Professor Wang Rongqi: Management of immune-related adverse reactions

Professor Wang Rongqi

• Deputy Director of the Department of Hepatology, Integrated Traditional Chinese and Western Medicine, The Third Hospital of Hebei Medical University

• Doctor of Medicine, Chief Physician, Professor, Master Supervisor

• Deputy leader of the Youth Group of the Hepatology Branch of the Chinese Medical Association

• Member of the Standing Committee of the Liver Disease Expert Committee of the Chinese Association of Integrative Physicians

• Member of the Standing Committee of the Liver Disease Branch of the Asia-Pacific Society of Medical Bioimmunology

• Member of the Severe Liver Disease and Artificial Hepatology Group of the Hepatology Branch of the Chinese Medical Association

• Chairman-elect of Hepatology Branch of Hebei Medical Association

• Member of the Standing Committee of Hebei Association of Integrated Traditional Chinese and Western Medicine Hepatology

• Standing Director of Hebei Hepatology Association

• Member of the Standing Committee of the Gastroenterology Professional Committee of Hebei Emergency Medical Association

• Member of Hebei Provincial Medical Doctor Association Liver Disease Branch

• Accrue expert of the Degree Center of the Ministry of Education

• Expert of Hebei Province Science and Technology Award Review

• Expert of medical malpractice technical appraisal in Hebei Province

At present, there are three main types of clinical ICIs, which are summarized
in Table 1.

Table 1 Current clinical ICIs

The mechanism of irAEs is as follows:

• Disrupt the original immune tolerance balance, so that autoimmune strengthening triggers irAE;

• Tumor cells release host antigens during treatment, and antigen cross-presentation occurs, triggering an autoimmune response;

• Immune cells release inflammatory mediators leading to tissue immune damage;

• off-target effects of ICls;

• The pro-inflammatory effect of microorganisms exacerbates the pro-inflammatory effect in the treatment of ICIs, causing irAE.
  
  

The clinical features of irAEs mainly include three aspects: site of occurrence, incidence and time
of occurrence.

1.
Site of occurrence

irAEs can affect all organs and tissues throughout the body (Figure 1).

Common sites include: skin, colon, endocrine organs, liver, and lungs; Rare sites include the nervous and cardiovascular systems
.
CTLA-4 monoclonal antibody differs from the common types of irAEs that PD-1 monoclonal antibody is associated
with.
In addition, irAEs caused by different diseases and ICIs also differ
.

Figure 1 irAEs can affect all organs and tissues throughout the body

2.
Incidence rate

Overall, grade 3/4 toxicity rates are low
.
The incidence of irAEs is higher than that of PD-1/PD-L1 monoclonal antibodies, while PD-1 monoclonal antibodies have a comparable
incidence of irAEs with PD-L1 monoclonal antibodies.
In addition, the incidence of irAE was higher with combination therapy, and the same ICI had different irAE toxicity profiles in different
tumors.

• A review of adverse events of PD-1 inhibitors and PD-L1 inhibitors published in 2018 included a total of 5744 patients with tumors (3284 PD-1 inhibitors and 2460 PD-L1 inhibitors), and the study showed that the incidence of adverse reactions of PD-1/PD-L1 inhibitors was comparable
  .
  

• A meta-analysis published in 2018 including 19,217 patients from 112 studies analysing ICI-related mortality showed a higher
  incidence and mortality of irAE with double-free combination than monotherapy.
  

• A meta-analysis published in 2017 included 48 clinical studies (2003~2015) of ICI monotherapy with a total of 6938 patients and found that the same ICI had different irAE toxicity profiles in different
  tumors.
  Compared with lung cancer, the PD-1 inhibitor irAE has a higher incidence of gastrointestinal and skin toxicity and a lower incidence of pneumonia in melanoma.
  Compared with kidney cancer, the PD-1 inhibitor irAE has a higher incidence of arthritis and myalgia and a lower
  incidence of pneumonia and dyspnea in melanoma.
  

3.
Time of occurrence

irAEs can occur
at any time after receiving treatment.
irAEs generally occur early, most between weeks and 3 months after administration, and some begin to occur
after treatment is discontinued.
Overall, the time of occurrence is: gastrointestinal tract, skin, liver, endocrine, nervous system, and lung (Figure 2).

Figure 2 The occurrence time of irAEs is different

Most irAEs are reversible and the time to remission varies
.
A study of Nivolumab published in 2016 showed faster remission times for pneumonia, gastrointestinal and hepatotoxicity, and longer remission times for endocrine events and cutaneous toxicity
.
Because irAEs lead to treatment interruption and overall mortality rate is lower than chemotherapy, meta-analysis of clinical trials shows that the overall incidence of all adverse reactions after ICI treatment is 54%~76%.

Principles of management of irAEs: Early prevention, full monitoring, and follow-up are essential
.
In the event of adverse events in treatment, three possibilities should be considered: disease progression, incidental events, or irAEs, the most common adverse events are related to disease progression, and irAEs
should still be considered when the disease is stable.

1.
Before ICIs treatment

Prior to treatment, clinicians assess the patient's susceptibility to irAEs and perform relevant tests to evaluate and judge
adverse effects.
This includes a comprehensive assessment
of the patient's family history, physical condition, autoimmune disease, baseline laboratory tests, and imaging studies.
For the following 10 special populations, ICIs should be chosen with caution (Table 2).

Table 2 Special populations should choose ICIs with caution

2.
Treatment of irAEs

After irAE occurs, severity should be accurately diagnosed and assessed, and treatment should be stratified according to the severity of adverse events (Figure 3).

Most irAEs can be controlled by withholding ± corticosteroids and can be reversed
.

Figure 3 Hierarchical processing of irAEs

3.
Post-treatment monitoring

The safety and necessity of ICls reuse should be evaluated
.
A study published in 2017 found that half of patients who had previously experienced irAEs would develop the same or new irAEs
after ICI treatment.
Most of the re-emerging irAEs were able to recover; First-time irAEs are more likely to occur when used again if hospitalization is required
.
After resuming ICI, irAEs
can be identified and prevented through close monitoring.
The general principles recommended by the 2020 NCCN guidelines for re-IO therapy in patients with prior irAE are shown in Table 3
.

Table 3 General principles of re-IO therapy in patients with prior irAE

4.
Patient education

It is recommended that medical staff educate patients on immunotherapy; Ensure timely access to a specialist; Strengthen the assessment of the patient's signs and symptoms; If necessary
, consult with relevant departments.

ICIs are monoclonal antibodies developed for the corresponding immune checkpoints, and their main role is to block the inhibitory effect
of tumor cells on immune cells.
Common irAEs include rash, pruritus, thyroid dysfunction, pituitary inflammation, hepatitis, diarrhea, colitis, and pneumonia, and should follow the principles of whole-course management and graded toxicity management, timely intervention, and follow-up monitoring
.
Restarting ICls should be treated with caution and should be followed closely to monitor for recurrence of symptoms
.