Understanding the Role of Immuno-Oncology in Treating Cancer

General Immunotherapies

Some immunotherapies work by enhancing the immune system overall, without targeting specific cancer cells. These types of immunotherapies include:

• **Interleukins are naturally occurring proteins that help cells communicate with each other in order to regulate cell growth and immune response. Interleukins are a subset of cytokines, molecules which dictate how cells behave and stimulate other types of immune cells to further enhance treatment response.

Interleukins made in the laboratory are used to modify biological responses to boost the immune system. More than fifteen types of interleukins have been identified, each with its own immunological function.

• Interferons, another type of cytokine, play an important role in regulating many types of cell function. Interferons can help the immune system fight cancer by inhibiting cell division, which can slow or stop the growth of cancer.

• Colony stimulating factors can strengthen the immune system and protect against infection by increasing the number of white blood cells produced in bone marrow.

Cancer-Targeting Immunotherapies

The purpose of cancer-targeting immunotherapy is to modify the immune system to recognize that the cancer is foreign to the body and needs to be attacked. This can be difficult, because the differences between cancer cells and healthy cells are often quite small and hard to detect.

Additionally, white blood cells have “immune checkpoint” molecules that prevent our immune system from attacking normal cells. These molecules can also shield cancer cells. Immune checkpoint inhibitors are designed to remove the shield so that the immune system will recognize the cancer cells as being foreign.

• PD-1, PDL-1 inhibitors work by interfering with PD-1 or PDL-1 proteins that prevent the body’s immune system from attacking cancer cells. Drugs in this category include nivolumab (Opdivo), atezolizumab (Tecentriq), pembrolizumab (Keytruda), avelumab (Bavencio), durvalumab (Imfinzi) and cemiplimab (Libtayo).

• CTLA-4 inhibitors seek out and lock onto cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a protein that helps keep immune system cells deactivated. Ipilimumab (Yervoy) is designed to help the immune system destroy cancer cells by blocking the action of CTLA-4.

• LAG-3 inhibitors attach to and block a protein that keeps the immune system in check. Relatlimab, in combination with the PD-1 inhibitor nivolumab, was approved by the U.S. Food and Drug Administration (FDA) in March 2022. The combination, known as Opdualag, can be used to treat melanoma and is being studied for use in other types of cancer.

In addition to checkpoint inhibitors, immunotherapy approaches fall into the following main categories:

• Monoclonal antibodies are lab-generated proteins that target specific tumor antigens (substances that the immune system sees as being foreign or dangerous). Some monoclonal antibodies help the immune system recognize and destroy cancer cells. Monoclonal antibodies used in the treatment of certain cancers include rituximab (Rituxan) and trastuzumab (Herceptin).

• Bispecific antibodies are lab-generated proteins that target specific tumor antigens (as do monoclonal antibodies) but also bind proteins on the surface of immune cells (T-cells). This allows the T-cells to get close to and destroy the cancer cells. Blinatumomab (Blincyto) is an example of a bispecific antibody.

• Therapeutic vaccines can boost the immune system and have the potential to treat cancer or prevent it from recurring (coming back) after treatment. The FDA has approved vaccines for certain cancers. Additionally, a number of vaccines are being studied in clinical trials.

• Adoptive T-cell transfer (also called cellular adoptive immunotherapy) is an approach in which T-cells are removed from the individual, grown to an increased number in a laboratory and infused back into the individual with the goal of improving the immune system’s anti-cancer response. One type of adoptive T-cell transfer is chimeric antigen receptor (CAR) T-cell therapy, which is used to treat certain blood cancers.

Immunotherapies can sometimes work well in combination with other treatment types, such as surgery, radiation, chemotherapy and targeted therapy (treatments designed to target the specific cell mechanisms that are important for the growth and survival of cancer cells).

Immunotherapies can be used as a delivery mechanism by attaching a monoclonal antibody to a chemotherapy drug to make an antibody drug conjugate (ADC). The antibody seeks out and hones in on a specific molecule on the tumor cell, bringing the chemotherapy with it. This approach can kill tumor cells or stop them from dividing while limiting the harm to normal cells.

