Immune Checkpoint Inhibitors

Learn how checkpoint inhibitors help your immune system fight cancer

Immune checkpoint inhibitors (ICIs) are a widely used type of immunotherapy that helps your immune system recognize and attack cancer. They work by blocking signals that can hold immune cells back, essentially releasing the immune system’s natural “brakes.”

The first checkpoint inhibitor was approved by the U.S. Food and Drug Administration (FDA) in 2011. Today, these treatments are used for many cancer types, sometimes alone and sometimes in combination with chemotherapy, radiation, targeted therapy, or other immunotherapy. They can be used for advanced cancers as well as before or after surgery for some earlier-stage cancers.

Checkpoint inhibitors are a very effective treatment for many people, but they do not work for everyone. Whether they may help depends on the cancer type and stage, biomarkers, previous treatment, and the patient’s overall health.

What Are Immune Checkpoint Inhibitors, and How Do They Work?

Your immune system has built-in safeguards that prevent immune cells from becoming too active and damaging healthy tissue. Some of these safeguards are proteins called immune checkpoints.

T cells, a type of immune cell, use these checkpoint signals to help determine when to slow down or stop an immune response. Cancer can take advantage of the same system. For example, some cancer cells have high levels of a protein called PD-L1. When PD-L1 interacts with a partner protein called PD-1 on a T cell, it can send a signal that reduces the T cell’s activity and helps prevent the T cell from attacking the cancer.

Checkpoint inhibitors are laboratory-made antibodies that block these signals. Some block checkpoint proteins on T cells, such as PD-1, CTLA-4, or LAG-3. Others bind PD-L1, which can be found on cancer cells and immune cells. By interrupting these signals, checkpoint inhibitors can help T cells stay active and attack cancer.

This is different from treatments such as chemotherapy, which acts directly on rapidly dividing cells. Checkpoint inhibitors change immune signaling so that your immune system can better respond to the cancer. In some patients, that immune response can be long-lasting, even after treatment has stopped.

Checkpoint inhibitors are one of six major types of cancer immunotherapy: immune checkpoint inhibitors, cell and gene therapies, cancer vaccines, immune cell engagers, oncolytic virus therapy, and cytokines and immune-stimulating agents. They may be used alone, together with another immunotherapy, or with treatments such as surgery, chemotherapy, radiation, or targeted therapy.

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What Types of Immune Checkpoint Inhibitors Are There?

Checkpoint inhibitors are generally grouped by the immune checkpoint protein they block. The FDA has approved 15 checkpoint inhibitors targeting four checkpoint pathways. PD-1 and PD-L1 inhibitors make up the largest group and are used across many different types of cancer.

*These CTLA-4 inhibitors may be used in combination with a PD-1 or PD-L1 inhibitor, depending on the type of cancer.

Most checkpoint inhibitors are given by IV infusion. The FDA has also approved three versions of checkpoint inhibitors that can be injected under the skin (subcutaneous): atezolizumab with hyaluronidase-tqjs (Tecentriq Hybreza®), nivolumab with hyaluronidase-nvhy (Opdivo Qvantig®), and pembrolizumab with berahyaluronidase alfa-pmph (Keytruda Qlex®).

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Who Might Benefit From an Immune Checkpoint Inhibitor?

Checkpoint inhibitors are FDA-approved for certain patients with different cancers, including melanoma and other skin cancers, lung, kidney, bladder, head and neck, gastrointestinal, gynecologic, and breast cancers, as well as mesothelioma and certain lymphomas.

However, having one of these cancers does not necessarily mean a checkpoint inhibitor is an option. The right checkpoint inhibitor depends on more than the type of cancer. Some treatments are approved only for certain cancer subtypes, stages, age groups, or treatment histories. In some cases, eligibility is based on a tumor biomarker rather than where the cancer started.

Doctors consider several factors when deciding whether a checkpoint inhibitor may be appropriate:

• Type and stage of cancer and treatment goal: Checkpoint inhibitors are used for some advanced disease and in a growing number of earlier-stage settings. Depending on the cancer, treatment may be given before surgery, after surgery to lower the risk of recurrence, or to control cancer that cannot be surgically removed.
• Biomarkers: Some checkpoint inhibitors require testing for biomarkers such as PD-L1, microsatellite instability-high (MSI-H), mismatch repair deficiency (dMMR), or tumor mutational burden-high (TMB-H). The test and cutoff can differ by cancer and treatment. 
• Other tumor features: Genetic mutations and other characteristics of the cancer may influence whether another treatment should be used instead of, before, or together with immunotherapy.
• Previous treatments: Some checkpoint inhibitors are approved as a first treatment, while others are used after chemotherapy or other therapies have stopped working. Prior immunotherapy treatment can also affect which options are available.
• Overall health and medical history: Autoimmune conditions, previous organ or stem-cell transplantation, medicines that suppress the immune system, certain organ problems, and pregnancy or plans for pregnancy may affect the risks and benefits of treatment.

