Immunotherapy for Bladder Cancer
Immunotherapy uses the body’s own immune system to treat many different types of cancer, including bladder cancer. Immunotherapy helps the immune system recognize and attack cancer cells that have been hiding and targets them for destruction, which is very different from other types of cancer treatments. Several types of immunotherapy have been approved for bladder cancer.
Intravesical Therapy
Bladder cancer was the first cancer type to receive an approved immunotherapy agent, which was a breakthrough for modern immunotherapy. This agent, bacillus Calmette-Guérin (BCG), was approved by the FDA in 1990 and continues to be one of the main treatments for nonmuscle-invasive bladder cancer.
BCG contains a weakened version similar to the bacterium that causes tuberculosis. It is delivered directly into the bladder through a catheter. This is called intravesical therapy (see Figure 1). BCG attaches to the inside lining of the bladder and stimulates the immune system to destroy the tumor. BCG is used for early-stage bladder cancer and as treatment to reduce the risk of recurrence in noninvasive bladder cancers, commonly after surgery to remove the tumors.
BCG is no longer the only immunotherapy approved to treat bladder cancer. More recently, other classes of immunotherapy have become available, including checkpoint inhibitors and a cytokine.
Immune Checkpoint Inhibitors
Several immune checkpoint inhibitors are approved to treat locally advanced or metastatic urothelial carcinoma, the most common form of bladder cancer, in people with whom disease progressed during or following chemotherapy containing a platinum drug or in whom disease progressed within 12 months after neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
To understand how immune checkpoint inhibitors work, it helps to learn about parts of the immune system. Lymphocytes (white blood cells) are a major part of the immune system. They begin in the bone marrow and develop from lymphoblasts (immature cells found in bone marrow). Lymphoblasts mature into infection-fighting cells. The two main types of lymphocytes are B-lymphocytes (B-cells) and T-lymphocytes (T-cells).
B-cells develop in the bone marrow and mature into either plasma cells or memory cells. Plasma cells make antibodies to fight germs and infection. Memory cells help the body remember which antigens attacked the body so it can recognize them if they return.
T-cells also develop in the bone marrow but travel to the thymus to mature into helper T-cells, killer T-cells, regulatory T-cells or memory T-cells. Each type of T-cell plays a part in the immune system.
- Helper T-cells identify foreign, or non-self, antigens and communicate with other immune system cells to coordinate with the B-cells or other T-cells for an attack.
- Killer T-cells directly attack and destroy cancer cells, or normal body cells infected with a virus, by inserting a protein that causes them to enlarge and burst. One type of killer T-cell specifically targets cancer cells.
- Regulatory T-cells slow down the immune system after an immune response is finished.
- Memory T-cells can stay alive for years, continuing to fight off the same invading cells. Memory is the basis of immune protection against disease in general and explains why we usually don’t become infected with some diseases, such as chicken pox, more than once.
Checkpoints keep the immune system “in check,” preventing an attack on normal cells by slowing down or eliminating activated immune cells, or through the use of regulatory T-cells that can block activated immune cells. A series of signals between the correct proteins and receptors on cell surfaces turn off activated T-cells or tell the regulatory T-cells to slow down the immune system after an immune response is finished.
To better understand how this happens, think of the proteins and receptors on a cell’s surface as puzzle pieces. Proteins have “tabs” that protrude (stick out), and receptors have “spaces” that curve inward. When the puzzle pieces fit together, chemicals and information are exchanged between the cells, triggering signals to slow the immune system.
- CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a receptor that binds with certain molecules to tell the immune system to slow down.
- PD-1 (programmed cell death protein 1) is a receptor involved with telling T-cells to die and to reduce the death of regulatory T-cells (suppressor T-cells). Both have an effect to slow down an immune response. PD-1 can only tell the immune system to slow down if it connects with PD-L1.
- PD-L1 (programmed death-ligand 1) is a protein that, when combined with PD-1, sends a signal to reduce the production of T-cells and enable more T-cells to die.
When PD-1 (the receptor) and PD-L1 (the protein) combine, the reaction signals the immune system that it is time to slow down. One of the ways cancer can outsmart the immune system is by producing PD-L1 (the protein) on the surface of its cells and using it to camouflage its appearance so that T-cells will think they are normal cells. When a T-cell encounters PD-L1 on a cancer cell, it sends a signal for the immune system to slow down. This is a normal way to prevent the immune system from attacking normal cells in the body.
