The Balancing Act of Immune Checkpoint Inhibitors: Immune-related Adverse Events

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Karli Norville

Immune checkpoint inhibitors (ICIs) have been so impactful in the treatment of cancer in recent years that the basic research supporting their development was the subject of the 2018 Nobel Prize in Physiology or Medicine (1). Despite their clinical success, the occurrence of immune-related adverse events (irAEs) within a large number of patients who receive ICI therapy still poses a significant challenge. Immune-related adverse events are a class of side effects wherein the negative symptoms or toxicity of the therapy are caused by the immune system, often manifesting in similar ways to auto-immune diseases. IrAEs can range from mild to severe and can impact multiple systems within the body. These toxicities negatively impact patients’ quality of life and can also cause patients or physicians to decide to discontinue treatment. Therefore, it is important to understand the underlying causes of irAEs and to find new ways to prevent, treat, and reduce the impact of irAEs in the clinic.

Some studies report that the incidence of irAEs during ICI is as high as 90%, while others report slightly lower ranges such as 70% incidence in anti-Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) therapies and 27-78% for anti- Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) ICIs (2). The specific ways that ICIs cause irAEs are still under investigation, and each ICI likely has its own signaling path to irAE induction. In general however, ICIs are meant to enhance the immune response against a tumor. Unfortunately however, they don’t only impact tumor cells or cells which are focused on killing tumor cells; any cell within the body that has the particular target for the ICI has the potential to be activated or enhanced by the ICI. It is speculated that under certain conditions this can lead to inappropriate attacks by immune cells against normal healthy cells within the body, manifesting as an irAE (3). Despite the seeming similarity in cause, irAEs resulting from ICI therapy can cover a broad spectrum of manifestations, including a range of intensities and organ systems impacted. How irAEs present is often related to which ICI is being used and what type of cancer it is employed to treat. For example, treatments targeting Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) such as ipilimumab often cause irAEs that impact the gastrointestinal tract such as diarrhea or colitis (3). Vitiligo and pneumonitis are more likely to be caused by treatments targeting Programmed cell death protein 1 (PD-1) (3). Regardless of the particular irAE, one major question of interest in the field is why do some patients develop irAEs while others don’t? Another question is why do some patients develop only mild irAEs, while others may have irAEs which prove fatal? 

The Common Terminology Criteria for Adverse Events (CTCAE) is a set of standardized guidelines and definitions for all adverse events published by the National Cancer Institute. It grades adverse events on a scale of 1-5: Grades 1 and 2 indicate mild and moderate adverse events, Grades 3 and 4 represent increasingly severe events, and Grade 5 designates patient death from the adverse event (4). Grades 2-4 require medical intervention, with Grades 3 and above usually requiring the discontinuation of treatment (5). While in some cases, treatment resumes after the irAE is resolved, in other cases patients may not continue the therapy. This means that in addition to the negative side effects the patient is now experiencing, they are no longer able to receive that treatment, even if it was effective against their cancer. There are as many treatments for irAEs as there are symptoms, and each comes with its own limitations and benefits. Steroids, a commonly used anti-inflammatory class of drugs, are often used as treatments for irAEs (5). However, steroids may also dampen the desired immune response against the tumor. Recently infliximab and vedolizumab, antibody based therapeutics designed to dampen the immune response by blocking Tumor necrosis factor alpha (TNFa) and certain integrin signals, respectively, have been used to help treat ICI-induced irAEs such as colitis (6). Although more specific than steroid treatments, even these antibody-based therapies may interfere with productive anti-tumor responses, and therefore there is still a need to hone irAE treatments. 

Aside from treating irAEs, another approach is to decrease irAE occurrence in patients altogether by evaluating patients for particular risk factors before starting treatment, or to evaluate them during treatment for biomarkers (easily measurable signs that may predict oncoming events) for irAEs (2). For example, patients who already have irritable bowel disease may be more likely to experience gastrointestinal irAEs during ICI treatment (7). And increased levels of certain inflammatory factors and cells such as interleukin-10 (IL-10), IL-4, and eosinophils in the blood have been associated with skin-related irAEs (8). Things like diet and the gut microbiome can also play a role in the development or prevention of gut-related irAEs. For example, supplementation with Vitamin D is associated with reduced risk of ICI-induced colitis (9). There have also been some studies showing that the dose of ICI administered may be correlated with occurrence rate or severity of irAEs (2). This means that even currently used therapies may require more research to be done to fully determine optimal dosing for a wider range of patients. 

There is an emerging idea that ICIs themselves may fall into distinct categories which may more heavily promote irAE occurrence. Within this paradigm, some could be considered “enhancers” of the immune system, while others are “normalizers”. In this sense, the enhancers press the gas on the metaphorical immune system car, while the normalizers remove inappropriately applied brakes (10). There is some speculation that enhancers may promote more irAEs than normalizers. By learning more about the currently available ICIs and how they function distinctly within both normal immune responses and the heavily suppressed anti-tumor immune responses, researchers may be able to find new targets for ICI, new ways to engineer ICIs such that they are less likely to cause irAEs, new ways to predict the occurrence of irAEs, and even better ways to treat irAEs that do arise. As more ICIs come into clinical development, a greater understanding of irAEs is imperative for the safe and effective treatment of cancer, such that patients can have their disease treated and maintain a high quality of life.  

Edited by Jessica Campbell

References: 

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