Immunotherapy for lung cancer is a modern approach that empowers the patient’s own biological defenses rather than directly attacking cancer cells. Unlike traditional chemotherapy, which uses toxic chemicals to kill rapidly dividing cells, immunotherapy uses specialized drugs to enhance the immune system. This allows the body to recognize and eliminate malignant cells more effectively. This strategy has become a standard part of care for many individuals with lung cancer, including both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). These treatments offer the potential for more durable responses in a subset of patients.
The Immune System and Cancer Evasion
The human immune system constantly surveys the body for abnormal cells, a process known as immune surveillance. Specialized T-lymphocytes, or T-cells, act as the primary defense, identifying and destroying cells that display foreign markers. To prevent an overactive response against healthy tissues, the immune system employs “checkpoint” mechanisms, which function as regulatory brakes. These checkpoints are normal proteins on the surface of immune cells that maintain self-tolerance.
Cancer cells hijack these natural regulatory mechanisms to avoid destruction. They often display high levels of certain checkpoint proteins on their surface, sending a “don’t attack me” signal to T-cells at the tumor site. This interaction, known as immune evasion, causes the T-cells to become functionally inactive or “exhausted,” allowing the tumor to grow unchecked.
One well-studied example involves the programmed death-1 (PD-1) pathway. When the PD-1 protein on a T-cell binds to its partner, programmed death-ligand 1 (PD-L1), often expressed on lung cancer cells, the T-cell is suppressed. This binding event is a brake that tumor cells engage to shield themselves from attack. Understanding this mechanism provided the foundation for developing drugs that specifically block these interactions.
Primary Immunotherapy Drug Classes for Lung Cancer
The primary category of immunotherapy for lung cancer is immune checkpoint inhibitors (ICIs). These drugs are monoclonal antibodies designed to block the interaction between the T-cell and the cancer cell, releasing the immune system’s brakes. The largest group targets the PD-1/PD-L1 pathway, restoring the T-cell’s ability to destroy malignant cells.
PD-1 inhibitors, such as nivolumab and pembrolizumab, bind directly to the PD-1 receptor on the T-cell, preventing the inhibitory signal. In contrast, PD-L1 inhibitors, including atezolizumab and durvalumab, block the PD-L1 protein on the tumor cell itself. Both types reactivate exhausted T-cells within the tumor microenvironment. These drugs are often used as a single agent, especially when the tumor displays high levels of PD-L1 protein.
Another class of ICIs targets the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway. CTLA-4 inhibitors, such as ipilimumab and tremelimumab, also release the brake, but they work earlier by promoting the initial activation of T-cells. Combining a CTLA-4 inhibitor with a PD-1 or PD-L1 inhibitor is sometimes employed in lung cancer because these pathways regulate T-cell activity at different stages. This dual blockade aims to generate a robust anti-tumor response, though it can increase the risk of side effects.
Determining Patient Eligibility and Biomarkers
Immunotherapy is not universally effective, so specific testing is required to determine the likelihood of a positive response. Biomarkers are biological characteristics that help predict how a patient will react to treatment. The most established biomarker for predicting response to PD-1/PD-L1 inhibitors is the expression level of PD-L1 on the tumor cells, measured using immunohistochemistry (IHC).
This test provides a Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing staining for the PD-L1 protein. A high TPS (50% or greater) often indicates a high probability of benefiting from single-agent immunotherapy as a first treatment. Patients with a TPS between 1% and 49% may receive immunotherapy combined with chemotherapy, while a TPS below 1% suggests a lower likelihood of response to the drug alone.
Another emerging biomarker is Tumor Mutational Burden (TMB), which measures the total number of mutations within a tumor’s DNA. Tumors with a high TMB are considered more “visible” to the immune system because they produce many abnormal proteins, or neoantigens, that T-cells can recognize. A high TMB score can indicate a greater potential for response to checkpoint inhibitors, especially when PD-L1 expression is low. These results, obtained from a small tissue sample, are essential for guiding personalized treatment decisions.
Managing Unique Immune Related Side Effects
Immunotherapy side effects are distinct from traditional cancer treatments because they result from activating the immune system. These unique adverse events are termed Immune-Related Adverse Events (IRAEs) and occur when unleashed T-cells mistakenly attack healthy tissues and organs. IRAEs can affect nearly any part of the body, but they most commonly involve:
- The skin
- The gastrointestinal tract
- Endocrine glands
- The lungs
A potentially serious IRAE is pneumonitis, which is inflammation of the lung tissue. Colitis, or inflammation of the colon, is another frequent IRAE, leading to diarrhea and abdominal pain. Dermatologic reactions, such as rash and pruritus (itching), are also common and often appear early in treatment.
Effective management of IRAEs relies on early detection and the use of immunosuppressive medication. Corticosteroids, such as prednisone, are the mainstay of treatment, as they dampen the overactive immune response causing the inflammation. For moderate to severe reactions, immunotherapy is often temporarily held, and high-dose steroids are initiated to prevent permanent organ damage. Close monitoring is necessary to manage these autoimmune-like reactions and ensure patient safety.