalls

Critical distinction required: When patients on combination chemo-immunotherapy develop diarrhea, hepatotoxicity, skin eruptions, or fatigue, clinicians must differentiate between cytotoxic side effects and immune-related adverse events, as management strategies are completely different—no biomarkers currently exist in routine practice to make this distinction 1

Treatment-related mortality: While combination chemo-immunotherapy increases all-grade adverse events (RR 1.11) and serious adverse events (RR 1.16), it does not increase treatment-related mortality compared to chemotherapy alone 1