Immune-Related Adverse Reactions: An Overview

Generally speaking, in the past, the methods of treating cancer were often achieved by directly killing the tumor tissue, such as chemotherapy, radiotherapy or surgical resection, etc.
Now there is a new treatment method that does not directly kill the tumor tissue, but through Training our immune system to kill tumors, this new treatment is called immunotherapy (Immunotherapy)
.

Immunotherapy has set off an upsurge of domestic and foreign pursuit (Figure 1)
.

Tumor immunotherapy mainly includes three categories: cellular immunotherapy, tumor personalized vaccines and immune checkpoint inhibitors
.

However, treatment methods will bring corresponding side effects.
Today, let us stand on the shoulders of others and discuss the immune-related adverse events caused by immune checkpoint inhibitors
.

Figure 1 Overview of immune checkpoint inhibitor publications Introduction: Immune checkpoint inhibitors (ICIs), including antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) , showed durable therapeutic effects in a variety of tumor types by enhancing anti-tumor immunity
.

However, eliminating self-tolerance can induce autoimmunity and produce a unique, immune-driven toxicity profile known as immune-related adverse events (irAEs)
.

With the widespread use of ICIs, clinicians must improve their awareness and management of irAEs
.

This article reviews the etiology, manifestations, dynamics, and treatment of irAEs with the aim of providing practical guidance for clinicians
.

Introduction: A complex interplay of co-stimulation and inhibition exists between pathways in the immune system to maintain a balance between pathogen recognition, elimination, and self-reactivity
.

These inhibitory pathways are called immune checkpoints, and some of these pathways are used by tumors to evade immune destruction
.

As we learn more about the dynamic relationship between the immune system and tumors, more and more anticancer immunotherapy strategies are being discovered
.

But the most certain clinical effects are drugs targeting regulatory checkpoints - cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1)
.

While CTLA-4 mainly downregulates early activation of naive and memory T cells, PD-1 can regulate T cell activity in peripheral tissues during the effector phase of T cell activation (Figure 1)
.

Figure 2 briefly illustrates the underlying immune activation mechanisms and the roles of CTLA-4, PD-1, and PD-L1
.

 The roles of CTLA-4 and PD-1 checkpoints in autoimmunity and immune homeostasis are fundamental to our understanding of the mechanism of irAEs
.

Although the exact cause of irAEs is not fully understood, the occurrence of irAEs involves complex dynamics including regulation of effector T cell and Treg activity, toxic effects of macrophages and granulocytes, release of cytokines, and production of antibodies by B cells ( Figure 1)
.

As more and more novel immune-targeted therapeutic regimens enter the clinic, such as ICIs, costimulatory molecule agonists, cytokines and vaccines
.

We must gain a deeper understanding of the etiology, manifestations, dynamics, and significance of anti-tumor therapy of irAEs in order to improve our knowledge and ability to deal with irAEs
.

This review aims to explore these questions and focuses on the three most studied ICIs - ipilimumab (anti-CTLA-4), nivolumab (anti-PD-1) and pembrolizumab (anti-PD-1) and their role in solid tumors.
clinical data
in .

The authors conducted a literature search using MEDLINE, Embase and Cochrane databases
.

Keywords include tumor, immune checkpoints, CTLA-4, PD-1 and PD-L1
.

This review assessed prospective clinical trials, selected large retrospective series, case series and recent abstracts
.

In conclusion, antibodies targeting immune checkpoints, CTLA-4, and PD-1/PD-L1 have improved patient outcomes in a variety of malignancies and provide a paradigm for future immunotherapy development
.

However, the majority of patients will have immune-related adverse events, while only a small proportion of patients benefit
.

Therefore, the in-depth study of irAE is necessary
.

1.
Anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody: ipilimumab incidence of immune-related adverse events (irAEs) Ipilimumab is the first ICI to enter clinical trials, and its toxicity profile is the clearest
.

In phase III trials of single-agent ipilimumab 3 mg/kg as the treatment arm, the vast majority of patients (73-86%) experienced at least one irAEs, mostly immune-related (~60%, Table 1)
.

