May 28, 2024

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Important issues of immune checkpoint inhibitor toxicity

Important issues of immune checkpoint inhibitor toxicity


important issues of immune checkpoint inhibitor toxicity.


Over the past decade, immunotherapy has fundamentally changed the treatment landscape for solid and hematological malignancies.

Monoclonal antibodies that block the immune checkpoint receptors CTLA-4 , PD-1 , and their ligand PD-L1 have shown broad activity against a variety of tumor types, leading to prolonged survival and even durable remissions in many patients.


However, despite the enormous potential of immune checkpoint inhibitors ( ICIs ), their success has been limited in part by various inflammatory toxicities, collectively known as immune-related adverse events ( irAEs ).

These toxicities can lead to delays and interruptions of treatment and, in rare cases, can be life-threatening. Compared with chemotherapy- and targeted therapy-induced adverse events, the severity and timing of irAEs are less predictable.


Therefore, understanding the molecular and cellular mechanisms that drive irAEs is clearly of great importance. Here, we address several questions about the inflammatory toxicity of ICIs , answers to which will deepen our understanding of irAE pathogenesis, therapeutic approaches, and some major unresolved questions.

These will help to better predict toxicities and develop optimized therapies against these toxicities without interfering with anti-tumor immunity.




How does ICI affect the development of irAE?


CTLA-4 and PD-1/PD-L1 have very different roles in immune regulation. CTLA-4 is a decoy receptor for the costimulatory proteins B7-1 and B7-2 expressed on antigen- presenting cells ( APCs ), preventing B7 from interacting with the costimulatory receptor CD28 on T cells.

Thus, CTLA-4 reduces the activation of naive T cells and may also interfere with the sustained stimulation of T cells in inflamed tissues.

CTLA-4 is also highly expressed on regulatory T cells ( Tregs ), inducing DC cell tolerance, which further suppresses the ability of T cells through IDO.

PD-1 is an inhibitory receptor expressed after T cell activation, and its expression level is highest after repeated stimulation. PD-1, upon binding to its ligands PD-L1 or PD-L2, directly inhibits TCR and CD28 signaling by activating SHP-2 phosphatase.



Important issues of immune checkpoint inhibitor toxicity


The distribution, severity, and frequency of irAEs were clearly related to the ICI class used . In most cases, CTLA-4 blockade resulted in more severe and frequent toxicities than PD-1 blockade.

In particular, intestinal inflammation was more common with CTLA-4 blockade than with PD-1 or PD-L1 inhibitors.

Hypophysitis is also more common with CTLA -4 blockade. In contrast, PD-1 blockade was more common with thyroiditis, or pneumonia and autoimmune diabetes.

Furthermore, combined immunotherapy targeting CTLA-4 and PD-1 was much more toxic than either treatment alone.




Why are certain organs more likely to be targets of irAEs? 


The inflammatory toxicity of checkpoint inhibitors can affect any organ system in the body. However, most toxicity occurs in barrier organs, including the skin, gastrointestinal tract, liver, and lungs.


Colitis is by far the most common serious toxicity of ICIs. About 20% of patients with PD-1 blockade had mild gastrointestinal inflammation, and 25% had more severe inflammation.

With CTLA-4 inhibitors, nearly 40% of patients experience gastrointestinal inflammation, and 10-15% develop severe disease. Cutaneous toxicity was more common, affecting the vast majority of patients treated with ICIs.


Important issues of immune checkpoint inhibitor toxicity


The fact that barrier organs are so ubiquitously involved suggests that the antigenic target of the immune response may be the commensal microbiome.

The adaptive immune system develops through a complex selection process that removes most high-affinity self-reactive T and B cells.

In contrast, immune cells that recognize harmless microbes and environmental proteins are only regulated through peripheral tolerance mechanisms such as CTLA-4 and PD-1/PD-L1 pathways.

Indeed, inflammation of barrier organs is a common feature of many genetic defects in peripheral tolerance mechanisms.


Endocrine toxicity is also common in ICI therapy, and endocrine organs are also common targets in many autoimmune diseases.

These tissues express many specialized proteins that are not involved in any other processes in the body.

Although central tolerance typically removes most self-reactive cells, these mechanisms are imperfect.

Research has shown that peripheral tolerance plays a key role in protecting these organs even when central tolerance is functioning properly.




What is the relationship between ICI toxicity and spontaneous autoimmune disease?


Understanding the relationship between ICI toxicity and spontaneous autoimmune disease has important scientific and clinical implications.

Understanding the relationship of ICI toxicity to other autoimmune diseases will provide insights into the mechanisms of autoimmunity and potentially identify new therapeutic targets and new ways to predict risk of autoimmune STDs.