ADCs approved by the FDA include brentuximab vedotin (Adcetris), ado-trastuzumab emtansine (Kadcyla), inotuzumab ozogamicin (Besponsa), gemtuzumab ozogamicin (Mylotarg), polatuzumab vedotin-piiq (Polivy), enfortumab vedotin (Padcev), sacituzumab govitecan (Trodelvy), trastuzumab deruxtecan (Enhertu), belantamab mafodotin-blmf (Blenrep), Ioncastuximab tesirine-lpyl (Zynlonta) and tisotumab vedotin-tftv (Tivdak).

Immunotherapy travels through the bloodstream, helping to prompt what is called an “immune response.” Because immunotherapy can affect healthy cells as well as cancer cells, certain side effects may be experienced, including digestive tract symptoms, loss of appetite, fatigue, flu-like symptoms and changes to the skin.

Report any side effects that you experience to your health care team right away so they can help you manage them. The side effects can range in severity; reporting them early can minimize their intensity and seriousness, allowing you to keep to your treatment plan. It’s important to remember that not all individuals experience all side effects, and individuals may experience side effects not listed here.

Following are tips and guidance for managing these side effects.

Managing Digestive Tract Symptoms

Nausea and vomiting

• Avoid food with strong odors, as well as overly sweet, greasy, fried, or highly seasoned food.
• Eat meals cold or at room temperature, which often makes food more easily tolerated.
• Nibble on dry crackers or toast. These bland foods are easy on the stomach.
• Having something in your stomach when you take medication may help ease nausea.

Diarrhea

• Drink plenty of water. Ask your doctor about using drinks such as Gatorade which provide electrolytes as well as liquid. Electrolytes are body salts that must stay in balance for cells to work properly.
• Over-the-counter medicines such as loperamide (Imodium A-D and others) and prescription drugs are available for diarrhea but should be used only if necessary. If the diarrhea is bad enough that you need medicine, discuss it with your doctor or nurse.
• Choose foods that contain soluble fiber—for example beans, oat cereals, oranges, and flaxseeds. High-pectin foods such as peaches, apples, oranges, grapefruit, bananas, and apricots can also help to avoid diarrhea.
• Avoid food high in refined sugar and those sweetened with sugar alcohols such as sorbitol and mannitol. Look for this low-calorie sweetener on food labels; the names of this type of sweetener usually end with the letters “ol.”
• Low fat food choices are less likely to cause diarrhea than fatty, greasy, or fried foods. The fats you eat should come from healthy sources, such as olive oil, canola oil, avocado, olives, nuts, and seeds.
• Limit or avoid lactose, especially if you are lactose-intolerant. There are plant-based milk alternatives you can try, such as soy or rice milk. If lactose is an essential part of your diet, there are dairy products with added lactase (which breaks down lactose) and dietary lactase supplements.
• Any change in bowel habits, including frequency of bowel movements and any change in the quality or quantity of your stool, should be immediately be reported to your doctor or nurse.

Managing Loss of Appetite

• To help maintain your weight, eat small meals throughout the day. That’s an easy way to take in more protein and calories. Try to include protein in every meal.
• To keep from feeling full early, avoid liquids with meals or take only small sips (unless you need liquids to help swallow). Drink most of your liquids between meals.
• Be as physically active as you can. Sometimes, taking a short walk an hour or so before meals can help you feel hungry.
• Keep high-calorie, high-protein snacks on hand such as hard-boiled eggs, peanut butter, cheese, ice cream, granola bars, liquid nutritional supplements, puddings, nuts, canned tuna, or trail mix.
• Eat your favorite foods any time of the day. For example, if you like breakfast foods, eat them for dinner.
• If you are struggling to maintain your appetite, talk to your health care team about whether appetite-building medication could be right for you.

Managing Fatigue

Fatigue (extreme tiredness not helped by sleep) is one of the most common side effects of many cancer treatments. If you are taking a medication, your doctor may lower the dose of the drug, as long as it does not make the treatment less effective. If you are experiencing fatigue, talk to your doctor about whether taking a smaller dose is right for you.

There are a number of other tips for reducing fatigue:

• Take several short naps or breaks.
• Take short walks or do some light exercise, if possible.
• Try easier or shorter versions of the activities you enjoy.
• Ask your family or friends to help you with tasks you find difficult or tiring.
• Save your energy for things you find most important.

Fatigue can be a symptom of other illnesses, such as anemia, diabetes, thyroid problems, heart disease, rheumatoid arthritis, and depression. So be sure to ask your doctor if he or she thinks any of these conditions may be contributing to your fatigue.

