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Immune Checkpoints

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2. What is Shared Decision-Making?

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An adaptive response is slower to respond, but is smarter and more targeted. The adaptive response identifies threats based on small particles of them called antigens. An example of an antigen is the pieces of viruses included in the seasonal flu vaccine. There are special immune cells that spot antigens and haul them in front of the immune system's main protector: the T cell. T cells inspect the antigen to see if it’s really a threat. If it is, T cells that specifically target that antigen start to multiply and attack the source it came from. The key feature of the adaptive immune response is memory: the ability of the immune system to remember what it has identified and attacked as abnormal or foreign.

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3. But I’m not a doctor, what can I bring to the table?

Tips for Immunotherapy Success

4. What are the benefits of SDM?

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2. What kinds of ICIs are available?

At the heart of shared decision-making is the idea that successful treatment takes more than just clinical knowledge. Because every cancer case and every cancer patient is unique, you actually have quite a lot to bring to the table—your experiences, preferences, values, questions, concerns, plans, fears, expectations, hopes, and more. Just like you’ll be learning about immunotherapy from your doctor, your doctor will be learning about you from…well, you! Open communication will make both of you better teachers and better learners and help establish a solid foundation of trust between you and your doctor.

Understanding Immunotherapy

PD-1 Inhibitors • Pembrolizumab (Keytruda) • Nivolumab (Opdivo) • Cemiplimab (Libtayo)  PD-L1 Inhibitors • Atezolizumab (Tecentriq) • Avelumab (Bavencio) • Durvalumab (Imfinzi)  CTLA-4 Inhibitors • Ipilimumab (Yervoy)

Innate Response

Sharing the Caring: Recognizing irAEs

These drugs are all given by intravenous (IV) infusion. ICIs can be used by themselves, but are often combined with chemotherapy or each other depending on the type of cancer. Each ICI is approved for certain types of cancer, but the list of cancers they can be used for is constantly being researched and expanded.

This resource is intended to help patients understand their immunotherapy journey better, and we want to make sure it does! You can help us improve this and future resources by answering a brief survey about your experience today. All responses are voluntary and anonymous. Thank you!

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Recognizing irAEs

• Lungs • Gastrointestinal

Most Common • Skin • Thyroid • Liver

irAEs in the liver often don't cause symptoms, but your doctor may recognize them on lab tests. When liver irAEs do cause symptoms, they're usually tough to distinguish from other causes with similar symptoms, such as abdominal discomfort, nausea, and vomiting. These irAEs can occur anywhere from 4 to 25 weeks after the start of ICI therapy. Liver irAEs are less common than other irAEs, and occur in 5-10% of patients. They happen more often with CTLA-4 inhibitors than with PD-1/PD-L1 inhibitors, and combination therapy further increases the risk. Reducing or eliminating alcohol consumption can decrease the risk of liver irAEs.

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5. What are the most common irAEs?

Liver irAEs: What to Watch for

What to Share

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Traditional chemotherapy drugs kill rapidly growing cells by chemically damaging them. Chemotherapy affects cancer cells more than normal cells, because cancer cells multiply much faster. But it also damages other fast-growing normal cells like those in the skin and GI tract. This results in somewhat predictable side effects, such as hair loss, anemia, and mouth sores. ICIs don't directly damage either cancer cells or normal ones. Instead, they make it easier for the immune system to identify and attack cancer cells. ICIs still have side effects, but these are caused by the immune system attacking normal cells by mistake.

Less Common • Blood or bone marrow • Cardiovascular • Joints or muscles • Neurological 

Understanding Immunotherapy

There are many ICIs currently approved by the FDA for patient use. There are 3 categories, based on how they work

Skin

Gastrointestinal

1. Are there different types of irAEs?

Liver

Lungs

Endocrine

2. Are they the same as side effects from chemo?

Tips for Immunotherapy Success

Grade 1 (mild) and 2 (moderate) irAEs are usually managed by treating the symptoms with oral steroids and anti-inflammatory medications. You can usually continue your ICI without interruption, but for persistent side effects, your ICI may be held until your symptoms get better.

