Chronic immunotoxicity of immune checkpoint inhibitors

preface

Immune checkpoint inhibitors (ICIs) have become a central pillar of cancer treatment, and in economically developed countries, almost half of patients with metastatic cancer are eligible to receive ICIs
.
As of December 2021, there are eight approved drugs for 17 different malignancies, and these drugs are increasingly
used in multiple (new) adjuvant and maintenance therapies.
ICIs are also frequently used in combination regimens, including those
involving other classes of ICIs, chemotherapy, cell therapy, and/or targeted therapy.
In this way, long-lasting responses are becoming more common, so it is becoming increasingly important
to describe the long-term physiological significance of ICIs treatment.

Patients with durable responses appeared to broaden the peripheral T and B cell repertoire and appeared to develop immune memory
compared to patients who relapsed after treatment.
The molecular basis of these reactions is not fully understood, but regardless of their mechanism of action, the extended duration of the therapeutic effect of ICIs often far exceeds their pharmacokinetic half-life
.
This long-lasting effect also has an effect
on toxicity.

Emerging evidence suggests that persistent toxicity may be more common than expected, and while these chronic sequelae are often low-grade, they can affect endocrine, rheumatology, lung, nerve, and other organ systems
.
Fatal toxicity also includes a variety of clinical manifestations, occurring in 0.
4–1.
2% of patients
.
This risk is a particularly important consideration given the likelihood of long-term survival
for the patient.

In addition, immune checkpoint blockade has effects on a variety of immune processes, including atherosclerosis, heart failure, neuroinflammation, obesity, and hypertension, which have not been described but are still an important area of research that may be relevant to
cancer survivors.

Immune activation with irAEs

The tumor-specific hypothesis that immune activation of most immune-related adverse reactions (irAEs) may be related to the activity required for an anti-tumor immune response, supported
by a reproducible positive correlation between treatment response and the incidence of irAEs.
However, there is also evidence that irAEs have mechanisms unrelated to antitumor activity, including those
involving microbiome, virus, or tissue-specific factors.

Different ICI regimens have different toxicity profiles, and for regimens containing anti-CTLA4 antibodies (30–55% combination of ipilimumab plus nivolumab), high-grade irAEs usually occur in a dose-dependent manner, but are not dose-dependent for anti-PD-1–PD-L1 antibodies used as monotherapy (10–15% incidence
).

irAE can occur in basically any organ system, including the heart, bone marrow, kidneys, bones, pituitary, and other organs
.
irAEs most often occur during the first three months of treatment, but can occur at any time during treatment, even months after treatment
ends.
Despite the lack of strong evidence from randomised clinical trials, acute severe IRAE can be managed
reasonably and effectively by providing symptom management, stopping ICIs, and taking high-dose corticosteroids.

Most irAEs appear early in the treatment process, but delayed events can also occur, i.
e.
, irAEs
that appear after 1 year of treatment.
In one study involving 118 patients, the estimated incidence of high-grade, delayed irAEs was 5.
3%.

The most common late-onset irAEs were colitis, rash, and pneumonia, and two patients died
.
Notably, most patients (74%) received anti-PD-1 antibody therapy at the onset of irAE, 12% stopped treatment within the first 3 months, and 14% stopped treatment
more than 3 months.
These observations reinforce the idea that irAEs (acute or delayed) may occur occasionally after discontinuation but usually occur during
active treatment.

Chronic irAEs

So far, acute irAE has received most attention
because it has a more pronounced clinical presentation and requires urgent treatment.
However, the data suggest that chronic irAEs are more prevalent
than previously recognized.
There is a lack of general consensus on the definition of chronic irAE, which is defined here as the duration of irAE ≥ 12 weeks
after ICIs stop treatment.
According to this definition, approximately 43% of patients have at least one chronic irAE.

