Hodgkin lymphoma is a cancer of the lymphatic system, a network of tissues that helps the body fight infection. Treatment has advanced to include immunotherapies, which use the body’s own defenses to target cancer cells. These therapies help the immune system recognize and attack the disease more effectively. This article explains how this class of immunotherapy functions, what patients can expect during treatment, and how potential side effects are addressed.
The Immune System’s Role in Hodgkin Lymphoma
The immune system is the body’s natural defense against disease, equipped with specialized cells that identify and eliminate threats, including cancer. A key player is the T-cell, a white blood cell trained to destroy abnormal cells. To prevent T-cells from attacking healthy tissues, the immune system uses a series of safety checks known as immune checkpoints. These checkpoints act like brakes, slowing down or stopping an immune response when it is no longer needed.
One of the checkpoint proteins on the surface of T-cells is called Programmed Death-1, or PD-1. When PD-1 binds to its partner protein, Programmed Death-Ligand 1 (PD-L1), it sends a signal to the T-cell to stand down. This interaction is a normal part of maintaining immune balance. Healthy cells throughout the body may display some PD-L1 to signal that they are not a threat and should be left alone.
This safety mechanism, however, can be exploited by some cancers. Classical Hodgkin lymphoma is characterized by the presence of large, abnormal cells called Hodgkin and Reed-Sternberg (HRS) cells. A feature of these cancerous cells is a high amount of the PD-L1 ligand on their surface. This overexpression of PD-L1 is sometimes caused by genetic alterations.
By displaying so much PD-L1, the HRS cells effectively engage the PD-1 “brakes” on the T-cells that are meant to destroy them. This interaction tricks the immune system into seeing the cancer cells as friendly, allowing them to hide and continue to grow. The T-cells become suppressed in the tumor’s local environment, a state often referred to as T-cell exhaustion. This method of immune evasion is why Hodgkin lymphoma can persist despite the presence of capable immune cells.
How PD-1 Inhibitors Work
Scientists developed PD-1 inhibitors to counteract how Hodgkin lymphoma cells evade the immune system. These therapies are a type of monoclonal antibody, which are lab-created proteins designed to target a very specific substance in the body. In this case, the target is the PD-1 receptor located on the surface of T-cells. The primary goal of a PD-1 inhibitor is to prevent the cancer cell’s PD-L1 from interacting with the T-cell’s PD-1.
The drug works by physically binding to the PD-1 receptor on the T-cell. This action places a shield over the PD-1 “brake,” making it impossible for the PD-L1 signal from the cancer cell to connect with it. By blocking this connection, the inhibitor cuts the “off” signal the cancer cells were sending. The braking mechanism is released, and T-cells are freed to do their job.
With the inhibitory signal blocked, the T-cells can once again recognize the Hodgkin and Reed-Sternberg cells as dangerous and mount a targeted attack. This reinvigoration of the immune response can lead to the shrinking of tumors and control of the disease. The U.S. Food and Drug Administration (FDA) has approved specific PD-1 inhibitors for treating classical Hodgkin lymphoma, with two prominent examples being nivolumab (Opdivo) and pembrolizumab (Keytruda).
The Treatment Process for Patients
Treatment with PD-1 inhibitors is managed in an outpatient setting. These drugs are not pills but are administered directly into the bloodstream through an intravenous (IV) infusion. This ensures the medication is distributed throughout the body to reach the T-cells. Each session involves having a small IV line placed into a vein, through which the drug is infused over 30 to 90 minutes.
The frequency of these infusions depends on the specific drug being used and the prescribed regimen. A treatment schedule for nivolumab or pembrolizumab might be once every two, three, four, or even six weeks. The healthcare team determines the appropriate cycle length for each patient. Treatment with a PD-1 inhibitor is often continued for an extended period, sometimes for up to two years, as long as the patient’s lymphoma is responding and the side effects are manageable.
PD-1 inhibitors are most commonly used for patients with classical Hodgkin lymphoma who have already tried other standard treatments. This therapy is a second-line or third-line option. It is recommended for individuals whose cancer has either relapsed, meaning it returned after remission, or was refractory, meaning it did not respond to initial treatments like chemotherapy. In many cases, patients will have already undergone a stem cell transplant before a PD-1 inhibitor is considered.
Managing Potential Side Effects
While PD-1 inhibitors empower the immune system to fight cancer, this enhanced activity can sometimes lead to side effects. Because the therapy “releases the brakes” on T-cells, the immune system can become overactive and attack healthy tissues. These side effects are known as immune-related adverse events (irAEs) and are distinct from the side effects associated with chemotherapy.
The most common irAEs are inflammatory. Patients may experience:
- Skin problems, such as a rash or itching.
- Inflammation in the digestive tract that can cause diarrhea or colitis.
- Lung inflammation (pneumonitis), which can lead to a cough or shortness of breath.
- Issues with hormone-producing glands, particularly the thyroid, which can become underactive or overactive.
- Inflammation of the liver, known as hepatitis.
It is important for patients to report any new or worsening symptoms to their medical team right away. Early communication allows for prompt management, which is key to preventing the side effects from becoming severe. Most irAEs are mild to moderate and can be managed effectively.
The standard approach for managing moderate to severe irAEs is to use medications that suppress the immune system, such as corticosteroids like prednisone. These drugs calm the overactive immune response and reduce inflammation. In some cases, treatment with the PD-1 inhibitor may need to be temporarily paused until the side effect resolves. For severe reactions, the immunotherapy may be discontinued permanently.