Consistent with earlier phase I and II studies, the most common irAEs involved the gastrointestinal tract and skin, including diarrhea (23-33%), colitis (8-9%), pruritus (24-35%), and rash ( 15%-33%)
.

Other less common irAEs include endocrine disorders: thyroid, pituitary, and adrenal dysfunction (2% each), and hepatitis, asymptomatic elevations in transaminases, and fulminant liver failure (1%-4%)
.

Pneumonia was relatively uncommon (1% of patients)
.

In addition, rare irAEs such as pancreatitis, nephritis, severe skin reactions (eg, Steven Johnson syndrome), neurological disorders (including Guillain-Barré syndrome and myasthenia gravis) have been described in the literature
.

In phase III trials, the incidence of grade 3/4 irAEs with ipilimumab was approximately 20-30%; the most common high-grade adverse reactions (≥3) were diarrhea and colitis (10-15%)
.

In addition, the most common symptoms of systemic toxicity were fatigue and asthenia (21%-42%), anorexia (13%-27%) and nausea (9%-35%), which were almost all low-grade adverse reactions
.

Fever and infusion-related reactions are relatively rare
.

The etiology of these systemic toxicity symptoms is unknown, but they may be related to immune-mediated mechanisms, such as the release of nonspecific cytokines
.

In addition, some patients may have underlying diseases themselves, and others may have undiagnosed endocrine diseases, such as hypothyroidism or hypophysitis caused by ICIs
.

Notably, with the exception of a few small studies in prostate cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC), most studies testing ipilimumab were conducted in patients with melanoma
.

Therefore, the toxicity profile of ipilimumab in other tumor types is not well characterized
.

Management of irAEs Overall, the guidelines emphasize early identification of low-grade irAEs and supportive measures; for high-grade events, drug discontinuation and systemic corticosteroids are recommended; for refractory cases, the guidelines recommend the use of secondary immunomodulation agents, such as the tumor necrosis factor (TNF) inhibitor infliximab
.

Under current guidelines, most irAEs are controllable and reversible with treatment cycles of 4 to 8 weeks
.

Of course, there are also some endocrine diseases that are special cases, which may require long-term hormone replacement
.

In addition, in experienced medical centers, serious adverse reactions can occur despite adherence to toxicity management guidelines
.

For example, despite early treatment with corticosteroids and anti-TNF-a, there was a 1% incidence of intestinal perforation in patients with melanoma treated with ipilimumab
.

Time to Treatment Discontinuation and Grade 5 Adverse Events About 10%-15% of patients with advanced melanoma treated in phase III trials discontinued ipilimumab due to irAEs, with diarrhea being the most common event leading to discontinuation
.

Despite the lack of clear recommendations and individual circumstances, events that permanently discontinue ICIs include the occurrence of grade 3/4 events (except for dermatological events), difficulty de-escalating corticosteroids, and the requirement for secondary immunomodulators
.

Additionally, a systematic review and meta-analysis of 1265 patients in 22 clinical trials investigating anti-CTLA-4 agents found that 0.
86% of patients died from irAEs, the most common cause being intestinal perforation in colitis patients
.

Other reported causes include opportunistic infections with sepsis and/or prolonged immunosuppression, liver failure, nephritis and myocarditis, and severe dermatological and neurological events
.

Time point of irAEs The onset of irAEs due to ipilimumab treatment is temporally characterized, with skin-related AEs appearing as early as 2-3 weeks, followed by gastrointestinal and hepatic events at 6-7 weeks, while the mean time to onset of endocrine AEs for 9 weeks
.

While we already know the information, they can vary widely in practice
.

In fact, gastrointestinal and hepatic events can occur as early as after the first dose
.

In general, irAEs tended to occur during induction therapy with ipilimumab and within the first few treatment cycles
.

In the phase III study, the median time to onset of severe AE was 39.
5 days or after two doses of ipilimumab
.