Almost all cells in your body have a complete set of instructions that guide everything the cell does. These instructions are written into a very long, ladder-like molecule called DNA that is tightly coiled into X-shaped chromosomes and stored in each cell's nucleus. Within the DNA chain are sections called genes, which contain all the instructions to perform a specific task, like making a protein, for example. Think of genes like apps on your phone or programs on your computer. When a gene is activated and performs its task, we call the result the gene expression.

Grade 3 (severe) and 4 (very severe) irAEs will likely require being admitted to a hospital to be seen by a specialist. They are managed with intravenous steroids and additional immunosuppressant medications. ICI treatment will be put on hold and often needs to be discontinued permanently.

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Yes. General adverse events affect the entire body, and the symptoms they cause are symptoms of many other diseases. These include symptoms such as fatigue, fever, chills, and infusion reactions. There are also organ-specific side effects. These only occur in specific organs like the lungs, liver, or skin. The symptoms they cause are an indicator of what part of the body is affected by the irAE.

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Immunotherapy and Immune-related Adverse Events

Cancer and Immune Checkpoints

1. How are immune checkpoint inhibitors (ICIs)    different from chemotherapy?

Cancer

Immunotherapy and Immune-Related Adverse Events (irAEs)

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Cancer is thought to start from changes in a cell's genes that interfere with normal cell processes. Eventually, these changes allow the cell to grow and multiply out of control. Cancer cells use a lot of tricks to avoid being detected or killed. Some examples include: • Stimulating the growth of more cancer cells • Overcoming normal body processes and barriers that limit cell growth • Causing new blood vessels to grow to supply nutrients to tumor cells • Multiplying an unlimited number of times • Invading other tissues in the body • Preventing the immune system from recognizing and destroying the cancer cells

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The Immune System and Cancer

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Immune checkpoint inhibitors (ICIs) are a type of immunotherapy that blocks checkpoint proteins like PD-1, PD-L1, or CTLA-4. Cancer cells are especially sensitive to these drugs because they rely on using these proteins to avoid being detected and killed by T cells.

PD-1 and PD-L1 inhibitors attach to one of these markers and prevent cancer cells from using them to deactivate T cells and slip past the immune checkpoint.

Gene Expression

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Adverse events affecting the skin are the most common and earliest to appear irAEs. They can show up after as little as five weeks of treatment. Most are mild to moderate, but up to 10% of cases can become severe. Skin rash and itching is reported in up to 40% of patients on one ICI and 50-70% of patients on combination therapy with two ICIs.

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Immune System and Cancer

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Immunotherapy and How it Works

Skin irAEs: What to Watch for

What to Share

GI irAEs typically show up as diarrhea and symptoms of colitis, which is inflammation of the large intestine. Most common with CTLA-4 inhibitors (30-40%), less common with PD-1/PD-L1 inhibitors (15-20%). Can start after approximately three infusions. Potentially fatal. Early recognition and treatment are critical!

Gene Expression

Activating the immune system can kill cancer cells but may also cause inflammation towards normal cells. This can be seen in any organ and can occur weeks to months (or longer) after treatment. irAEs most often show up within a few weeks or months of starting treatment. irAEs that affect the skin and GI tract tend to show up earlier than other side effects. Combination therapy with more than one ICI tends to cause more severe side effects than one-drug ICI.

Cancer

Immune System

1. How are immune checkpoint inhibitors (ICIs)    different from chemotherapy?

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3. How do they happen?

Immune System And Cancer

Immune-related adverse events, or irAEs, are side effects that are unique to immunotherapy treatments like checkpoint inhibitors. While most irAEs are mild to moderate and reversible if addressed early on, they can lead to serious and even life-threatening harm if they aren’t treated. This section will help familiarize you with the basic facts about irAEs, as well as the more common symptoms they cause. You play a key role in your care by alerting your oncologist if these symptoms occur. You can click on the different organs in the figure to learn how irAEs show up in each area of the body.

Carry a card in your wallet or purse that details any ICI therapy you’re receiving.

Antibody

Immune System and Cancer

Cancer and Immune Checkpoints

00 mins 56 secs

Innate Response (body’s natural response)

Immune Checkpoint Inhibitors

Your immune system can distinguish between “you” (the cells and substances that are a normal part of your body) and those that aren’t. If your immune system couldn’t, it would attack and destroy your own cells, a condition called “autoimmunity”.