There may be several
reasons for the lack of consensus in chronic irAEs.
First, most acute irAEs improve at least with steroid use and are usually resolved
by alternating therapies.
Second, adverse event reports in clinical trials tend to focus on the most common treatment-related toxicities, so low-frequency events are often underestimated or ignored
.
Third, most preliminary clinical trials recruit patients with metastatic cancer, and describing chronic and long-term events in patients with metastatic disease is challenging because these patients typically have a limited life expectancy, thus limiting long-term follow-up
.
Such patients may also receive follow-up systemic therapy, surgery, and/or radiation therapy, making attribution of toxicity more difficult
.
Finally, the presence of multiple comorbidities common in cancer patients may further impair the recognition
of chronic irAEs.

Despite these challenges, however, the persistent clinical response observed in a subset of patients treated with ICIs has allowed some follow-up studies to yield preliminary insights
.
Among these studies, endocrine diseases (such as hypothyroidism and emerging type 1 diabetes) and rheumatic viral (such as arthritis) became the most common chronic irAEs
.
A variety of other low-incidence events have also emerged, including neurological disorders, dermatitis, and pneumonia
.

Endocrine irAE

The earliest chronic irAEs were those that affected the endocrine organs, occurring in 15–40% of patients treated with ICIs
.
Hypothyroidism is the most common endocrine irAE, occurring in approximately 10% of patients receiving anti-PD-1/PD-L1 as monotherapy and up to 20%
of patients receiving ipilimumab plus nivolumab.

Pituitary inflammation is almost unique to
patients treated with ICIs.
It occurs more frequently (5–10%) and has an earlier onset (median 9–12 weeks)
in patients treated with ipilimumab compared with patients receiving anti-PD-1/PD-L1 antibodies.
72
。 The preference of patients receiving ipilimumab appears to be related to the expression of CTLA-4 on pituitary hormone-secreting cells, which leads to antibody and complement binding
.

Other endocrine irAEs, although less common, have similar persistence
.
ICI-induced diabetes mellitus (ICI–DM) occurs in <1% of treated patients, but may present with diabetic ketoacidosis, which usually requires lifelong insulin
supplementation.
In stark contrast to hypophysitis, ICI–DM is almost exclusively seen in patients receiving anti-PD-1/PD-L1 antibodies and is less common
in patients receiving anti-CTLA-4 monotherapy.

Rheumatism irAE

Considering that rheumatism belongs to the category of autoimmune diseases, the emergence of various rheumatic irAEs does not seem surprising
.
Interestingly, systemic lupus erythematosus and mixed connective tissue diseases have so far been unrelated to ICIs, with cases such as RA, polymyalgia rheumatica, polymyositis, and Sjögren syndrome
.

About half of patients experience persistent arthritis symptoms
that last for at least 6-12 months after ICI discontinuation.
Data from a small range suggest that ICI-induced chronic arthritis has a large negative impact on quality of life, at least comparable to
other irAEs.
In other rheumatology irAEs, ICI-induced Sjogren's syndrome has both similarities and differences to Sjögren syndrome, i.
e.
, xerostomia predominates rather than ocular involvement
.

A major challenge for rheumatic irAEs is the management of chronic low-toxicity, which applies to multiple organ systems but is most pronounced
in the case of rheumatic irAEs.
Rheumatic irAEs may impair quality of life, but are usually not sufficient to consistently take high-dose steroids or stop ICI
.
Therefore, in the case of ICI therapy, patients usually continue to receive low-dose steroids and/or antirheumatic drugs (DMARDs).

Gastrointestinal irAE

In patients treated with anti-PD-1 antibodies, colitis occurs in up to 5% and is usually presented with diarrhea with less frequent abdominal pain and blood
in the stool.
However, any grade of diarrhoea (44%) or severe diarrhea/colitis (15%) was more
common in patients receiving ipilimumab-containing regimens.

Hepatitis occurs in 3-10% of patients and is asymptomatic or may present with nonspecific symptoms, including malaise and myalgia, and less often jaundice and acute liver failure
.
Delayed diarrhea may also reflect pancreatic insufficiency
.
In one cohort, a 1% incidence of steatorrhea was reported in patients receiving anti-PD-1 antibodies, with a median onset of 9 months
.
Notably, 10% of this group of patients developed radiographic signs of pancreatic atrophy, although the mechanism and clinical significance of this finding in asymptomatic patients remain to be observed
.

