Immunotherapy for Bladder Cancer

Immunotherapy is the use of medicines to help a person’s own immune system recognize and destroy cancer cells. This type of treatment is sometimes used to treat bladder cancer.

Intravesical immunotherapy

These treatments are put directly into the bladder. They are used mainly for early-stage bladder cancers that haven’t grown deeply into the wall of the bladder.

Bacillus Calmette-Guerin (BCG) is made from a type of bacteria related to the one that causes tuberculosis. While it doesn’t usually make a person sick, it can help trigger an immune response. BCG can be put right into the bladder as a liquid. This activates immune system cells in the bladder, which then attack the bladder cancer cells.

Nadofaragene firadenovec (Adstiladrin) is made up of a virus that contains the gene to make interferon alfa-2b, an important immune system protein. When the virus is put into the bladder as part of a liquid, it delivers the gene into the cells lining the bladder wall. The cells then start making extra interferon alfa-2b, which helps the body’s immune system attack the cancer cells.

Nogapendekin alfa inbakicept (Anktiva) is an interleukin-15 (IL-15) receptor agonist. When put into the bladder as a liquid, it activates some of the body’s immune cells, including natural killer (NK) cells and T cells, which then attack the cancer cells.

For more details on these treatments, see Intravesical Therapy for Bladder Cancer.

Immune checkpoint inhibitors

An important part of the immune system is its ability to keep itself from attacking normal cells in the body. To do this, it uses “checkpoint” proteins on immune cells, which act like switches that need to be turned on or off to start an immune response.

Cancer cells sometimes use these checkpoints to keep from being attacked by the immune system. But drugs that target these checkpoints, called checkpoint inhibitors, can help restore the immune response against cancer cells.

PD-1 and PD-L1 inhibitors

Avelumab (Bavencio) and durvalumab (Imfinzi) target PD-L1, a protein on cells (including some cancer cells) that helps keep the immune system from attacking them. By blocking PD-L1, these drugs boost the immune system's response against the cancer cells. This can shrink some tumors or slow their growth.

Nivolumab (Opdivo) and pembrolizumab (Keytruda) target PD-1, a protein on certain immune cells (called T cells) that normally helps keep these cells from attacking other cells in the body. Blocking PD-1 can allow the immune system to attack the cancer cells, which can shrink some tumors or slow their growth.

These drugs can be used in different situations to treat bladder cancer. For example:

• Pembrolizumab can be used with enfortumab vedotin (see below), to treat advanced bladder cancer.
• Nivolumab can be used along with chemotherapy to treat advanced bladder cancer.
• Avelumab can be used as an additional (maintenance) treatment in people with advanced bladder cancer that did not get worse during their initial chemotherapy treatments.
• Most of these checkpoint inhibitors can be used in people with advanced bladder cancer that starts growing again after chemotherapy.
• Pembrolizumab can be used to treat certain bladder cancers that are not growing into the muscle wall of the bladder, are not getting smaller with intravesical BCG, and are not being treated with a cystectomy.
• Nivolumab might be offered to people with muscle-invasive bladder cancer (MIBC, cancer that has invaded the muscle wall of the bladder) that has been removed with surgery but is at high risk of recurring (coming back). In this situation, it is given for one year.
• Durvalumab can be used along with chemotherapy before a cystectomy in people with MIBC, and then again by itself after the cystectomy, for up to about 8 months.

These drugs are usually given as intravenous (IV) infusions, every 2 to 6 weeks, depending on the drug. Some can now be given as injections under the skin over several minutes as well.

Possible side effects

Side effects of checkpoint inhibitors can include:

• Fatigue
• Nausea
• Loss of appetite
• Fever
• Urinary tract infections (UTIs)
• Rash
• Diarrhea
• Constipation

Less often, more serious side effects can occur:

Infusion reactions: Some people might have an infusion reaction while getting one of these drugs. This is like an allergic reaction, and can include fever, chills, flushing of the face, rash, itchy skin, feeling dizzy, wheezing, and trouble breathing. It’s important to tell your doctor or nurse right away if you have any of these symptoms while getting one of these drugs.

Autoimmune reactions: These drugs work by basically removing one of the safeguards on the body’s immune system. Sometimes the immune system starts attacking other parts of the body, which can cause serious or even life-threatening problems in the lungs, intestines, liver, hormone-making glands, or other organs.

It’s very important to report any new side effects to your health care team right away. If serious side effects do occur, treatment may need to be stopped and you may get high doses of steroids to suppress your immune system.

Antibody-drug conjugates

Antibodies are proteins made by your immune system to help fight infections. Man-made versions, called monoclonal antibodies, can be designed to attach to a specific target, such as a protein on the surface of bladder cancer cells.

Antibody-drug conjugates (ADCs) are monoclonal antibodies that are linked to a chemo drug. Once inside the body, the antibody part of the ADC acts like a homing device, bringing the chemo directly to the cancer cells.

Enfortumab vedotin (Padcev)

Bladder cancer cells usually have the Nectin-4 protein on their surface. Enfortumab vedotin is an anti-Nectin-4 antibody attached to a chemo drug. The antibody part acts like a magnet to bring the chemo drug to the bladder cancer cells with Nectin-4 on them. The chemo enters the cancer cells and kills them.

This drug can be used along with the immunotherapy drug pembrolizumab (see above) in people with advanced bladder cancer.

It can also be used by itself to treat people with advanced bladder cancer who:

• Have already been treated with a platinum-based chemo drug (such as cisplatin) and immunotherapy (specifically, a PD-1 or PD-L1 inhibitor), OR
• Can’t be treated with cisplatin for some reason, and who have already had at least one type of drug treatment

Enfortumab vedotin is infused into a vein (IV), typically once a week for 2 or 3 weeks, followed by a week off.

Common side effects include fatigue, peripheral neuropathy (a type of nerve damage that can lead to numbness or tingling in the hands or feet), nausea, taste changes, decreased appetite, diarrhea, rash, hair loss, dry eyes or vision changes, dry skin, itching, and high blood sugar levels.

Less common but more serious side effects can include severe skin reactions, inflammation (swelling) in the lungs, and very high blood sugar levels.