Immune related adverse events

Immune checkpoint inhibitors have revolutionized drug-based tumour therapy. A large number of checkpoints are known. Antibody-induced blockade of the most important checkpoints CTLA-4 and PD-1/PDL-1 is now a key therapeutic principle in numerous different tumor entities (melanoma, squamous cell carcinoma, Merkel cell carcinoma and non-dermatological tumors: bronchial, breast, kidney, liver, bladder and head and neck tumors). Immune checkpoint inhibitors cause a broad spectrum of side effects. As these side effects (ADRs/immune related adverse events/irAEs) are attributable precisely to the mechanism of action of this substance group, the spectrum of side effects is similar in principle, but with a very different frequency distribution. They result primarily from an immune response against normal tissue, whereby any organ can be affected. However, the activation or reactivation of pre-existing diseases is also possible.

Tumors and the tumor microenvironment (TME) express multiple inhibitory signaling pathways that lead to T cell dysfunction and immune escape. Although blockade of PD-1 and/or CTLA-4 can promote the activation of T cells and exert an effective antitumor function, the excessive activation of autoreactive T cells with the resulting excessive autoimmunity is thought to be the cause of immune-related adverse events (irAE) (Dai S et al. 2014). The clinical benefit of checkpoint inhibitors in the treatment of numerous tumors, e.g. metastatic melanoma, but also other tumor entities (breast cancer, kidney, head and neck tumors) is undisputed.

PD-1 is an inhibitory receptor that is expressed on the surface of activated T and B cells and induces and maintains peripheral tolerance to autoreactive T cells (Dai S et al. 2014). PD-1 binds to the ligands PD-L1 and PD-L2, which are expressed on antigen-presenting cells (APCs) and tumor cells. This interaction leads to suppression of T-cell activation and tumor-mediated immune evasion. Inhibition of PD-1 exacerbates T cell effector functions and optimizes B cell and natural killer cell activation. In addition, PD-L1 and PD-L2 play distinct roles in the immune response (Tanaka R et al. 2022). In APCs, stimulation with interferon (IFN)-γ and interleukin (IL)-17A significantly induces PD-L1 expression, while PD-L2 expression is induced by stimulation with IL-4. PD-L1 plays an important role in Th1- and Th17-type immunity, whereas PD-L2 is associated with Th2-type immunity. Therefore, PD-1 blockade can shift the immune balance towards a Th1/Th17 response (Tanaka R et al. 2022). Furthermore, it has been shown that the binding of PD-1, PD-L2 and PD-1-PD-L1 leads to TCR-PD-1-PD-L2 conglomerates (signalosomes). These signalosomes suppress the T-cell reactions. Similar to the effect of anti-PD-L1 agents, PD-L2 blockade can also have an anti-tumor effect. To date, however, there are no therapeutic agents that target PD-L2.

CTLA-4 is expressed on the surfaces of activated T cells and Tregs. It can bind with higher affinity to B7 molecules (CD80/86) on APCs and thereby inhibit CD28- B7 binding, thereby suppressing T cell activation (Phan GQ et al. 2003). Blockade of CTLA-4 prevents its binding to B7 and induces the binding of CD28 and B7, which reactivates T cells. It also decreases the immune inhibitory effects of Tregs and further reduces the number of Tregs in tumor tissue through antibody-dependent cellular cytotoxicity (ADCC) (Zhang P et al. 2020)-

Pharmacological class-specific irAEs: According to the different functions of immune checkpoints, the response modes of irAEs associated with single-drug therapy differ depending on whether the inhibition targets the CTLA-4 or PD-1 signaling pathways. In general, PD-1 and PD-L1 inhibitors are better tolerated than CTLA-4 inhibitors. In systematic reviews, grade 3 and 4 irAEs occur more frequently with CTLA-4 inhibitors than with PD-1 inhibitors (Ramos-Casals M et al. 2020). It is conceivable that CTLA-4 blockade induces greater T cell proliferation or less immunosuppression mediated by regulatory T cells (Treg). PD-1 blockade could activate a reduced number of T cell clones, and although most circulating T cells do not express PD-1, they could be stimulated to do so upon stimulation during TCR-dependent signaling.

It is likely that additional antigenic effects of immunotherapies lead to the development of neutralizing antibodies. In fact, the formation of antibodies against the pharmaceutical corpus of the drugs is not uncommon. This antibody formation may depend on the degree of "humanization" of the therapy. (Lu R-M et al. 2020). With nivolumab, antibodies against its pharmacological corpus were found in 12.7 % of patients. However, these were only permanently detectable in 0.3 % of patients when checked. The most frequent anti-drug antibody-positive rates were still found

• with 54.1 % for atezolizumab,
• 5.9 % for durvalumab,
• 2.9 % for avelumab
• with 2.1 % for pembrolizumab.

Although the clinical effects of anti-ICI antibodies have not yet been clearly clarified, these effects appear to primarily impair the efficacy of treatment rather than cause adverse events (Enrico D et al. 2020).

Skin (see below Immune-related adverse events, cutaneous):

• Cutaneous irAEs are among the most frequent and also among the earliest occurring immune-mediated adverse events. The following non-specific cutaneous side effects are detectable: xerosis cutis, pruritus. Furthermore, specific cutaneous skin changes can be detected:

  • Exanthematic IrAEs: They may appear as multiforme or lichenoid exanthema.