Lung irAE

Pneumonia is one of the leading sources of morbidity and mortality of anti-PD-1 antibodies, most commonly presenting with dry cough, decreased oxygen saturation, and bilateral ground-glass opacities (including interstitial and organicized pneumonia).

Although most patients have persistent imaging findings at least 1 to 2 years after symptom onset, most of these patients have achieved symptom remission
.

In addition, rare patients with chronic wheezing or coughing, reactivation of pulmonary tuberculosis can also occur
.
Data from retrospective studies suggest similar rates in cancer patients who did not receive ICIs, so it is unclear whether ICIs play a role
in this effect.

Cardiovascular irAE

Acute fulminant myocarditis is the earliest ICI-associated cardiovascular irAE and typically presents with ECG disturbances, including arrhythmias and intercurrent myositis
.
Other recognized cardiac sequelae include pericarditis, which is more common in lung cancer patients receiving anti-PD-1/PD-L1 antibodies, is usually less fulminant, and is more sensitive
to corticosteroids.
Vascular irAEs are also described, including acute vasculitis, particularly temporal arteritis and polymyalgia
rheumatica.
Overall, these events can occur in up to 1–2% of
treated patients.

Combination regimens involving ICI and other conventional or targeted therapies are another important area of research, both of which may have inherent chronic cardiotoxicity
.
Similarly, in patients with RCC and several other cancers, ICIs are often used in combination with vascular endothelial growth factor inhibitors such as axitinib or renvatinib, which have been linked to many cardiovascular sequelae, including hypertension, vascular disease, and cardiomyopathy
.

Neurological irAE

Neurological irAEs occur in up to 5% of patients, which is more common
in ipilimumab-containing regimens.
These events can affect the neuromuscular junction (myasthenia gravis and Lambert–Eaton myasthenic syndrome), the central nervous system (meningoencephalitis), and peripheral nerves (sensory and motor neuropathy, including Guillain-Barré syndrome).

Meningoencephalitis is usually resolved with acute treatment, and it is unclear
whether some patients develop chronic defects.
The long-term prognosis for ICI-related myasthenia gravis is unclear, although in most patients ICI-related myasthenia gravis appears to either be in complete remission or controlled
with disease-specific treatment.
ICI-associated Guillain-Barré syndrome has a high case fatality rate (19%), and even patients who do improve with immunomodulatory symptoms often have residual weakness and/or loss
of sensation.
Peripheral neuropathy appears to be the neurological disease
most likely to evolve into chronic symptoms.
Approximately 2% of patients were reported to receive adjuvant anti-PD-1 antibody therapy for resection of melanoma, and nearly half of them developed chronic peripheral neuropathy
.

Skin irAE

Skin toxicity is one of the most common complications in patients with ICIs, including various inflammatory dermatitis syndromes, itching, and vitiligo
.
These events often present a challenging clinical dilemma because they are bothersome but not life-threatening and do not seem to have enough symptoms to stop treatment, or require large doses of steroids
.
Patients with ICI-induced dermatitis or pruritus may require ongoing use of antihistamines, topical steroids, and/or GABAERGIC agonists
.
Based on experience, although dermatitis and itching usually persist for weeks or months after stopping the drug, these IRAEs tend to eventually disappear
.
Vitiligo is more common in people with melanoma than in other cancers, is often incurable, and can become a lifelong complication
.
Severe skin reactions, such as Stephens-Johnson syndrome and bullous pemphigoid, can also have life-threatening long-term consequences
.

Other irAEs

Similar to acute IRAE, a wide range of low-frequency events can eventually turn into chronic irAEs
.
For example, nephritis, in a series, about 10% of patients require hemodialysis, and half of these patients fail to regain adequate kidney function and require renal replacement therapy
.