Immune checkpoint inhibitors are drugs that prevent the proteins and receptors (puzzle pieces) from fitting together and triggering the slowdown of the immune system.
When an immune checkpoint inhibitor is given, the immune system is not so easily fooled by the cancer. By not slowing down, it’s like the immune system develops X-ray vision and can see through the disguise. This keeps the immune response on and also helps the immune system recognize cancer cells as foreign cells.
The following types of immune checkpoint inhibitors are currently approved for bladder cancer.
- Anti-PD-1 drugs, which allow for the continued or increased activation of T-cells and enable them to continue fighting cancer.
- Anti-PD-L1 molecules, which allow the T-cells to see through the disguises of some tumor cells, recognize them as the enemy and attack them.
Cytokines
Cytokine immunotherapy is a type of nonspecific immune stimulation that aids in communication among immune cells and plays a big role in the full activation of an immune response. This type of immunotherapy works by introducing large amounts of laboratory-made cytokines to the immune system to promote specific immune responses. The cytokines approved for bladder cancer are interferons, which boost the ability of certain immune cells to attack cancer cells as well as stimulate the immune system.
Other types of treatment are also available. Be sure to talk with your doctor about which treatment options are best for you, especially since not all immunotherapies are approved for all types and stages of bladder cancer.
Common Side Effects
Like other cancer treatments, immunotherapy may have side effects (see Side Effects, page 13). Because these drugs work by stimulating the immune system, it’s important to pay attention to your side effects. Your doctor will monitor you closely for complications during treatment, and your medical team will rely on you to communicate your side effects frequently because they may develop rapidly and may range from mild to life-threatening. Seek treatment immediately, regardless of time of day, for symptoms including high fever, inflammation, swelling, severe abdominal pain or shortness of breath.
Immune-related adverse events are the most serious side effects of immune checkpoint inhibitors. They are not common but can occur when the immune system is overstimulated by the treatment, which may cause inflammation, swelling or redness. Symptoms may come on suddenly and require immediate medical attention, which is why monitoring them is critical to helping you recover. Following are some of the systems that may be affected by immune-related adverse events when being treated for bladder cancer:
- Cardiovascular (cardiomyositis)
- Endocrine (endocrinopathies)
- Gastrointestinal (colitis)
- Liver (hepatitis)
- Neurologic (encephalitis)
- Pulmonary (pneumonitis)
- Skin (dermatitis)
FDA-APPROVED BLADDER CANCER IMMUNOTHERAPIES
Cytokine
- interferon (Roferon-A, Intron A, Alferon)
Immune Checkpoint Inhibitors
- atezolizumab (Tecentriq)
- avelumab (Bavencio)
- durvalumab (Imfinzi)
- nivolumab (Opdivo)
- pembrolizumab (Keytruda)
Intravesical Therapy
- bacillus Calmette-Guérin (BCG)
As of 8/27/18
BLADDER CANCER TREATMENT POTENTIAL SIDE EFFECTS
Immune checkpoint inhibitors
- Abdominal pain
- Arthralgia (joint pain)
- Back pain
- Constipation
- Cough
- Decreased appetite
- Diarrhea
- Dyspnea (difficulty breathing)
- Fatigue
- Fever
- Headache
- Infusion-related reaction (fever, chills, low blood pressure during or after treatment)
- Musculoskeletal pain
- Nausea
- Peripheral edema (swelling in the lower limbs)
- Pruritus (itching)
- Rash
- Upper respiratory tract infection
- Urinary tract infection
- Weakness
Vaccines
- Back pain
- Chills
- Fatigue
- Fever
- Headache
- Joint ache
- Nausea
Cytokines
- Chills
- Confusion/delirium
- Decreased appetite
- Depression
- Diarrhea
- Fatigue
- Fever
- Headache
- Low blood pressure
- Myalgia (muscle pain)
- Rash
- Reversible kidney damage
- Swelling due to fluid below the skin
Illustration: Figure 1 Anatomy of bladder and BCG treatment (filename: Bladder Fig 1)