Also, it could be very valuable to talk to an oncology social worker or oncology nurse. These professionals can also help you manage fatigue. They can work with you to manage any emotional or practical concerns that may be causing symptoms and help you find ways to cope.

Managing Flu-Like Symptoms

The fever and aches that may occur with immunotherapy treatments can be managed with a combination of rest and medication. Acetaminophen (such as Tylenol) is often a doctor’s first choice to treat these symptoms. Nonsteroidal anti-inflammatory drugs (NSAIDs) can also help, but should be taken only if recommended by your doctor, as they can cause other side effects. NSAIDs include aspirin, ibuprofen (Motrin and others) and naproxen (Naprelan, Midol, Aleve and others).

Managing Changes to the Skin

About 20 to 30 percent of people being treated with immunotherapy experience changes to the skin, such as an itchy, measles-like rash. If this occurs, contact your health care team so the appropriate treatment can be prescribed. The rash and itching can be treated with prescription-strength medications that are applied directly to the skin or taken as tablets. These medications are typically either antihistamines (drugs used to treat allergic reactions) or corticosteroids (drugs that act against inflammation).

It’s especially important to contact your health care team if you have any open skin or painful areas, as this could indicate an infection. Infections can be treated with an oral antibiotic or topical antibiotic cream.

Managing Pain

Both cancer itself and the side effects of treatment can sometimes cause pain. To help your doctor prescribe the best medication, it’s useful to give an accurate report of your pain.

Keep a journal that includes information on:

• Where the pain occurs
• When the pain occurs
• How long it lasts
• How strong it is on a scale of 1 to 10, with 1 being the least amount of pain and 10 the most intense
• What makes the pain feel better and what makes it feel more intense

There are a number of options for pain relief, including prescription and over-the-counter medications. It’s important to talk to a member of your health care team before taking any over-the-counter medication in order to determine if it is safe and will not interfere with your treatments. Many pain medications can lead to constipation, which may make your pain worse. Your doctor can prescribe medications that help to avoid constipation.

Physical therapy, acupuncture and massage may also be of help in managing your pain. Other techniques, such as mindfulness meditation, deep breathing exercises and yoga may also be helpful. Consult with a member of your health care team before beginning any of these activities.

Frequently Asked Questions

Q: I’ve recently been diagnosed with cancer. What questions should I ask my oncologist about immunotherapy as a possible treatment approach?

A: Specific questions to discuss with your oncologist include:

• Does immunotherapy have a role in treating my type of cancer, alone or in combination with other treatments?

• Are there FDA-approved immunotherapies for my type of cancer?

• Are there any immunotherapies currently being studied in clinical trials for my type of cancer?

• What are the possible side effects of the immunotherapy approaches for my type of cancer?

Q: Will immunotherapy replace other types of cancer treatments?

A: There is much enthusiasm for immunotherapy as a treatment approach for many types of cancer. However, other forms of treatment are still considered to be effective, depending on the individual’s specific circumstances. This includes treatments that have been used for many years, such as radiation and chemotherapy, and newer approaches such as targeted therapy. It’s also important to note that immunotherapy can often be most effective when used in combination with other forms of treatment. Additionally, not all cancers survive and grow by evading the immune system. For those types of cancer, immunotherapy is not the right treatment approach.

Q: I am being treated with a vaccine for my cancer. Will this interfere with the other vaccines I usually get?

A: In order to stay as healthy as possible during any type of cancer treatment, it is generally recommended that you continue to receive the vaccines recommended for your specific situation, which can include shots for influenza, coronavirus, pneumonia and herpes zoster (shingles). However, this is an important issue to discuss with your health care team, as there can be exceptions to this general guidance.

Q: Is immunotherapy safe for people with an underlying autoimmune disease?

A: Common autoimmune diseases include diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and lupus. Studies have shown that people with an autoimmune disease can respond well to immunotherapy. However, the potential benefits must be measured against the potential risk, as the underlying condition may temporarily worsen during the course of immunotherapy. People with an autoimmune disease who are being treated with immunotherapy for cancer should be closely monitored by their health care team (including their oncologist and the specialist treating the underlying condition).

Q: How long do I have to stay on my immunotherapy treatment?

A: The duration of immunotherapy treatments depends on a number of factors, including the type of immunotherapy being received. For instance, a vaccine might be given just once, while other medications may be given at set intervals over a number of weeks. How long to continue certain immunotherapies is an area of ongoing research in clinical studies.