Hematologic toxicities, including idiopathic thrombocytopenic purpura, aplastic anemia, hemophagocytic lymphangiocytosis, and pure erythrocyte aplastic anemia, can also occur, although rarely, but can be fatal
.
Ocular symptoms may include uveitis and conjunctivitis
.
Other symptoms, such as fatigue, may also persist
after ICI discontinuation.
The pathophysiology, incidence, and temporal course of these nonclassical irAE sequelae have not been systematically studied
.

Fatal irAEs

Fatal irAEs are rare and may be caused
by severe autoinflammation that is difficult to resist with steroids and/or other immunosuppressants.
Although these events clearly fall into a different category from chronic toxicity, the risk
of fatal events needs to be given special consideration in the context of potentially persistent reactions produced by ICIs.

The data suggest that the incidence of lethal irAEs is low, ranging from 0.
4% anti-PD-1/PD-L1 antibody monotherapy to about 1.
2% of anti-CTLA-4/PD-1 combination regimens
.
Despite their incidence, these mortality rates are relatively low
compared to those associated with cytotoxic chemotherapy, molecularly targeted therapies, and even high-risk surgical procedures for cancer.

Death can be caused
by various organ-specific irAEs.
Myocarditis has the highest mortality rate of irAEs (25–50% of patients), mainly due to refractory arrhythmias
in critically ill patients.
Myositis can also be accompanied by myocarditis, leading to diaphragmatic paralysis and respiratory failure
.
Pneumonia is fatal in 10-15% of patients, usually due to respiratory failure
.
Hepatitis (caused by fulminant liver failure) and colitis (caused by colon perforation) can also lead to death, although their incidence is usually much
lower.

Neurogenic irAEs, although uncommon, can also be fatal in 10 to 15% of patients, usually due to refractory or prolonged Guillain-Barré syndrome, encephalitis, or myasthenia-like syndrome
.
Notably, fatal irAEs typically appear early in the treatment process, with a median of 15 days (combination therapy) and 40 days (anti-PD-1 antibodies as monotherapy), suggesting that pre-existing organ-specific inflammation rapidly released after ICI initiation may be responsible for
these events.

In addition, a trend towards older age in patients with fatal irAEs was observed, suggesting that older age and associated reduced functional reserve may make patients more likely to die
.
Long-term immunosuppression may be a direct cause of death in patients with long-term refractory toxicity, as the presence of opportunistic infections may also complicate
the clinical process.

Re-energized security

Another long-term effect of irAE is whether patients who gain some benefit from treatment but also have severe toxicities should be challenged
again after the irAE resolves.
Clinicians may seek to re-challenge a subset of patients, including those with early-onset toxicity who may benefit from further treatment, or who
still respond to ICI discontinuation and later develop disease progression.

There is a lack of forward-looking data
on re-energizing safety.
Data from retrospective studies suggest that IRAE relapses
in approximately 25–50% of patients who are re-treated with anti-PD-1/PD-L1 antibodies.
Currently, determining which patients are at highest risk of relapsing IRAE is challenging
.
One series of data suggests that relapse rates of colitis, pneumonia, and hepatitis are higher than other irAEs after re-excitation, and that older age is also associated with
irAE relapse.

A longer delay between discontinuation and reactivation may reduce the risk of recurrent toxicity (e.
g.
, in patients retreated
more than 12 months after discontinuation due to irAE).
Clinicians should consider the type and severity
of irAEs when making decisions about reactivation.
A theoretical approach that has not yet been extensively clinically conducted is to restore ICIs
in combination with selective immunomodulatory therapy.
For example, targeted inhibition of cytokines such as IL-6 could theoretically decouple the anti-tumor immune response from irAEs and allow for safe reactivation
.
Several clinical trials are currently underway to test these methods (NCT03293784, NCT03999749, and NCT04940299).

brief summary

ICIs have a long-lasting response in a wide variety of cancers and generally controllable toxicity, making them an attractive and widely used treatment option
for cancer patients.
This broad application broadens therapeutic-related and survival considerations beyond just generating an anti-tumor immune response, with lifelong effects on
quality of life.
Therefore, in addition to typical irAEs, it is important to understand the chronic irAEs that block immune checkpoint molecules and the long-term effects on overall immune function
.

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