Other novel treatments that are not yet FDA-approved for these and other GU cancers may be available through clinical trials as researchers continue to improve existing therapies and explore new ones. Additional strategies, such as using pembrolizumab (Keytruda) for the treatment of some solid tumors that are microsatellite instability-high cancer (MSI-H), may also be considered.
To be a candidate for immunotherapy, you must meet certain criteria, such as having a functioning immune system, not having an autoimmune disorder and not be taking immunosuppressive medications. Biomarker testing may also be a requirement because some immunotherapies are approved to treat cancers in people with specific biomarkers present.
The Role of the Immune System
To better understand how immunotherapy is effective against these types of cancer, it helps to have basic knowledge about the immune system. Your body faces harmful organisms every day that could negatively affect your health. To keep you healthy, you have an immune system that works steadily behind the scenes to identify and eliminate these organisms. You are typically aware of your immune system only when an infection or irritation occurs. When a bug bites your skin, for example, you may develop an itchy, red bump. The bump is a physical sign that your immune system is working. Over a period of days, your immune system causes the reaction to the bite and heals it.
Another example is when you develop a cold. Germs can sometimes get past the natural defenses of the immune system – your nostrils, skin, saliva and mucus coating the inner linings of organs, eyes and mouth – and you may experience a cold. Your healthy immune system works to destroy the virus or bacteria that caused your illness and helps you recover.
Key parts of the immune system
The immune system is a complex network of cells, molecules, organs and lymph tissues working together to defend the body against germs, cancer cells and other microscopic invaders. The first job of the immune system is to distinguish between what is part of the body (“self”) and what is not part of the body (“non-self”). Once the immune system determines that a cell is non-self, or foreign, to the body, it begins a series of reactions to identify, target and eliminate the non-self cells.
The key driver of the immune system is the lymphatic system. The lymphatic system circulates clear fluid called lymph through the body to do several things:
- Defend the body against harmful substances, such as germs
- Fight infections
- Drain fluids in the body’s tissues from the bloodstream to help the body maintain proper fluid levels
- Filter lymph through the lymph nodes
- Filter blood through the spleen
- Identify and eliminate cancer cells
Lymph nodes, located throughout the body (with larger concentrations near the chest, abdomen, groin, pelvis, underarms and neck), circulate lymph. Although lymph and lymph nodes make up a large part of the lymphatic system, it also includes other organs, such as the skin, thymus, spleen, appendix, tonsils and adenoids. These organs collect, filter and circulate lymph. The lymph moves to the lymph node, where the foreign objects, such as bacteria, viruses, toxins and chemicals, also known as antigens, are eliminated. You may notice swollen lymph nodes in your neck, for example, when you have a cold or sore throat. Those lymph nodes swell as they work to rid your body of the infection.
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).
Another major component is your skin, the immune system’s first barrier of protection. When you skin your elbow, for example, the barrier is broken and harmful substances can easily enter the body. Immediately after the injury occurs, immune cells in the injured tissue begin to respond. They call other immune cells that have been circulating in your body to gather at the site and release messenger proteins, called cytokines, to call other immune cells to help defend the body. This is called an immune response. The immune cells can recognize any bacteria or foreign substances as dangerous and begin to destroy them with a general attack.
How the immune system attacks cancer
Cancer develops when one or several abnormal cells divide and multiply to become a mass of abnormal cells (tumor). Mutations in DNA may cause normal cells to become abnormal or different enough from the body that the immune system may recognize the cancer cells as non-self, which may stimulate an immune response. But, because the cells started as normal cells, the immune system may still see the cancer cells as part of the body and not coordinate an attack. In this way, the tumor cells are able to “hide” from the immune system.
As you think about how cells in the body interact, it is important to know that the surface of a cell is not completely round and smooth. Instead, it contains various proteins, sugars, fats and other molecules that stick out of the cell’s surface. These components contain information that is shared between cells through chemical signals and their receptors.
One of the key cells needed to stimulate an immune response is the antigen-presenting cell (APC). APCs are able to find and pick up dangerous antigens, “eat” them and prepare them to be presented to other cells by sharing the antigens on their surface to be recognized by T-cells. In this manner, the APC sounds an alarm that there is an intruder in the body, and T-cells respond to this alarm. When a T-cell encounters an APC, it changes into either a killer T-cell to fight the intruder or a helper T-cell to begin assisting or “helping” the immune response.
How Cancer evades the immune system
Cancer cells are smart. Over time, not only can they change, they can use multiple methods to escape or confuse the immune system. They can produce proteins on their surface that they use to hide from the immune system, like camouflage. In addition, they can create their own messengers (cytokines), which means that the cancer cells can communicate and confuse other immune cells, allowing the cancer to take control of certain parts of the process that the body uses to regulate the immune response. This means that even if the immune system recognizes the cancer, it may not be able to successfully start or maintain an attack long enough to kill the cancer cells.
The longer the cancer cells face a weakened immune response, the more they are able to adapt, and the easier it is for them to manipulate immune cells inside the tumor’s location (sometimes called the microenvironment). The microenvironment typically contains cancer cells, normal connective tissues that form the structure of the tumor and provide access to blood vessels that drive tumor growth, and several cell types that contribute to tumor development. Immune cells found in this area are often referred to as tumor-infiltrating lymphocytes (TILs). Because the tumor can control the cells in the area, the tumor can trick TILs into becoming useless or even helping the tumor grow.
For example, APCs in the tumor area may be confused by signals from tumor cells, preventing them from functioning properly and making them incapable of sounding the alarm about a threat. In some cases, tumors can increase the activity of regulatory T-cells inside the area. These regulatory T-cells are designed to end immune responses. Thus, they naturally slow down the immune system after an immune attack is completed. By increasing the activity of regulatory T-cells, the tumor is recruiting the body’s own immune cells to fight off the attack, using the very processes that normally protect the body to help the cancer cells multiply undetected.
Tumors often contain more than one type of cell, and, when a tumor changes the composition of its cells, this can confuse the immune system. The longer the immune system is exposed to the tumor, the weaker the immune response becomes. Although your immune system can kill some of the dangerous cells, it may not be able to destroy all of them or prevent them from multiplying. Certain immunotherapy agents, however, are designed to help your immune system do just that. Immunotherapy treatments offer different ways to address how tumors manipulate the immune system and how immunotherapy drugs are designed to reverse those processes.
Illustration: Figure 1 Genitourinary anatomy (filename: Overview Fig 1)
Illustration: How cancer hides from the immune system (filename: Overview Policeman)
SIDEBAR: HOW THE IMMUNE SYSTEM REMEMBERS
Although cancer cells can be clever, the immune system has a long memory when it comes to battling dangerous cells. When your immune system encounters a virus, such as chicken pox, the memory T-cells check to see if that virus has any characteristics of cells they have attacked in the past. If they do, your memory T-cells offer you immunity from that virus, and you don’t come down with another case of chicken pox. If they don’t, the memory T-cells alert the rest of the immune system about the virus and tell it to make more immune cells to attack and keep you from getting the disease again. Memory T-cells stay alive and store this information for a long time, offering the ability to be effective long after treatment ends. Investigators believe that effective immunotherapy can result in cancer-specific memory cells providing long-term protection against cancer.