In the ipilimumab registry, all adverse reactions occurred during induction and re-induction
.

In one study, long-term follow-up of patients surviving more than 2 years found that 6 of 78 patients (8%) developed new toxicity 70 days after the last dose of ipilimumab
.

However, with the exception of one case of grade 3 colitis, all new events were low-grade
.

Therefore, physicians and patients must maintain adequate follow-up after ipilimumab is completed
.

Effects of Dose on Toxicity Early dose-escalation studies indicated that the frequency and severity of ipilimumab-related irAEs were related to increasing dose
.

In a meta-analysis of anti-CTLA-4 drug-related irAEs, the hazard ratio for high-grade irAEs with ipilimumab 10 mg/kg versus 3 mg/kg was 3.
1 (p=0.
0008)
.

However, the dose-dependent relationship has not been consistently recognized
.

For example, in retrospective studies of patients with skin diseases and patients with enterocolitis, no increase in the incidence of adverse reactions was found with increasing dose
.

Interestingly, substantial toxicity was found in a study with ipilimumab using a regimen of 10 mg/kg every 3 weeks for 4 doses followed by maintenance every 3 months (Table 1 )
.

In total, 91% of patients experienced irAEs, 43% of which were high-grade; 40% did not complete the 4-dose induction cycle
.

Although ipilimumab treatment improved recurrence-free survival in patients with stage III melanoma (high-risk resected), five (1%) patients died from drug-related causes (all prior to maintenance)
.

In conclusion, it is currently unclear whether the severity of irAEs is due to higher doses, longer treatment duration, or biological differences in resected melanoma patients
.

Second, anti-PD-1 antibodies: nivolumab and pembrolizumab FDA has approved two anti-PD-1 drugs for clinical use: nivolumab 3 mg/kg every 2 weeks for metastatic melanoma, NSCLC, RCC and refractory Hodgkin lymphoma tumor; Pembrolizumab 2 mg/kg every 3 weeks for metastatic melanoma, head and neck squamous cell carcinoma, and NSCLC
.

In large clinical trials, the overall incidence of treatment-related adverse reactions has been reported to be approximately 70%-80%, with the most common events being fatigue, diarrhea, rash, and pruritus (Table 1)
.

Based on current clinical data, there is little difference between pembrolizumab and nivolumab in terms of toxicity and antitumor activity
.

Overall, anti-PD-1 therapy appears to be less toxic than ipilimumab
.

This may be due to the activation of a wider variety of T cell subsets by CTLA-4 inhibition
.

The incidence of high-grade adverse reactions (10%-15%) and the rate of treatment discontinuation due to toxicity (5%-7%) were lower in nivolumab and pembrolizumab clinical trials compared with ipilimumab clinical trials
.

One study also noted that the onset of high-grade irAEs was later than ipilimumab (median 59-64 days instead of 40 days) during treatment with pembrolizumab
.

A meta-analysis of phase I-III nivolumab trials showed that 35% of patients required immunomodulatory agents, and irAEs resolved in nearly all cases
.

Interestingly, emerging evidence suggests that anti-PD-1 drugs may have a different pattern of immunotoxicity compared to anti-CTLA-4 drugs
.

A phase III study in melanoma found that pembrolizumab was more associated with thyroid dysfunction (14 vs 4%) than ipilimumab and was associated with colitis (2 vs 8%) and hypophysitis (<1 vs 2%) Correlation is low
.

Similar findings were found in a phase III study of nivolumab compared to ipilimumab
.

In both studies, the incidence of grade 3/4 diarrhea and colitis associated with anti-PD-1 therapy was low, only 2-4%, compared with 10-15% in patients treated with ipilimumab
.

However, pneumonia was rarely described in the ipilimumab trial, resulting in three deaths in an early dose-escalation study of nivolumab, including two patients with non-small cell lung cancer and one patient with colorectal cancer, with no clear relationship to dose level or duration of treatment relationship
.

In subsequent studies, the incidence of pneumonitis was approximately 1-5%, and in non-small cell lung cancer studies, the incidence of pneumonitis may be higher
.