This interactive resource is designed to provide key information for you through each phase of your immunotherapy treatment journey. You’ll learn what immunotherapy is and how it will be used to treat your cancer, as well as the potential risks and side effects that are unique to this kind of therapy. The journey can seem overwhelming, so to help with that this tool is divided into several phases that you will be guided through. Along the way, you’ll hear directly from a real-life patient and their oncologist about their personal experiences: the results they saw, the difficulties they encountered, and the advice they have for you to consider in your own immunotherapy journey.

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Immune Checkpoint Inhibitors

Welcome to Your Immunotherapy Journey

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1. What is my role in managing irAEs?

Rash

Shared decision-making, or SDM, is an approach to medical care where you and your doctor work together as partners to make decisions about your cancer care. It’s a way of thinking that combines the best medical evidence with your personal values and preferences. A shared decision-making approach to immunotherapy encourages open communication between you and your oncologist about the risks and benefits of these cutting-edge treatments. It also allows you to take an active role in your care by alerting your doctor to potential early symptoms of irAEs.

Redness/Rash

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Blistering

Cracking/Peeling Skin

Currently Approved ICIs

Adaptive Response

01 min 06 secs

Common Patient Questions

Pneumonitis is inflammation of the lungs isn’t caused by an infection. It occurs as a side effect in about 5% of patients on one ICI drug and a little more often with ICI combination therapy. Potentially fatal. Early recognition and treatment are critical! • Report any of the following to your healthcare provider the moment you recognize them—don’t wait, even if you think the symptoms are mild! Common Symptoms • Persistent cough that gets worse over time • Shortness of breath on exertion (going up stairs) • Chest pain felt in the lungs when breathing or coughing • Fever

Lung irAEs: What to Watch for

6. How are irAEs managed?

ICIs work by making the immune system more sensitive overall by interfering with the mechanisms that cause T cells to back off the cancer cells. Because ICIs block immune checkpoints all over, it sometimes results in the immune system inappropriately targeting normal cells, which is called an autoimmune reaction. Autoimmune reactions from ICI treatment can occur almost anywhere in the body, showing up as side effects called immune-related adverse events, or irAEs.

Common Symptoms • Diarrhea (loose, watery stools) • Abdominal pain or tenderness More Severe Symptoms • Dehydration from diarrhea • Severe abdominal pain • Severe nausea/vomiting • Fever

Improved understanding Knowing your choices, their risks, and their benefits helps you to make a fully informed decision about the treatment option that is right for you. Clearing the Confusion Discussion with your doctor can help address misconceptions or concerns you might have and alleviate anxiety about treatment decisions. Increased Satisfaction Feeling included and in-the-loop makes your treatment experience more positive by helping you feel comfortable about the decisions you make. Feeling Heard Where there aren’t multiple options, knowing that you still express your concerns can reassure you and give you the confidence to push forward.

Sharing the Caring: Recognizing irAEs

• Bleeding - may appear as:   - Black or tarry stools   - Bright red blood in stool or in toilet      bowl after using

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• Ocular • Pancreatic • Renal • Adrenal, or pituitary glands

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No PD-L1 T-cell kills Tumor cell

3. What are the risks of ICIs?

Speak Your Mind Cancer treatment isn’t a one-way street, and your relationship with your oncologist should be one where you feel heard, respected, and involved. You should be able to openly speak your mind and express yourself regarding your cancer care.

irAEs can also affect the endocrine system, a chemical messenger system that uses hormones to regulate the body. The major endocrine glands affected by irAEs are the thyroid, pituitary, and adrenal glands plus the pancreas. Endocrine side effects are usually mild to moderate, with the main effect being the loss of the hormone being made by the affected endocrine organ. This can be permanent and require lifelong hormone replacement therapy. The symptoms of endocrine side effects depend on the organ or gland affected. Below are irAE symptoms for the most commonly affected endocrine organs. Common Symptoms • Thyroid: Fatigue, slow speech, hot/cold sensitivity, constipation • Pituitary: Headache, double vision, excessive thirst, excessive urination, behavior changes • Adrenal: Extreme fatigue, weight loss, loss of appetite, darkening of skin, salt craving, GI symptoms (nausea, vomiting, diarrhea) • Pancreas: Excessive thirst, excessive urination, blurred vision, fruity odor on breath, abdominal pain

Doctors classify side effects from any cancer treatment by assigning them a "Grade" on a severity scale of 1 (lowest) to 4 (highest). The grade determines how the symptoms will be managed and whether ICI therapy can continue.

