Immune checkpoint inhibitor (ICI) treatment represents a significant advancement in cancer therapy. This form of immunotherapy harnesses the body’s own immune system, specifically its T-cells, to recognize and attack cancer cells. This strategy has transformed the landscape of cancer care by providing durable responses in some patients.
How Immune Checkpoint Inhibitors Work
The immune system naturally employs “checkpoints,” molecules on immune cells that act as brakes to prevent an overactive immune response from damaging healthy tissues. Cancer cells can exploit these natural brakes, such as PD-1, PD-L1, and CTLA-4, to evade detection and destruction by the immune system.
Immune checkpoint inhibitors are drugs, typically monoclonal antibodies, designed to block these inhibitory signals. For instance, anti-PD-1 antibodies or anti-PD-L1 antibodies prevent the binding of PD-1 on T-cells to PD-L1 on tumor cells. This action “releases the brakes” on T-cells, allowing them to become activated and attack cancer cells.
Similarly, CTLA-4 inhibitors block the CTLA-4 protein, another immune checkpoint that dampens T-cell activity. By blocking CTLA-4, T-cells remain active and proliferate, enhancing their ability to identify and eliminate cancer cells.
Conditions Treated with Immune Checkpoint Inhibitors
Immune checkpoint inhibitors have gained approval for treating a growing number of cancer types. Melanoma was one of the first cancers for which ICIs demonstrated extended survival, becoming a standard treatment for advanced stages. These therapies are also used in earlier stages of melanoma, sometimes before or after surgery, to reduce recurrence risk.
Non-small cell lung cancer (NSCLC) is another area where ICIs are effective, with drugs like pembrolizumab and nivolumab widely used. Kidney cancer (renal cell carcinoma) and bladder cancer have also seen improved outcomes. Additionally, Hodgkin lymphoma and various head and neck cancers respond to these immunotherapies.
Specific types of colorectal cancer, particularly those with microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), have shown favorable responses. ICIs are also approved for certain cases of liver cancer, stomach cancer, cervical cancer, and triple-negative breast cancer.
Common Side Effects and Their Management
Immune checkpoint inhibitors can cause immune-related adverse events (irAEs), which occur when the activated immune system targets healthy tissues. These side effects can affect nearly any organ system, most commonly the skin, gastrointestinal tract, endocrine glands, liver, and lungs. While most irAEs are mild to moderate and reversible, early detection and prompt reporting of symptoms are important for effective management.
Skin-related irAEs often manifest as rashes, itching, or changes in skin color. Mild rashes can be managed with topical steroids and oral antihistamines, and may not require ICI discontinuation. Gastrointestinal issues include diarrhea and colitis (inflammation of the colon), which can sometimes be severe and require hospitalization. Endocrine problems, such as inflammation of the thyroid or pituitary glands, can lead to hormonal imbalances, and liver inflammation (hepatitis) may also occur.
Pulmonary inflammation (pneumonitis) can cause cough and chest pain. Musculoskeletal symptoms like joint pain (arthralgias) and muscle pain (myalgias) are also reported. Management of irAEs often involves corticosteroids, which are powerful immunosuppressants, to dampen the immune response. In more severe cases, temporary or permanent cessation of the ICI may be necessary, and a multidisciplinary approach involving specialists is often recommended.
Patient Selection for ICI Treatment
Determining which patients will benefit most from ICI treatment involves considering several factors beyond cancer type and stage. A patient’s overall health status and pre-existing autoimmune conditions are important, as ICIs can exacerbate autoimmune responses. Patients with a history of autoimmune disorders may still be candidates, but require careful evaluation and monitoring.
Biomarkers play a growing role in predicting a patient’s likely response to ICI therapy. Programmed death-ligand 1 (PD-L1) expression on tumor cells or immune cells is a widely used biomarker; higher expression generally correlates with a greater likelihood of response to anti-PD-1 or anti-PD-L1 therapies. However, some patients with low or absent PD-L1 expression can still respond, indicating that PD-L1 alone is not a perfect predictor.
Tumor mutational burden (TMB), which refers to the total number of mutations within a tumor’s DNA, is another biomarker. Tumors with a high mutational load, like melanoma, tend to respond more favorably to checkpoint inhibition. Similarly, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors are often highly responsive to ICIs, regardless of their origin. The presence and density of tumor-infiltrating lymphocytes (T-cells within the tumor microenvironment) also provide insights into response likelihood.