Adverse events associated with immune checkpoint inhibitor treatment for cancer

What are immune checkpoint inhibitors and how do they work?

The idea of exploiting the host immune system to treat cancer relies on the insight that the immune system can eliminate malignant cells in a process termed immune surveillance.3 During this process, positive and negative immune checkpoints ensure a balance between the hosts’ defence against tumour antigens and autoimmunity. Tumour cells can distort some of these signals, allowing the cells to escape immune destruction and progress to cancer.4 Cytotoxic T-lymphocyte–associated protein 4 and programmed cell death 1 inhibitors are 2 important negative immunomodulatory checkpoints; they are T-cell surface receptors that, when engaged, turn off immune function at different stages of the immunity cycle (Figure 1). Their inhibition thereby allows for ongoing T-cell activation and enhances anti-tumour immunity.

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Figure 1:

A) Antigen presenting cells (APC), such as dendritic cells (DC), scout the human body, sampling different antigens, including tumour-associated antigens, which are then processed and presented through the major histocompatibility (MHC) complex. In a priming phase that takes place in peripheral lymph nodes, APC educate and activate antigen-specific T cells. T cell activation is kept in check by cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), a negative regulator of T-cell function. This negative signal can be blocked by CTLA-4 inhibitors (i.e., ipilimumab), allowing ongoing T-cell activation and migration to the tumour bed. B) Activated T cells also express programmed cell death 1 (PD1), and its ligands, PDL1 and PDL2, are commonly expressed on APC. PD1 and PDL1/PDL2 interaction also inhibits T-cell responses. Tumours can express PDL1 and PDL2 receptors, and engagement of these receptors with the PD1 receptor on T cells turns off T cells and allows tumours to escape destruction. These immune checkpoints can be blocked by PD-1 inhibitors (i.e., nivolumab, pembrolizumab) or PDL-1 inhibitors (i.e., atezolizumab, avelumab and durvalumab). CTLA-4 inhibition results in more widespread and severe immune-related adverse events (irAE), as it regulates T-cell function early in the immunity cycle. Blocking PD-1, on the other hand, is more specific to the tumour microenvironment and, in general, results in less widespread and severe irAE. Note: CD28 = cluster of differentiation 28, TCR = T-cell receptor.

Health Canada’s clinical indications for the use of immune checkpoint inhibitors are summarized in Table 1. Because more than a thousand clinical trials are underway assessing different immune checkpoint inhibitors alone or in combination with other standard cancer therapies such as chemotherapy, surgery and radiotherapy, the number of approved indications and patients exposed to these treatments is expected to rise substantially in coming years.

Why do immune-related adverse events occur?

If immune tolerance is defined as a state of unresponsiveness of the immune system toward antigens or tissues able to elicit an immune response, immune-related adverse events represent the other end of the spectrum, where an activated immune system reacts against both tumour antigens and antigens on healthy tissues. This process is tightly regulated by a complex network of cell surface receptors and signalling pathways. By blocking the inhibitory signals, immune checkpoint inhibitors can sway immune responses away from tolerance and in favour of an activated state.5 Although this is useful for targeting cancer, an immune episode targeted to healthy tissue is also possible. As such, both cytotoxic T-lymphocyte–associated protein 4 and programmed cell death 1 inhibitors have been associated with inflammatory or autoimmune reactions of the human body’s organs (Figure 2). The rates of various immune-related adverse events may differ depending on the particular drug, but the full spectrum of these adverse events can occur with all drugs (Table 2).7

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Figure 2:

Organs affected by and manifestations of immune-related adverse events.

Similarly, although some temporal patterns have emerged for each specific immune-related adverse event, it is important to highlight that any such adverse event can occur at any time during treatment. Some cases of autoimmune disease have been attributed to immune checkpoint inhibitors months after cessation of treatment.8 Clinicians must be on the lookout for any new symptoms reported by patients who have been exposed to immune checkpoint inhibitors. Early recognition is key, as immune-related adverse events are usually reversible, even when severe in presentation.

How are immune-related adverse events diagnosed and managed?

We previously reported the case of a patient who developed cerebritis, which rapidly evolved to a profound comatose state after delays in consultation with the treating oncology team and administration of corticosteroids.9 This example highlights a critical step in the management of immune-related adverse events, which is early recognition and prompt administration of treatment. Patients may present to their primary care physician or to the emergency department outside their routine oncological visits. As such, frontline health care workers may be involved in the initial assessment and management of immune-related adverse events and are encouraged to rapidly consult with the treating oncologists.