Endocrine irAEs: What to Watch for

An innate response is a rapid-response, first line of defense against outside threats. The innate immune system doesn’t identify specific targets to attack, but attacks based on certain molecular patterns it knows don’t belong. Innate immune cells release substances that cause inflammation and activate the adaptive immune system to help clear the threat.

Immunotherapy and Immune-Related Adverse Events

Gene Expression

We know that the immunotherapy journey is a challenging one, and we hope that this resource has helped you better understand this cutting-edge cancer treatment and its risks. Remember, you don’t need to know everything there is to know about irAEs. Your part is to do your best to learn and watch for the symptoms of immune-related adverse events. If you think you recognize one, report it to your doctor right away. It’s always better to over-report than under-report! Thank you for sharing your time with us today. We hope this web tool has made you more comfortable with immunotherapy.

When a normal cell is inspected at one of these checkpoints, its PD-L1 marker links up with a matching marker on the T cell called PD-1. This lets the T cell know they're on the same side. Think of it as a “shut-down” switch that prevents T cells from attacking normal cells.

Normal cells have a special marker called PD-L1 that helps the immune system recognize these cells as you.

T cells guard against intruders by inspecting cells they encounter to see if they belong or not, a step called an immune checkpoint.

Non-human cells like bacteria don’t have the PD-L1 marker, so when T cells catch them, it tells the immune system to get ready for a fight. Abnormal cells often don’t have a PD-L1 marker, either. When a T cell inspects a cancer cell and doesn’t detect PD-L1, it immediately attacks and kills it. But some tumor cells can express PD-L1 to disguise themselves as normal cells.

CTLA-4 is a special molecule that allows T cells to be deactivated when not needed. This acts like a brake on the immune system so it doesn't respond excessively.

Make a List Make a list of the questions you have and topics you want to discuss with your oncologist. Cancer treatment can be overwhelming, and sometimes simply writing something down is the best way to organize your thoughts and avoid forgetting anything.

4. Who gets them? Are they more common than other     adverse events?

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Do Some Research Do some background research about your cancer type to learn about immunotherapies available for your cancer type. The Cancer Research Institute is an excellent resource for accurate, plain-language information about cancer, the immune system, and immunotherapy. Visit their Immunotherapy Patient Resources page to learn more. A new window will open to view this page. Be sure to return to this window to continue with this activity.

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Bring Others Into Your Circle You aren’t in this alone, even if it feels that way sometimes. Share what you’re learning with the people who are important to you. Consider asking them to accompany you to doctor visits…just knowing that someone else is listening takes the weight of having to remember everything off your shoulders.

Patient Resources and Tools for Immunotherapy and Immune-Related Adverse Events

An Interactive Patient Journey

Immune-Related Adverse Events

Immune System

2. What kinds of ICIs are available?

These side effects are different from the ones associated with chemotherapy. They can be unpredictable and hard to recognize. While the range of immunotherapy side effects is mostly known, extremely rare effects are just being understood. It's also relatively clear that immune side effects can still occur several months (but not years) after treatment discontinuation.

Immune Checkpoint Inhibitors

3. What are the risks of ICIs?

When it comes to immune-related adverse events, more information is always better than less. Your doctor trusts in you to promptly report information and will be able to tell whether something you share points to a potential irAE. Your doctor may be able to provide you with an immunotherapy wallet card. If not though, here's an excellent version from the Oncology Nursing Society that you can print out: Immunotherapy Wallet Card A new window will open to view this print out. Be sure to return to this window to continue with this activity. Be sure to share with doctors or emergency room staff: • Any treatment with ICIs within the past year • Current ICI treatment you’re receiving Be aware that your ICI treatment history will be very helpful for a doctor to know if you are having vague symptoms, for example, fatigue. Lots of conditions cause fatigue, but fatigue caused by irAEs can progress to much more serious symptoms if not recognized early.

