Immune-related adverse events of checkpoint inhibitors

Abstract

Cancer immunotherapies have changed the landscape of cancer treatment during the past few decades. Among them, immune checkpoint inhibitors, which target PD-1, PD-L1 and CTLA-4, are increasingly used for certain cancers; however, this increased use has resulted in increased reports of immune-related adverse events (irAEs). These irAEs are unique and are different to those of traditional cancer therapies, and typically have a delayed onset and prolonged duration. IrAEs can involve any organ or system. These effects are frequently low grade and are treatable and reversible; however, some adverse effects can be severe and lead to permanent disorders. Management is primarily based on corticosteroids and other immunomodulatory agents, which should be prescribed carefully to reduce the potential of short-term and long-term complications. Thoughtful management of irAEs is important in optimizing quality of life and long-term outcomes.

Figure 1.. Mechanism of immune checkpoints and ICIs.

The main immunotherapy approaches that are approved for clinical use in cancer are the immune checkpoint inhibitors (ICIs). These therapies are monoclonal antibodies that target the receptors CTLA-4 and PD-1 and the PD-1 ligand, PD-L1, which are involved in the regulation of T cell activation. A| T cell activation requires two signals: first, antigen recognition by the T cell receptor (TCR) following antigen presentation by major histocompatibility complex (MHC) class II molecules on the surface of antigen-presenting cells and, second, signal modulation by CD80 or CD86 binding to the CD28 receptor. CTLA-4 is located on the T-cell surface and competes with the CD28 receptor to bind CD80 or CD86, thereby blocking T cell activation. CTLA-4 inhibitors block CTLA-4–CD80 or CTLA-4–CD86 binding to facilitate T cell activation (dashed line). B| PD-1 is a surface receptor that is expressed by T-cells and promotes apoptosis of antigen-specific T-cells and reduces apoptosis of regulatory T-cells ^, through its interaction with its ligand PD-L1, which is expressed by tumour cells and myeloid cells. This interaction is useful in preventing autoimmunity in physiological conditions, but cancer cells exploit this process to escape from immune system activity upregulating PD-L1 expression.^, PD-1 and PD-L1 inhibitors block the PD-1–PD-L1 interaction, facilitating T cell activation and survival (dashed lines).

Figure 2.. Mechanism of irAE.

The mechanisms of immune-related adverse events (irAE) owing to immune checkpoint inhibitors (ICIs) depend on the type of ICI therapy used (anti-PD-1 or anti-PD-L1 inhibitors versus anti-CTLA-4 inhibitors). CTLA-4 inhibitors can induce several cellular alterations, such as T cell activation and proliferation, impaired regulatory T cell (T_reg) survival and increased levels of T_H17 cells, in addition to the induction of cross-reactivity between antitumour T cells and antigens on healthy cells and autoantibody production. PD-1 and PD-L1 inhibitors lead to a reduction in T_reg survival and T_reg inhibitory function and increase cytokine production. TCR, T cell receptor.

Figure 3.. Common radiological and/or photographical appearance of irAEs.

A| CT image of immune checkpoint inhibitor (ICI)-associated before the onset of immune related colitis. B| CT image of ICI-associated colitis after colitis onset. C| Vitiligo. D| High-resolution pulmonary CT showing interstitial lung disease of ICI-associated pneumonitis. E| MRI with T2 flair of ICI-associated encephalitis; an abnormal signal can be observed bilaterally in the insula and medial temporal lobes. The patient presented with new-onset confusion and weakness whilst using anti PD-1 therapy. F| Pulmonary CT showing multiple hilar adenopathy in a patient with sarcoidosis after ipilimumab treatment. Biopsy of an adenopathy demonstrated non-caseating granulomas. G| Cutaneous purpura in a patient treated with nivolumab.

Figure 4.

Rate of reactivation/flare of pre-existing autoimmune diseases after ICI therapy. We searched MEDLINE for articles published until January 1st 2020 using the terms “pre-existing (preexisting)” and “autoimmune” in combination with “checkpoint”, ”CTLA-4”, ”PD-1” and “PD-L1”, with no search restrictions. Study designs were considered in the following order (listed from highest to lowest evidence quality): systematic reviews, controlled trials, prospective cohort studies, case-control studies, retrospective studies and case series. The following relevant information was defined as selection criteria: a well-defined “population at risk” (patients diagnosed with an autoimmune disease before the initiation of the ICI therapy), available information to calculate the rate of relapse (patients who relapsed/total number of patients exposed to the drug, to be calculated for every different type of underlying autoimmune disease), and whether the relapse was linked to the underlying autoimmune disease or not. Duplicate publications, case reports, experimental studies and articles including incomplete/irrelevant information were excluded. We also manually searched the reference list of relevant articles retrieved and the EMBASE database. The following Figure shows a flow diagram of our search results. The available information about the use of immune checkpoint inhibitors was extracted from nine studies including patients with cancer and pre-existing autoimmune diseases^,,–. Rates of reactivation/flare were defined as “number of patients who relapsed/total number of patients exposed to the drug”, to be calculated for each underlying autoimmune disease. Rates in individual diseases or grouped diseases with at least 5 treated individuals are represented in this Figure. For more detailed information about the methodology and rates for each individual autoimmune disease, see the Supplementary Material.

Figure 5.

Suggested therapeutic algorithm for the organ-by-organ management of irAEs. When a systemic therapy is considered in patients presenting with immune-related adverse events owing to immune checkpoint inhibitors (irAEs), the first-line treatment are glucocorticoids with the exception of adverse effects that affect the endocrine system. Other therapies to be considered in severe/refractory cases depend on the affected organ system but can include synthetic immunosuppressants, intravenous immunoglobulin (IVIG), plasma exchange and monoclonal antibodies. These therapeutic suggestions are based on recommendations included in official guidelines, data from some retrospective studies, isolated published cases and personal experience of the authors. SAD: systemic autoimmune diseases; ILD: interstitial lung disease. ^aAvoid etanercept owing to the risk of autoimmune inflammatory colitis; ^b consider abatacept or alemtuzumab; ^c consider infliximab or tocilizumab.