Immunotherapy offers a distinct approach to cancer care alongside traditional treatments like surgery, chemotherapy, and radiation. This method harnesses the body’s immune system to combat malignant cells. Among these therapies, PD-1 inhibitors are a class of drugs that help the immune system recognize and attack certain forms of bladder cancer more effectively, providing a new therapeutic avenue for some patients.
The PD-1/PD-L1 Pathway in Bladder Cancer
The immune system’s T-cells are constantly patrolling the body for threats, including cancer cells. To prevent these powerful cells from attacking healthy tissues, the body has a system of checks and balances. One such mechanism involves a protein on T-cells called Programmed Death-1 (PD-1). When PD-1 is activated, it functions like a brake, telling the T-cell to stand down and preventing an immune attack.
Many bladder cancer cells exploit this safety feature by producing high levels of a partner protein called Programmed Death-Ligand 1 (PD-L1). When the PD-L1 on a tumor cell connects with the PD-1 on a T-cell, it sends a “stop” signal. This molecular interaction is a mechanism of immune escape for the tumor.
By engaging this pathway, the cancer creates an immunosuppressive environment that shields it from attack. This allows the bladder cancer to grow and spread without interference from the body’s defenses. The higher the expression of PD-L1 on tumor cells, the more effectively they can suppress the immune response.
How PD-1 Inhibitors Function as Treatment
PD-1 inhibitors are monoclonal antibodies designed to disrupt the communication between cancer cells and T-cells. They work by physically blocking the PD-1 receptor on the surface of T-cells. This action prevents the PD-L1 protein on bladder cancer cells from binding to the T-cell’s PD-1 receptor.
By obstructing this connection, the inhibitor drug cuts the “stop” signal sent by the cancer cell. This releases the brakes on the T-cell, reactivating the body’s immune response against the bladder cancer. The T-cells can then perform their function of destroying malignant cells, which can lead to shrinking tumors or slowed growth. A similar class of drugs, PD-L1 inhibitors, functions by binding to the PD-L1 protein on the tumor cells.
Approved PD-1 and PD-L1 Inhibitors
The U.S. Food and Drug Administration (FDA) has approved several PD-1 and PD-L1 inhibitors for treating bladder cancer. These drugs are used based on the stage of the disease and prior treatments, particularly for advanced or metastatic urothelial carcinoma, the most common type of bladder cancer.
- Pembrolizumab (Keytruda): A PD-1 inhibitor for high-risk non-muscle invasive bladder cancer (NMIBC) unresponsive to BCG therapy. It can also be a first-line treatment for advanced cancer in patients ineligible for cisplatin chemotherapy (if tumors have high PD-L1 levels) or a second-line treatment after platinum-based chemotherapy.
- Atezolizumab (Tecentriq): A PD-L1 inhibitor approved as a first-line option for metastatic cancer in patients ineligible for cisplatin chemotherapy, or as a second-line treatment after platinum-containing chemotherapy.
- Nivolumab (Opdivo): A PD-1 inhibitor for patients with advanced or metastatic bladder cancer that has progressed during or following platinum-based chemotherapy.
- Avelumab (Bavencio): A PD-L1 inhibitor used as a maintenance therapy for patients with advanced or metastatic cancer that has not progressed after first-line platinum-based chemotherapy.
- Durvalumab (Imfinzi): A PD-L1 inhibitor for patients with advanced or metastatic bladder cancer who have disease progression during or after platinum-containing chemotherapy.
Patient Candidacy and Treatment Stages
Candidacy for PD-1 inhibitor therapy depends on the cancer’s stage and molecular characteristics. These treatments are most commonly used for advanced or metastatic urothelial carcinoma. In this context, they can be an initial treatment for certain patients or a subsequent therapy after chemotherapy has failed.
Another application is for high-risk non-muscle invasive bladder cancer (NMIBC). For patients whose NMIBC has not responded to standard Bacillus Calmette-Guérin (BCG) therapy, and who are not candidates for bladder removal surgery, certain PD-1 inhibitors can be an effective option.
A factor in determining candidacy for first-line treatment of metastatic disease is biomarker testing. Doctors test a tumor tissue sample to measure the amount of PD-L1 protein it expresses through a laboratory test called immunohistochemistry (IHC).
The result is reported as a score that assesses the number of PD-L1-staining cells. A high PD-L1 expression level may indicate that a patient is more likely to respond to an inhibitor. For some drug approvals, a specific PD-L1 score is required to be eligible for the therapy.
Managing Immune-Related Side Effects
While PD-1 inhibitors empower the immune system, this heightened activation can sometimes lead it to attack healthy tissues, causing immune-related adverse events (irAEs). The severity of irAEs can range from mild to life-threatening. Early detection and intervention are necessary for managing these side effects effectively.
Common side effects involve the skin, manifesting as rashes and itching. Inflammation can also occur in the intestines (colitis), causing diarrhea and abdominal pain, or in the lungs (pneumonitis), presenting with shortness of breath and a cough.
Other organ systems can be impacted. Inflammation of hormone-producing glands, such as the thyroid or pituitary, can disrupt normal hormone levels. Less commonly, the liver (hepatitis), kidneys, or nervous system can be affected, with side effects appearing weeks or months after treatment starts.
Patients are instructed to report any new or worsening symptoms to their medical team immediately. Management often involves the use of corticosteroids to suppress the immune system and prevent more severe complications.