CLINICAL SCENARIO

A 64-year-old male with lung cancer presents to the emergency department with one week of cough and increasing shortness of breath. At triage, his temperature is 37.3° Celsius, heart rate 106 beats per minute, blood pressure 136/80, and oxygen saturation 87% on room air, which improves to 94% with 3 L of oxygen via nasal prongs. He has a chest X-ray that demonstrates bilateral patchy infiltrates. He is treated for pneumonia with antibiotics. His respiratory status worsens, with an increasing oxygen requirement. Additional history reveals that the patient recently finished treatment for lung cancer with an immune checkpoint inhibitor.

KEY CLINICAL QUESTIONS

1.

What is cancer immunotherapy?

Novel cancer immunotherapies are increasingly being used in the management of many malignancies. Immunotherapy modifies the immune response, allowing the immune system to recognize and destroy cancer cells.^{Reference Pallin, Baugh and Postow1,Reference Papaioannou, Beniata, Vitsos, Tsitsilonis and Samara2} Immunotherapy can be passive or active. Examples of passive immunotherapies include tumor-specific monoclonal antibodies (i.e., trastuzumab), cytokines (i.e., interferon-alpha, interleukins), and adoptive cell transfer (i.e., chimeric antigen receptor [CAR] T-cell therapy).^{Reference Papaioannou, Beniata, Vitsos, Tsitsilonis and Samara2} Active immunotherapies include vaccines, viruses, and immune checkpoint inhibitors.^{Reference Papaioannou, Beniata, Vitsos, Tsitsilonis and Samara2}

The immune system has multiple “checkpoints” that modulate the immune response. These checkpoints involve proteins on the surfaces of either the T-cell (CTLA-4 and PD-1) or the antigen presenting cell, such as a cancer cell (PD-L1) that, when engaged, can lead to T-cell inhibition.^{Reference Pallin, Baugh and Postow1} Immune checkpoint inhibitors target these proteins leading to increased T-cell activity, allowing the immune system to destroy cancer cells.^{Reference Michot, Bigenwald and Champait3} Immune checkpoint inhibitor classes include CTLA-4 inhibitors (ipilimumab), PD-1 inhibitors (nivolumab, pembrolizumab), and PD-L1 inhibitors (atezolizumab, avelumab, durvalumab). These drugs have shown benefit in treating various malignancies, such as melanoma, renal cell carcinoma, lung cancer, and some hematological malignancies.^{Reference Michot, Bigenwald and Champait3} While the majority of immune checkpoint inhibitors are used for advanced and/or metastatic cancers, use of these treatments in the earlier stage of disease is an active area of research. In the United States in 2018, it was estimated that over 40% of cancer patients were eligible for checkpoint inhibitor immunotherapy.^{Reference Haslam and Prasad4} Given the increasing use of immune checkpoint inhibitors, this article will focus on these therapies.

2.

What types of adverse events occur with immune checkpoint inhibitor treatment?

Blocking immune checkpoints with immune checkpoint inhibitors promotes anti-tumor immunity; however, this can overstimulate the immune system against the host, leading to adverse events related to autoimmune toxicity. These adverse events are known as immune-related adverse events. Immune-related adverse events are common in patients treated with an immune checkpoint inhibitor, with reports of up to 50% of patients on nivolumab experiencing an adverse event.^{Reference Pallin, Baugh and Postow1,Reference Michot, Bigenwald and Champait3} Mild-to-moderate adverse events are more common than severe events; however, some adverse events can be potentially life-threatening (< 1% of cases).^{Reference Pallin, Baugh and Postow1} The use of a combination of immune checkpoint inhibitors is associated with higher rates of significant toxicity.^{Reference Pallin, Baugh and Postow1}

Immune-related adverse events can affect any organ system or multiple systems simultaneously. The most common immune-related adverse events involve the skin and gastrointestinal tract.^{Reference Pallin, Baugh and Postow1,Reference Michot, Bigenwald and Champait3} See Table 1 for some organ-based adverse events reported with immune checkpoint inhibitor use.^{Reference Pallin, Baugh and Postow1,Reference Michot, Bigenwald and Champait3,5}

Table 1. Organ-based immune-related adverse events associated with immune checkpoint inhibitor treatment^{Reference Pallin, Baugh and Postow1,Reference Michot, Bigenwald and Champait3,5}

Note: *May present as headache and fatigue and can lead to insufficiency of any pituitary hormones.