In clinical studies, the dose-to-toxicity relationship of PD-1 drugs has been inconsistent
.

The phase I dose-escalation study of nivolumab did not determine a maximum tolerated dose, but the spectrum, frequency, and severity of irAEs were broadly similar across dose levels
.

However, a multiple-dose study of pembrolizumab showed a higher incidence of adverse reactions in the high-dose group of 10 mg/kg every 2 weeks; subsequently, in melanoma and non-small cell lung cancer, 2 every 2 (or 3) weeks Trials of pembrolizumab at mg/kg and 10 mg/kg did not show a significant difference in side effects
.

3.
Anti-PD-L1 Antibodies Although the results of phase III studies are currently lacking, many trials are investigating some mAbs against programmed cell death protein-ligand 1 (PD-L1)
.

Theoretically, inhibition of PD-L1 might result in a different immune profile than PD-1 because of the different targets involved, but direct comparative data are not available
.

Clinical trial data of two PD-L1 antibodies applied to multiple tumor types indicated that most patients experienced treatment-related AEs
.

The anti-PDL1 antibody MPDL3280A (atezolizumab), a second-line treatment for advanced urothelial carcinoma, showed durable activity in a phase II study, which led to FDA approval of atezolizumab for the treatment of advanced urothelial carcinoma
.

The study found that treatment-related AEs occurred in 69% of patients, with 16% of patients experiencing grade 3/4 events and no treatment-related deaths
.

Overall, fatigue, nausea, decreased appetite, and pruritus were the most common toxicities
.

BMS-936559, an anti-PD-L1 antibody in advanced solid tumors, found a grade 3/4 AE rate of 9% in a phase I study, similar to PD-1 formulations, but with anti-PD-1 antibody infusion-related reactions The relatively high rate (10% vs <1%) is noteworthy
.

Early trial results of another anti-PD-L1 antibody, MSB0010718C (Avelumab), showed a similar incidence of infusion-related reactions (10%).
Table 1 ICIS-related immune-related adverse events IV.
Various biomarkers associated with irAEs Immunological markers have been evaluated to identify individual susceptibility and enhance our understanding of the mechanisms of irAEs
.

For example, in two phase II trials of ipilimumab, gene expression profiling was performed in 162 melanoma patients
.

This study identified early changes in gene expression, including increased expression of CD177 and CEACAM1 on treatment, two markers of neutrophil activation; however, these potential biomarkers are less sensitive and cannot be used alone Predict irAEs
.

In addition to monitoring immunomodulatory changes in the circulation and tumor microenvironment, the impact of underlying genetic factors, such as the human leukocyte antigen (HLA) gene and environmental and disease factors on the occurrence of irAEs, requires further investigation
.

Expansion of ideas: In recent years, tumor immunotherapy targeting immune checkpoints has attracted much attention due to its remarkable curative effect
.

However, with the popularization and application of immune checkpoint inhibitors (ICIs), more and more reports of their related adverse events (irAEs) have been reported
.

Not only does this interfere with treatment, but it can also lead to life-threatening conditions
.

Therefore, irAEs impose an additional fatal risk on tumor patients treated with ICIs, limiting the use of ICIs
.

So far, it has not been possible to predict which patients will experience adverse effects and how severe they will be
.

Therefore, an entry point I want to introduce to you is - biomarkers (predicting adverse reactions, severity)
.

Intestinal flora is a general term for a group of microbial communities living in the body's gut.
In recent years, more and more research evidence has shown that the intestinal flora is directly related to the occurrence of various human diseases
.

Gut microbiota is associated with irAEs induced by immunotherapy in different cancers
.

However, much remains unclear about the impact of gut microbiota on various malignancies undergoing immunotherapy
.

The imbalance of gut microbiota may exacerbate the symptoms of immune-related adverse reactions in patients
.

