Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events

Abstract

Immune checkpoint inhibitors (ICIs) block inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1) and enhance antitumor T-cell activity. ICIs provide clinical benefits in a percentage of patients with advanced cancers, but they are usually associated with a remarkable spectrum of immune-related adverse events (irAEs) (e.g., rash, colitis, hepatitis, pneumonitis, endocrine, cardiac and musculoskeletal dysfunctions). Particularly patients on combination therapy (e.g., anti-CTLA-4 plus anti-PD-1/PD-L1) experience some form of irAEs. Different mechanisms have been postulated to explain these adverse events. Host factors such as genotype, gut microbiome and pre-existing autoimmune disorders may affect the risk of adverse events. Fatal ICI-related irAEs are due to myocarditis, colitis or pneumonitis. irAEs usually occur within the first months after ICI initiation but can develop as early as after the first dose to years after ICI initiation. Most irAEs resolve pharmacologically, but some appear to be persistent. Glucocorticoids represent the mainstay of management of irAEs, but other immunosuppressive drugs can be used to mitigate refractory irAEs. In the absence of specific trials, several guidelines, based on data from retrospective studies and expert consensus, have been published to guide the management of ICI-related irAEs.

Keywords: PD-L1; cancer; cytotoxic T lymphocyte-associated protein (CTLA-4); immune checkpoint inhibitor (ICI); immune-related adverse event (irAE); immunotherapy; programmed cell death protein -1 (PD-1).

Figure 1

Schematic representation of immune mechanisms of immune checkpoints and immune checkpoint inhibitors (ICIs). (A) T cells, particularly CD4⁺ T cells in the lymph node, recognize tumor antigens in the context of MHC molecules or antigen-presenting cell (APC) and T cell receptor (TCR) on T cells. The interaction between CD80 (also known as B7-1) or CD86 (also known as B7-2) on APC and CD28 mediates T cell co-stimulation in conjunction with TCR signals. CTLA-4 on activated T cell interacts with both ligands (i.e., CD80 or CD86) with higher affinity and avidity than CD28 and, unlike CD28, sends an inhibitory signal to T cell. Monoclonal antibodies anti-CTLA-4 (i.e., ipilimumab) block this inhibitory pathway restoring T cell activity. (B) T cells, particularly cytotoxic CD8⁺ T cells, which recognize tumor antigens in the context of MHC class, result in the adaptive expression of PD-L1 on the surface of tumor cells. The interaction between PD-1 and PD-L1 negatively regulates the anti-tumor T cell response. This interaction is useful in preventing autoimmunity in physiological conditions, whereas cancer cells exploit this mechanism to escape from immune system upregulating PD-L1 expression. Anti-PD-1 (i.e., pembrolizumab, nivolumab and cemiplimab) and anti-PD-L1 mAbs (i.e., atezolizumab, avelumab and durvalumab) block this inhibitory pathway restoring T cell activity.

Figure 2

Proposed immunopathogenic mechanisms for the development of immune checkpoint-induced immune-related adverse events. A proposed mechanism postulates that self-antigens (e.g., heart and skeletal muscle antigens) activate T cell clones driving antitumor responses and organ-specific autoimmunity (24). Thyroid autoantibodies may be involved in patients who develop thyroid dysfunction (44, 59, 60), ICI-associated diabetes (42, 43), bullous pemphigoid (61), hypophysitis (62, 63), and myasthenia gravis (64). Cytokines/chemokines released from immune cells can cause immune-mediated tissue damage (12, 65, 66). The pivotal role of genetic factors in the development of ICI-associated irAEs, originally highlighted in mice (67, 68), has been confirmed in patients with arthritis (69), ICI-associated diabetes (42, 43, 70), and pruritus (71). There is growing evidence that gut microbiome may play a role in the development of experimental irAEs (72, 73) and of colitis in patients with melanoma (74, 75). irAEs contributing to most fatalities are presented in red.

Figure 3

The spectrum of organs affected by irAEs associated with immune checkpoint inhibitors (ICIs) is very broad. Shown are the most common immune-related adverse events (irAEs) that clinicians can encounter in cancer patients treated with ICIs. irAEs contributing to most fatalities are highlighted in red [modified from (19)]. ICI-associated diabetes is almost exclusively seen in patients treated with anti-PD-1/PD-L1 antibodies, and rarely with ipilimumab monotherapy (42, 118). By contrast, hypophysitis occurs more often in patients receiving ipilimumab (119). Colitis occurs more commonly with ipilimumab and with combined immune checkpoint blockade than with anti-PD-1/PD-L1 alone (112, 120). Endocrinopathies (such as hypothyroidism, hypophysitis, and adrenal insufficiency) and rheumatological disorders have the highest incidence of development into subacute/chronic toxicity (49). Endocrine toxicities, unlike many other irAEs, are not managed using high-dose glucocorticoids, which have no effect on either initial severity and resolution (121, 122). Although acute myocarditis was the first cardiovascular irAEs associated with ICIs (123), an important unanswered question relates to the long-term cardiovascular sequelae of ICIs (49, 56, 57).