immune checkpoint inhibitor

Q: What are immune checkpoint inhibitors (ICIs)?

Immune checkpoint inhibitors (ICIs) are drugs that enhance the immune system ’s ability to detect and attack cancer cells by blocking proteins known as checkpoints, which help regulate immune activity.

Q: How did the concept of immune checkpoint inhibitors develop?

The concept of leveraging the immune system for the treatment of disease emerged in the mid-20th century, facilitated by the discovery of molecules involved in immune surveillance. By the late 1990s researchers understood the role of regulatory molecules such as CTLA-4, PD-1, and PD-L1 in limiting T-cell activity, which cancer cells exploit to evade detection.

Q: What was the first immune checkpoint inhibitor (ICI) approved by the U.S. Food and Drug Administration (FDA)?

Ipilimumab was the first immune checkpoint inhibitor (ICI) approved by the FDA. It was approved in 2011 for the treatment of advanced melanoma .

Q: What challenges have immune checkpoint inhibitors (ICIs) introduced to cancer care?

Although highly effective in some patients, immune checkpoint inhibitors (ICIs) have introduced challenges for cancer care, particularly in the area of immune-related toxicities, which are highly variable and unpredictable. Other issues associated with ICIs center on treatment cost and access.

medicine

Also known as: ICI

Written by

Kara Rogers

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Britannica Editors

History

What are immune checkpoint inhibitors (ICIs)?

How did the concept of immune checkpoint inhibitors develop?

What was the first immune checkpoint inhibitor (ICI) approved by the U.S. Food and Drug Administration (FDA)?

What challenges have immune checkpoint inhibitors (ICIs) introduced to cancer care?

immune checkpoint inhibitor (ICI), class of drugs that enhance the ability of the immune system to detect and attack cancer cells. Immune checkpoint inhibitors (ICIs) are so-named because they block proteins known as checkpoints, which normally help regulate the immune system by preventing it from becoming overactive and damaging healthy cells. The development of ICIs is considered one of the most significant breakthroughs in cancer treatment since the advent of chemotherapy.

History and development

The concept of immune surveillance—the idea that the immune system can recognize and destroy cancer cells—emerged in the mid-20th century. By the late 1990s researchers had elucidated the role of regulatory molecules such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1) in limiting the activity of T-cells—one of the two major types of immune cells that determine the specificity of immune response to antigens (foreign substances). While these checkpoints normally maintain self-tolerance and prevent autoimmune disease, it became evident that cancer cells could exploit them to evade immune detection.

Early preclinical studies demonstrated that blocking checkpoint pathways unleashes powerful antitumor responses. This proof-of-principle was first shown in animal models, using monoclonal antibodies to block CTLA-4. Initial clinical trials of anti-CTLA-4 antibodies, namely ipilimumab and tremelimumab, began in the early 2000s and were oriented toward safety and tolerability testing in patients with advanced cancers. Some patients in these early trials, particularly those with advanced melanoma, experienced tumor regression, sparking cautious optimism but also concerns because of significant immune-related toxicities.

Later refinements in dosing schedules and the identification of strategies to manage immune-related adverse events fueled the advance of ICIs. Early on this was most notable for ipilimumab, where improvements in tolerability enhanced its impact on patient survival. In 2011 ipilimumab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma, making it the first ICI to reach the market. Soon after, antibodies against PD-1, including nivolumab and pembrolizumab, and antibodies targeting PD-L1, such as atezolizumab and durvalumab, were developed, broadening the ICI therapeutic landscape.

Uses

Since 2011 ICIs have gained regulatory approval for a wide array of malignancies, including non-small cell lung cancer, renal cell carcinoma, head and neck cancer, urothelial carcinoma, Hodgkin lymphoma, and triple-negative breast cancer. In 2017 the ICI pembrolizumab became the first cancer therapy to be approved based on a biomarker (microsatellite instability-high [MSI-H] or mismatch repair deficiency [dMMR]) rather than tumor origin. This move toward a more personalized approach based on genetic characteristics of a tumor was a groundbreaking development in cancer immunotherapy.

ICIs are used in single-agent regimens, in combination with other ICIs, or alongside chemotherapy, targeted therapies, and radiation therapy. ICI combination regimens, such as nivolumab plus ipilimumab, have shown enhanced efficacy in some cancers but are also associated with increased immune-related adverse events. Not all patients respond to ICIs, however; patients are selected for treatment with ICIs based on biomarkers, such as PD-L1 expression or MSI-H, and other clinical factors to maximize benefit and minimize side effects and cost.

Impact on cancer care

The impact of ICIs has been profound. Following ICI treatment, patients with advanced cancers experience durable remissions, in some cases lasting years; historically, these patients often had survival measured in months. ICIs have helped to redefine treatment goals, shifting oncology from short-term disease control toward potential long-term survival and even cure in subsets of patients. At the same time, they have introduced challenges, including immune-related toxicities, which can be unpredictable and highly variable, as well as issues of cost and access.

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