From a clinical perspective, understanding the relationship between autoimmunity and ICI toxicity may help identify potential treatments for ICI toxicity.


Patients with certain autoimmune diseases do appear to be at increased risk of ICI toxicity associated with their autoimmune disease.

In a large retrospective study of IBD patients treated with ICIs, the risk of gastrointestinal toxicity was approximately 40%, compared with 11% in a control cohort of patients with ICIs without IBD.

Likewise, patients with microscopic colitis, a unique inflammatory disease of the colon , are at increased risk of gastrointestinal toxicity from ICIs.


However, because autoimmune diseases are often chronic and immunosuppressive therapy is used over a long period of time, differences may arise between autoimmune disease and ICI toxicity related to the length of time the disease exists or the treatment-induced are related to changes in disease biology rather than fundamental differences in disease biology.




What factors determine who will develop an irAE?


Understanding the factors that determine who will develop an irAE is of crucial clinical importance.

Inflammatory toxicity is a major limitation of combination immunotherapies, and the ability to predict specific inflammatory toxicity is an important step in the development of preventive therapies and may aid in the selection of optimal cancer treatment options.


Taking ICI colitis as an example, after treatment with CTLA-4 or PD-1 inhibitors, CD8+ colon-resident memory T cells ( Trms ) are activated, proliferate and produce granzyme B ( GZMB ) and IFN-γ.

Trms are thought to largely recognize antigens in the microbiome, which may be in response to antigen recognition from the microbiome, and perhaps interactions between Trms and specific microbial products determine whether immune homeostasis balances in some patients lead to inflammation.

This interaction may be influenced by diet, other medications, or concurrent infections.

Interestingly, there are some data showing that fecal microbiota transplantation can resolve refractory ICI colitis, further showing the role of the microbiome in this syndrome.


Important issues of immune checkpoint inhibitor toxicity


Whether lessons learned from ICI colitis can be generalized to other toxicities remains a question.

Trms are present in every barrier organ, but are not found in large numbers in ” sterile ” organs such as endocrine tissue or the myocardium.

Therefore, a detailed analysis of various toxicities is necessary to understand whether different toxicities have different immune origins.

In addition, pretreatment, organ-level immune profiling of patients independently of ICI toxicity outcomes is critical to determine whether there are differences in baseline immunity that subsequently lead to irAEs .





How to choose the best treatment strategy for irAE?


The vast majority of patients who develop inflammatory toxicity from ICI therapy can be treated with glucocorticoids, and early intervention with these agents will almost certainly reduce morbidity and mortality associated with irAEs, especially in critical organs such as the heart and nervous system The irAE. However, the use of glucocorticoids may also carry risks.

In addition to the large number of side effects associated with systemic glucocorticoids, they are also broadly immunosuppressive and may interfere with antitumor responses.


The development of antitumor responses and irAEs may not differ mechanistically, that is, patients who develop irAEs have the potential to develop robust antitumor responses.

The use of glucocorticoids in these patients may inhibit the “synergism” of some of these mechanisms.

In a retrospective analysis of patients treated with low-dose and high-dose glucocorticoids, overall survival and treatment failure were found to be longer in patients treated with low-dose glucocorticoids compared with those treated with high-dose glucocorticoids The time is significantly extended.


Furthermore, IFN-γ signaling can be targeted by several drugs, including the JAK inhibitor tofacitinib, which may be effective against ICI colitis but may also directly interfere with antitumor responses.

Similarly, CTLA-4 fusion proteins such as abatacept have also been suggested for the treatment of ICI toxicity, especially myocarditis.

While these drugs are likely to be effective in controlling ICI toxicity, they may also directly reverse the activity of the ICI itself.







Optimizing the management of irAEs in cancer immunotherapy is an urgent clinical issue.

Although there are management guidelines for irAEs , these guidelines are almost entirely based on expert opinion and small retrospective clinical studies, and prospective treatment trials are still lacking.

Because the mechanism, severity, and treatment response of each toxicity may be different, these trials should address different toxicities rather than bundle them together.


We are only just beginning to understand the mechanisms that drive these toxicities, and they promise to provide new insights into human autoimmunity and immune homeostasis. Advances in these areas are critical to advancing cancer immunotherapy more broadly.








1. Immune mechanisms of toxicity from checkpoint inhibitors. Trends Cancer. 2023 Jul;9(7):543-553.

Important issues of immune checkpoint inhibitor toxicity 

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Important Note: The information provided is for informational purposes only and should not be considered as medical advice.