Both the American Society of Clinical Oncology and the European Society of Medical Oncology have released comprehensive clinical guidelines on the diagnosis and management of immune-related adverse events.10^,11 In summary, adverse events are graded according to the Common Terminology Criteria for Adverse Events (Table 3).12

Principles of treatment are outlined in Figure 3, which is adapted from the latest American Society of Clinical Oncology guideline.10 Close observation and symptomatic management without interruption of immune checkpoint inhibitors are recommended for grade 1 reactions.

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Figure 3:

Summarized management strategies for immune-related adverse events (irAE), adapted from the latest American Society of Clinical Oncology (ASCO) guideline.10 The only exception to this algorithm is the management of endocrine irAE, where physiologic hormone replacement, rather than high-dose steroid use, is recommended for any grade irAE. *High-dose steroids, defined as 1 mg/kg, or oral prednisone or 2 mg/kg of intravenous solumedrol. Note: CTCAE = Common Terminology Criteria for Adverse Events, ESMO = European Society for Medical Oncology, ICI = immune checkpoint inhibitors.

Oral corticosteroids (0.5–1 mg/kg) are recommended for grade 2 reactions, while treatment with immune checkpoint inhibitors is held. Once a grade 2 reaction has subsided to grade 1 or resolved and steroids have been tapered and stopped, immune checkpoint inhibitors can be resumed at the same dose and schedule.

Grade 3 or higher reactions are managed with high-dose oral or intravenous corticosteroids (prednisone 1 mg/kg or methylprednisolone 2 mg/kg). Intravenous therapy is the preferred route for severe grade ≥ 3 reaction owing to faster onset of action. Patients should be monitored daily until resolution of symptoms, either in hospital or by outpatient visits. Escalation of immunosuppressive treatment is recommended for grade 3 or higher reactions that fail to improve within 48 to 72 hours of high-dose corticosteroid therapy. Tumour necrosis factor inhibitors such as infliximab are preferred as a second-line immunosuppressant. Other drugs that inhibit T cells, including mycophenolate mofetil, have also been used with success.10 In most cases, grade 3 or higher reactions are considered grounds for permanent discontinuation of immune checkpoint inhibitors. Corticosteroids should be tapered slowly, in most cases no faster than over 4 weeks, as flare-ups are common if immunosuppression is tapered too quickly. As with any immunosuppressive treatment, appropriate prophylaxis against opportunistic infections and monitoring patients for other corticosteroid adverse effects are important.

Endocrine immune-related adverse events (i.e., hypothyroidism, adrenal insufficiency, hypogonadism and hypophysitis) are the only adverse events that do not require permanent discontinuation of immune checkpoint inhibitors, regardless of the severity of the reaction, as long as patients achieve a stable clinical status on physiologic hormonal replacement therapy.10

One of the most important reasons for complications and morbidity from immune-related adverse events is delay in the prompt administration of corticosteroids. Because immune-related adverse events (e.g., colitis, pneumonitis, encephalitis) are sometimes difficult to distinguish from infectious complications of the same organs (e.g., infectious colitis, pneumonia, meningitis), steroids are often delayed while invasive procedures (e.g., colonoscopy, bronchoscopy, lumbar puncture) are planned and microbiology results are awaited. However, for patients with severe grade ≥ 3 reactions, prompt high-dose intravenous corticosteroid therapy should not be delayed in favour of other investigations. Invasive diagnostic tests and confirmatory biopsies are often challenging to obtain and can lead to complications or delays in treatment. For instance, diagnostic colonoscopies in the setting of colitis from immune checkpoint inhibitors could induce bowel perforation, and should not be routinely performed.13

Conclusion

Immune checkpoint inhibitors have rapidly established themselves as a new pillar in cancer therapy alongside chemotherapy, radiotherapy and surgery. Some patients previously deemed incurable are now achieving long-term remissions with these novel therapeutics, but at the expense of frequent and sometimes fatal immunerelated adverse events. These adverse events can be challenging to both diagnose and manage. A high clinical suspicion and multidisciplinary approach are often necessary to optimize clinical outcomes. Deciphering the mechanisms driving the immune-related adverse events is a great opportunity for novel research and will likely shed new insights on the interplay between autoimmunity and oncogenesis. As more advances are made in the field and experience with immune checkpoint inhibitors increases, front-line health care workers will be increasingly involved in managing patients who are being treated with these agents.