Glioblastoma is an aggressive brain cancer, prompting continuous exploration of new therapies. Pembrolizumab, a type of immunotherapy, is being investigated for its potential role in addressing this difficult disease. This article explores glioblastoma, the mechanism of pembrolizumab, its current status in research, and patient considerations.
Understanding Glioblastoma
Glioblastoma, also known as glioblastoma multiforme (GBM), is the most common and aggressive primary malignant brain tumor in adults. It originates from glial cells and is classified as a Grade 4 tumor by the World Health Organization due to its rapid growth and invasive nature. These tumors often infiltrate surrounding brain tissue, making complete surgical removal difficult and contributing to high recurrence rates.
Traditional treatment involves surgery to remove as much of the tumor as possible, followed by radiation therapy and chemotherapy, usually with temozolomide. Despite these efforts, the prognosis for glioblastoma remains poor, with a median survival rate of 12 to 15 months after diagnosis. New strategies are sought to improve these outcomes.
How Pembrolizumab Functions
Pembrolizumab is a humanized monoclonal antibody that functions as an immune checkpoint inhibitor. It targets the programmed death-1 (PD-1) receptor, found on T-cells, a type of white blood cell that recognizes and destroys cancerous cells. Cancer cells often evade the immune system by expressing ligands like PD-L1 and PD-L2, which bind to the PD-1 receptor on T-cells. This binding sends an inhibitory signal, “switching off” T-cells and preventing them from attacking the tumor.
Pembrolizumab blocks this interaction by binding to the PD-1 receptor on T-cells. This “releases the brakes” on T-cells, allowing them to remain active and destroy cancer cells more effectively. By reactivating T-cells, pembrolizumab restores the body’s anti-tumor immune response. This mechanism has led to its approval for various cancer types, though its application in glioblastoma presents challenges.
Pembrolizumab and Glioblastoma: Current Status and Research
The application of immunotherapy, including pembrolizumab, in glioblastoma faces unique challenges due to the distinct environment of the brain. The blood-brain barrier (BBB) is a protective network of blood vessels that restricts the passage of substances, including many therapeutic drugs like pembrolizumab, from the bloodstream into the brain. This barrier can limit the amount of the drug that reaches the tumor, potentially reducing its effectiveness. Research is exploring methods to temporarily disrupt the BBB, such as using magnetic resonance imaging-guided focused ultrasound (MRgFUS) with microbubbles, to enhance drug delivery to glioblastoma tumors.
Another significant obstacle is the highly immunosuppressive tumor microenvironment within glioblastoma. Glioblastoma tumors create conditions that actively suppress the immune system, featuring cytokines like interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), which hinder T-cell function and promote the expansion of regulatory T cells (Tregs). This environment allows tumor cells to evade immune detection and destruction. Studies have shown that even with pembrolizumab, the tumor microenvironment in glioblastoma can be rich in immunosuppressive macrophages, which may limit the immune response.
Clinical trials investigating pembrolizumab for glioblastoma have yielded varied results, indicating it is not yet a standard first-line treatment. For instance, a randomized phase II trial combining pembrolizumab with bevacizumab for recurrent glioblastoma showed limited benefit, with a median overall survival of 8.8 months for pembrolizumab alone and 10.3 months for the combination. The objective response rate was 0% for pembrolizumab alone and 20% for the combination, suggesting modest efficacy. Another study evaluating pembrolizumab monotherapy in recurrent glioblastoma found a median progression-free survival of 4.5 months and a median overall survival of 20 months, with only three out of 14 patients achieving a partial response. These findings suggest that pembrolizumab alone may not induce a strong enough immune response in most glioblastoma patients, likely due to the scarcity of T-cells and the dominance of immunosuppressive macrophages within the tumor.
Some research suggests potential benefits in specific patient populations or when combined with other therapies. A phase II study combining re-irradiation with pembrolizumab for recurrent glioblastoma showed improved survival in patients who were refractory to bevacizumab, but not in those who had not received it. The overall response rate was low (3.3% and 6.7% for respective cohorts).
A case study of a glioblastoma patient with high tumor mutation burden (TMB-high) and mismatch repair deficiency (dMMR) showed a significant and sustained response to pembrolizumab, highlighting precision oncology’s potential in select cases. Ongoing clinical trials explore pembrolizumab in combination with other treatments, such as oncolytic viral therapy or neoadjuvant therapy before surgery, to overcome glioblastoma’s challenges. Continued research is important due to current limitations, as new approaches are needed to enhance efficacy and identify patient subsets most likely to benefit.
Patient Experience and Considerations
Patients receiving pembrolizumab receive it as an intravenous (IV) infusion, administered over about 30 minutes in an outpatient clinic or hospital. Frequency varies, often every three or six weeks, depending on the treatment plan. Before each treatment, patients undergo regular blood tests to monitor health and ensure safety.
Pembrolizumab can cause immune-related adverse events by enhancing the immune system’s activity, potentially leading to attacks on healthy organs and tissues. Common side effects include fatigue, diarrhea, skin rash, nausea, vomiting, and musculoskeletal pain. More serious, but less frequent, immune-mediated reactions can affect organ systems, including the lungs (pneumonitis), intestines (colitis), liver (hepatitis), kidneys (nephritis), and endocrine glands (thyroid disorders, type 1 diabetes, hypophysitis). Patients may also experience infusion-related reactions like chills, fever, or flushing during administration.
Healthcare providers monitor patients for signs of these adverse reactions, as early detection and management are important. Patients are considered for pembrolizumab in recurrent glioblastoma or as part of clinical trials, especially if they have specific tumor characteristics like high tumor mutation burden or mismatch repair deficiency, which might indicate a greater likelihood of response. The medical team decides on pembrolizumab use, considering the patient’s overall health, previous treatments, and potential benefits versus risks.