  • Alopecia areata/universalis; vitiligo (Sibaud V 2018); panniculitis/erythema nodosum

  • Bullous exanthema: bullous pemphigoid; pemphigus; dermatitis herpetiformis; non-autoimmunological bullous exanthema

  • Sarcoidosis: sarcoidosis of the lung, sarcoidosis of the skin, granuloma anulare;

  • Collagenoses: sicca syndrome/Sjoegren's syndrome; antiphospholipid syndrome; lupus erythematosus (especially subcutaneous lupus erythematosus); systemic sclerosis

    Vasculitides: cryoglobulinemia; eosinophilic granulomatosis with polyangiitis; giant cell arteritis (giant cell arteritis)

  • For further information see below. Cutaneous immune-related adverse events

Other organs affected are:

• Stomach: Autoimmune gastritis (K29.5); Lymphocytic gastritis (K29.6)
• Intestine: Ileitis; Ileocolitis; Ischaemic colitis (K55.9); Microscopic colitis (K52.8); Ulcerative colitis (K51.9); Immunological colitis due to checkpoint inhibitor therapy
• Liver: Autoimmune hepatitis; Eosinophilic hepatitis
• Heart: Autoimmune myocarditis; Myocardial fibrosis; Autoimmune pericarditis
• Endocrine: hypophysitis, thyroiditis; autoimmune diabetes mellitus; hyperparathyroidism; hypogonadism
• Lung: Alveolitis; Pneumonitis; Pulmonary fibrosis
• CNS: Aseptic meningitis; Encephalitis; Polyneuropathies
• Eye: Conjunctivitis; Episcleritis/scleritis; Orbital inflammation; Uveitis; Vogt-Koyanagi-Harada syndrome
• Kidney: Acute tubulointerstitial nephritis; Renal tubular acidosis; Glomerulonephritis
• Skeleton: Arthralgias/polyarthralgias; Arthritides
• Vasculitis of the lungs; Schönlein-Henoch purpura.

In relation to the individual immune checkpoint inhibitors ( ICIs), the following distribution pattern was observed:

• with ipilimumab, dermatological, gastrointestinal and renal irAEs are to be expected most frequently,
• for pembrolizumab with arthralgias, pneumonitis and liver toxicities,
• endocrine side effects with nivolumab
• hypothyroidism with atezolizumab

Combination therapies: The increasing use of combination strategies (combining immunotherapies with conventional treatments such as chemotherapy or combining two types of immunotherapies) could improve the efficacy of cancer immunotherapy, but also increase irAEs. The incidence of adverse events is higher and more severe with combination therapy than with monotherapy (Wolchok JD et al 2017)

In addition, the phenotype of organ-specific irAEs can be altered by combination therapies. A study of 30 patients with clinically confirmed arthritis showed that individuals treated with ICI combination therapy were more likely to have earlier onset of irAEs, arthritis and higher C-reactive protein levels compared to those treated with ICI monotherapy. Patients treated with ICI monotherapy were more likely to initially experience small joint involvement and arthritis as the only irAEs. In addition, combination therapy was associated with a higher risk and earlier onset of irAEs, with up to five times shorter time to onset compared to monotherapy (32/ 146 days)

The incidence of irAEs varies greatly depending on the ICI used and the organ-specific damage induced, suggesting that there is a distinct population of individuals who are susceptible to developing irAEs, possibly due to an unknown genetic background (Sandigursky S et al. 2018). In addition, there is considerable individual reactivity, as some patients do not develop irAEs after months of therapy, while others develop life-threatening irAEs after a single infusion. One explanation for this could be that some individuals have a familial predisposition to autoimmunity, for example. In addition, a number of CTLA4 and PDCD1 polymorphisms (encoding PD-1) have been associated with several autoimmune diseases (Pizarro C et al.(2014) PD-L1 gene polymorphisms and low serum level of PD-L1 protein are associated to type 1 diabetes in Chile. Diabetes Metab Res Rev 30: 761-766; Vaidya B et al. (2002) An association between the CTLA4 exon 1 polymorphism and early rheumatoid arthritis with autoimmune endocrinopathies. Rheumatology (Oxford). 41: 180-183). Whether other epidemiologic characteristics, such as the patient's ethnicity, are associated with the risk of irAEs is not known. Age does not appear to play a role.

The severity of cutaneous irAEs is classified according to the CTCAE classification (Common Terminology Criteria for Adverse Events) (grades I-V). Most exanthema associated with immunotherapy is classified as mild, with less than 3% higher grade reactions (≥ CTCAE grade III) with monoimmunotherapy and less than 5% with combined immunotherapy (PD-1 inhibitors plus CTLA-4 inhibitors). Even severe skin rashes requiring dermatologic consultation led to interruption of oncologic treatment in only 25% of cases, of which 16% were subsequently able to resume treatment.

In several studies, cutaneous irAE under immunotherapy was associated with a better therapeutic response. This was particularly true for vitiligo in melanoma patients. However, some studies indicate a similar positive relationship between immunotherapy-associated exanthema and therapeutic response (Watanabe T et al. 2023)

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