Brain metastases, cancer cells that have traveled to the brain from a primary tumor elsewhere in the body, present a treatment challenge. Because the brain is a complex organ, therapies must reach these secondary tumors without harming healthy tissue. One treatment being used is Keytruda (pembrolizumab), a type of immunotherapy that harnesses the body’s immune system to combat cancer. It works by enabling immune cells to recognize and attack cancer cells more effectively, an approach being explored for managing metastases within the brain.
The Mechanism of Keytruda
Keytruda operates by targeting a specific interaction between immune and cancer cells. The body’s T-cells, which patrol for abnormal cells, have a protein on their surface called PD-1. Some cancer cells express a corresponding protein, PD-L1. When PD-L1 on a cancer cell connects with PD-1 on a T-cell, it acts as an “off switch,” signaling the T-cell to leave the cancer cell alone.
This is a natural “immune checkpoint” that prevents the immune system from becoming overactive and attacking healthy tissues. However, certain cancers exploit this system to hide from the immune response. Keytruda is a monoclonal antibody that blocks this interaction by attaching to the PD-1 receptor on T-cells, preventing cancer cells from deactivating them.
This action effectively “releases the brakes” on the immune system, allowing T-cells to attack. The drug itself does not kill cancer cells directly; instead, it empowers the patient’s own immune system to recognize and destroy them.
Clinical Effectiveness for Brain Metastases
Keytruda’s effectiveness against brain metastases depends on the cancer’s primary origin and is still under investigation. A primary challenge is the blood-brain barrier, a protective membrane that can block therapies. However, evidence shows Keytruda can be active against brain tumors from certain cancers, particularly non-small cell lung cancer (NSCLC) and melanoma.
For patients with NSCLC that has spread to the brain, Keytruda has produced positive responses. A phase II clinical trial of patients with PD-L1-positive NSCLC showed a brain metastasis response rate of nearly 30%. Responses ranged from partial tumor reduction to complete disappearance, improving on historical outcomes for this population.
Studies of patients with melanoma that has spread to the brain show similar outcomes. One phase II trial reported a 22% brain metastasis response rate in melanoma patients treated with Keytruda. These responses were often durable, lasting for a significant period, suggesting Keytruda can be a viable strategy for managing these tumors.
Combination with Radiation Therapy
Combining Keytruda with stereotactic radiosurgery (SRS), a focused form of radiation, is a strategy for treating brain metastases. SRS delivers precise, high-dose radiation to tumors while minimizing damage to healthy brain tissue. This approach is investigated for its potential to create a synergistic effect, enhancing the body’s overall anti-tumor response.
Radiation may act as a catalyst for the immune system. Damaging cancer cells with radiation can cause them to release tumor-specific proteins called antigens. This release helps the immune system, already stimulated by Keytruda, to better recognize and target the cancer cells, amplifying the attack at the radiation site.
This combination may also trigger the abscopal effect, where local radiation on one tumor leads to the shrinkage of other tumors elsewhere. The immune response generated at the irradiated site becomes systemic, allowing activated T-cells to attack cancer throughout the body. Clinical trials are exploring this combination in patients with brain metastases from melanoma and NSCLC.
Managing Side Effects in Brain Treatment
Keytruda’s heightened immune activity can sometimes cause the immune system to attack healthy tissues, leading to immune-related adverse events (irAEs). These side effects can affect various organs, causing conditions such as colitis, hepatitis, and skin rashes. Patients are monitored for these general side effects, which can occur during or after treatment has concluded.
When treating tumors within the brain, there are specific risks related to the confined space of the skull. A primary concern is inflammation and swelling, or edema, around the brain tumor as the immune system attacks it. This swelling can increase intracranial pressure, leading to neurological symptoms such as severe headaches, dizziness, confusion, or seizures, which require immediate management.
Physicians monitor patients undergoing Keytruda treatment for brain metastases for any new or worsening neurological signs. If inflammation or swelling occurs, it is often managed with medications like corticosteroids. These drugs help to reduce the immune-related swelling in the brain, alleviating pressure and controlling the neurological symptoms.