Immune System

The immune system is made up of many different parts in your body that work together to protect you. Some of these parts—such as the skin, the cornea of the eye, and the membranes lining your insides—act as a physical or chemical barrier against outside invaders. Other parts, like lymph nodes, bone marrow, the spleen, and thymus gland contribute by making white blood cells (WBCs). WBCs are the soldiers of the immune system; they do the dirty work of killing germs and cancer cells. The immune system has two kinds of responses to threats: an innate response and an adaptive response.

Many types of cancer can slip through immune checkpoints by making a lot of PD-L1, which tricks T cells into leaving them alone

CTLA-4 inhibitors "take the brakes off" the immune system by preventing it from deactivating T cells. Activated T cells are able to find and kill cancer cells, so having more of them around helps them attack cancer more effectively.

Cancers can also make the markers that link with CTLA-4 on T cells, allowing the cancer cells to deactivate them and avoid being attacked

Common Symptoms • Rash • Pruritus (itchy skin, with or without rash) • Vitiligo (loss of skin color that appears as white patches) • Sensitivity to sunlight More Severe Symptoms • Cracked, flaking, or peeling skin • Blistering • Rash covering large areas of the body     (like your entire back or arm, for example) • Severe itching

Examples of Skin irAEs

Mild to moderate

Severe

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Immune Checkpoints

Gastrointestinal (GI) irAEs: What to Watch for

You may be surprised to learn that most of the time, your immune system can quickly identify and destroy abnormal cells like cancer. Just like how bacteria can become resistant to antibiotics, some cancer cells develop ways to outsmart the immune system and evade destruction. One of those ways is by pretending to be a normal cell so the immune system doesn’t recognize it as a threat.

Your role is to pay careful attention to any symptoms you experience. This includes monitoring them throughout the day everyday and reporting them to your oncologist who will help manage them as needed. Since everyone's body is different, its important to remember how you normally feel (breathing, bowel movements, etc) BEFORE starting immunotherapy. This way you'll know how to compare them to any changes or new symptoms that might develop.

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Immune Checkpoints

Anyone being treated for cancer with PD-1, PD-L1, and/or CTLA-4 blockers can potentially develop an irAE in any part of the body. There isn’t a reliable way to know who will develop irAEs, where they will turn up, or when they will occur. Combination treatment with other ICIs or chemotherapy increases the risk. ICIs all have slightly different rates of adverse events. In general, CTLA-4 inhibitors cause more gastrointestinal side effects, while PD-1/PD-L1 inhibitors cause more skin side effects.

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Cancer and Immune Checkpoints

Innate Response (body’s natural response)

1. How are immune checkpoint inhibitors    (ICIs) different from chemotherapy?

1. How are immune checkpoint inhibitors     (ICIs) different from chemotherapy?

Common Patient Questions

Sharing the Caring

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Immune System And Cancer

Immune System and Cancer

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Immune-Related Adverse Events

This web tool is best viewed on Google Chrome or Mozilla Firefox. Free software downloads are available: Progress will be lost if this web tool is closed, please do not close the web tool until it is completed.

Cancer and Immune Checkpoints

Non-human cells like bacteria don’t have the PD-L1 marker, so when T cells catch them, it tells the immune system to get ready for a fight. Abnormal cells often don’t have a PD-L1 marker, either. When a T cell inspects a cancer cell and doesn’t detect PD-L1, it immediately attacks and kills it.

Immunotherapy and irAEs

We know that the immunotherapy journey is a challenging one, and we hope that this resource has helped you better understand this cutting-edge cancer treatment and its risks. Remember, you don’t need to know everything there is to know about irAEs. Your part is to do your best to learn and watch for the symptoms of immune-related adverse events. If you think you recognize one, report it to your doctor right away. It’s always better to over-report than under-report! Thank you for sharing your time with us today. We hope this web tool has made you more comfortable with immunotherapy.

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