The authors collected samples at multiple time points before and after treatment, systematically integrated high-throughput multi-omics data such as gut microbiome sequencing and database mining to reveal biomarkers of adverse reactions to immunotherapy, and confirmed that they have certain conversion potential
.

Immune-related cells play a huge role in anti-tumor immunity, and excessive activation (or inhibition) of their functions may lead to autoimmune diseases
.

It should be noted that it is not just immune cells, but refers to cells related to tumor immunity (various cells of tumor microenvironment)
.

For example, the complete immunosuppressive state in the tumor microenvironment (TME) is an important reason for the occurrence and rapid development of cancer
.

Tumor-associated fibroblasts (CAFs) also play an important role
.

So how do these cellular transcriptome signatures differ? Which regulatory pathways show significant changes? How is the heterogeneity of these immune cells different (single cell sequencing)? Targeting these studies will advance the understanding of immune dysregulation in cancer and contribute to the efficient stratification and management of irAEs, that is, targeting this specific immune-related cell may lead to new therapeutic approaches and Offers hope for developing predictions for irAEs
.

Cytokines, with the comprehensive development of tumor immunity, cytokines have entered a new era of development
.

Many cytokines such as interleukin, tumor necrosis factor and interferon have become an indispensable part of tumor immunity
.

In patients with irAEs, certain cytokines must be significantly changed before and after treatment, and these cytokines may be signaling molecules that are partially enhanced by the immune system and, in turn, play a role in patients with immune-related adverse events
.

In previous immunotherapy, it was found that the level of cytokines was closely related to the incidence of irAEs
.

Therefore, in-depth research on cytokines is conducive to the prediction and timely intervention of irAEs
.

Tumor burden is defined as the number of cancer cells in the body, the size of the tumor, or the total amount of cancer foci
.

There is currently evidence that high tumor burden has a negative impact on anticancer immunity
.

In the past, tumor burden was mostly assessed by imaging.
At present, some biomarkers can be used to reflect tumor burden, and some serum biomarkers are usually associated with poor response of patients to immune checkpoint inhibitors (ICIs)
.

There is already evidence that tumor burden can be used as a biomarker to guide the use of immune checkpoint inhibitors, so tumor burden is also likely to be used as a biomarker for irAEs
.

specific genetic alterations
.

In recent years, molecular maps associated with the emergence of NGS have provided information on actionable targets and identified specific genetic alterations associated with responses to ICIs
.

We should also fully consider its application in clinical practice
.

The development of research techniques such as NGS, single-cell RNA sequencing, etc.
will allow us to gain a more comprehensive understanding of the various components of the TME and their interactions, and allow extensive screening of potential biomarkers at the genome scale to identify ideas for the combination of predictors of irAEs : Maybe the content you are currently researching has been studied by others, or maybe the in-depth research consumes your energy and so on
.

It's better to try combined biomarker prediction
.

As there are no mature biomarkers for predicting irAEs
.

The above are all candidate biomarkers
.

Combining these candidate markers can more accurately predict irAEs
.

Conclusion: The discovery of immune checkpoint pathways and the subsequent development of corresponding inhibitors targeting these pathways have revolutionized tumor therapy in the past decade
.

Monoclonal antibodies targeting immune checkpoints PD-1/PD-L1 and CTLA-4 have made breakthroughs in clinical tumor treatment
.

Despite this, more than half of patients do not benefit from these treatments and are often accompanied by autoimmune toxicities, known as immune-related adverse events (irAEs)
.

If the possible risks of patients can be predicted and monitored through irAEs-related biomarkers, and effective preventive and intervention measures can be taken in time to avoid the deterioration of adverse events, it is of great significance to ensure the safety of subjects and the smooth progress of clinical trials
.

More information on bioinformatics analysis questions: 18501230653 (same number on WeChat) Bioinformatics analysis good article recommends 01 8 markers of failure of immune checkpoint inhibitors02 Another hot spot of cell death: Immunogenic cell death , Copper Death 04TCGA Featured Series-Immunotherapy Predictive Markers 05Immunotherapy Related: New Findings Under the Same Research Logic