Can Biomarkers Qualify Someone for Treatment Regardless of Cancer Type?

Sometimes. In 2017, pembrolizumab became the first cancer treatment approved by the FDA based on a tumor biomarker rather than the part of the body where the cancer started.

Today, some people with advanced solid tumors that are MSI-H, dMMR, or TMB-H may be eligible for a checkpoint inhibitor under these “tumor-agnostic” approvals. Eligibility still depends on the specific approval, including factors such as age, previous treatment, and available treatment alternatives.

What Can I Expect if I Receive a Checkpoint Inhibitor?

The details depend on the checkpoint inhibitor and whether it is being given alone or with other treatments.

Most checkpoint inhibitors are given by IV infusion at a cancer center or infusion clinic. Some can be given as an injection under the skin. Depending on the treatment, doses may be several weeks apart.

Before and during treatment, your health care team may use blood tests, imaging scans, physical exams, and other tests to monitor the cancer and look for side effects. Because checkpoint inhibitors work through the immune system, doctors may also monitor organs such as your liver, kidneys, thyroid, and other hormone-producing glands.

Length of treatment can vary. Some treatments are given for a set period of time or number of doses, while others may continue until the cancer progresses, side effects become unacceptable, or a planned course is completed.

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10 Questions to Ask Your Doctor

Being diagnosed with cancer may feel overwhelming, and understanding your treatment options can make a big difference. Asking the right questions can help you take an active role in your care, make informed decisions, and feel more confident as you move forward.

Here are 10 key questions to use in your conversations with your doctor to talk about cancer and immune checkpoint inhibitors.

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What Side Effects Can Immune Checkpoint Inhibitors Cause?

Because checkpoint inhibitors increase immune activity, the immune system can sometimes affect healthy organs and tissues along with the cancer. These are called immune-related adverse events, or immune-related side effects.

They can affect almost any part of your body. Examples include your skin (rash, itching), gut (diarrhea, colitis), hormone-producing glands such as your thyroid, pituitary, and adrenal glands, lungs, liver, kidneys, joints, heart, and nervous system.

Side effects vary widely from person to person and can develop during treatment or after treatment has ended.

Not every side effect is caused by the immune system. Fatigue and infusion- or injection-related reactions can also occur. If checkpoint therapy is combined with chemotherapy, targeted therapy, or another treatment, those treatments have their own possible side effects as well.

Many immune-related side effects are mild to moderate and can be managed, especially when recognized and treated early. Treatment may include temporarily stopping the checkpoint inhibitor and using medicines such as corticosteroids to reduce immune activity. Some hormone-related side effects can be permanent and may require long-term hormone replacement.

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Are There Clinical Trials, and What Are Researchers Studying?

Yes. Clinical trials are carefully monitored research studies that test new treatments or new ways of using existing treatments. They may be available at any stage of cancer treatment, not only after standard options have stopped working

Clinical trials are helping researchers answer some of the biggest remaining questions about who benefits, why treatment stops working, how early immunotherapy should be used, and how to make treatment safer.

How Has CRI Helped Make Checkpoint Inhibitors Possible?

Checkpoint inhibitors are now a major part of cancer treatment. However, the idea that releasing the immune system’s brakes could treat cancer was once unproven, and CRI helped support the research that changed that.

In 1992, CRI began funding research in the laboratory of Dr. James P. Allison, then at University of California, Berkeley, before checkpoint blockade had been shown to work against cancer. In the years that followed, Dr. Allison helped establish CTLA-4 as a brake on T-cell activity and then demonstrated that blocking it could unleash an immune response capable of rejecting tumors.

In 2011, ipilimumab (Yervoy®), a treatment based on CTLA-4 blockade, became the first immune checkpoint inhibitor approved by the FDA. Dr. Allison and Tasuku Honjo, MD, PhD, later shared the 2018 Nobel Prize in Physiology or Medicine for discoveries that established cancer therapy by blocking negative immune regulation.

CRI-supported scientists also helped establish the scientific foundation for targeting another checkpoint that would become central to cancer treatment: PD-1. In 2006, then CRI postdoctoral fellows E. John Wherry, PhD, and David Masopust, PhD, working with Rafi Ahmed, PhD, Emory University, showed that blocking PD-1 could restore the activity of exhausted T cells. This study helped demonstrate that an immune response thought to be spent could be reinvigorated.

Those discoveries changed the central question in cancer immunology. Researchers no longer had to ask simply whether the immune system could be used to treat cancer. They could begin asking how to make that response work for more people, make it last longer, and make it safer.

How CRI is Advancing Checkpoint Inhibitor Research