3.

When do immune-related adverse events occur in patients who have been treated with immune checkpoint inhibitors?

The majority of immune-related adverse events occur within 3 to 6 months of starting treatment with immune checkpoint inhibitors. However, some immune-related adverse events can occur as early as weeks following initiation of treatment, which is more commonly seen with dual agents.^{Reference Nishino, Giobbie-Hurder, Hatabu, Ramaiya and Hodi6} Some immune-related adverse events have been reported to occur up to one year after starting treatment and even months after treatment has been discontinued.^{Reference Michot, Bigenwald and Champait3} Therefore, it is important to obtain a thorough patient history, including details of previous treatments received.

4.

How are immune-related adverse events associated with immune checkpoint inhibitor treatment managed?

Immune-related adverse events associated with immune checkpoint inhibitor treatment are typically managed according to the organ system affected and the Common Terminology Criteria for Adverse Events (CTCAE) severity grade.^{Reference Michot, Bigenwald and Champait3,5} Cancer Care Ontario has an approach to grading and management of organ-specific adverse events associated with these treatments, which is available for reference at https://www.cancercareontario.ca/en/guidelines-advice/modality/immunotherapy/immune-therapy-toolkit.

It is essential to consider and rule out alternative causes of the clinical syndrome that may be presenting. For instance, in a patient with possible pneumonitis, pulmonary infection (including atypical infections) should be considered. Following this, if an immune-related adverse event is felt to be the most likely cause of the clinical presentation, corticosteroids are generally used as first-line treatment for most moderate-to-severe immune checkpoint inhibitor-associated, immune-related adverse events.^{Reference Pallin, Baugh and Postow1,Reference Michot, Bigenwald and Champait3,5} However, there should be a close collaboration with oncology colleagues regarding the decision to initiate steroids, the dose, and duration of steroids and steroid tapering. Some mild adverse events may only require observation as an outpatient. Some dermatological adverse events may be treated with topical corticosteroids. Other adverse events will require oral steroids (doses can range between 0.5 to 2 mg/kg of prednisone) or intravenous steroids (doses may range between 1 to 2 mg/kg of methylprednisone).^{Reference Pallin, Baugh and Postow1,5} In patients where there is a high suspicion of severe Grade 3 to 4 immune-related adverse events, or who are unstable, high dose corticosteroids should be considered early and possibly concurrently with empiric coverage for alternative diagnoses with early referral to the appropriate specialists.^{Reference Michot, Bigenwald and Champait3}

Patients with immune-related adverse events that are steroid-refractory may require other immunosuppressants, such as tumor necrosis factor (TNF) alpha inhibitors, azathioprine, or mycophenolate mofetil.^{Reference Michot, Bigenwald and Champait3}

5.

What are the treatment implications for a patient who has an immune-related adverse event to immune checkpoint inhibitor therapy?

It is unclear whether steroids for the management of immune-related adverse events impact the anti-tumor activity of immune checkpoint inhibitors in the long term.^{Reference Michot, Bigenwald and Champait3} The majority of immune-related adverse events associated with these treatments are thought to be reversible with early steroids at the appropriate dose.^{Reference Michot, Bigenwald and Champait3} However, some adverse events may be permanent. In patients where there is concern of an immune checkpoint inhibitor-associated adverse event, it is important to consult oncology colleagues. Ideally, there should be discussion with the patient's own oncologist because the patient may be required to temporarily suspend immunotherapy and, in cases of severe immune-related adverse events, may be required to discontinue the treatment permanently. In severe immune-related adverse events, the appropriate organ specialist should be involved early on, along with critical care colleagues. If patients develop a severe immune-related adverse event, they will likely not be candidates for ongoing treatment with that particular immune checkpoint inhibitor.

CASE RESOLUTION

A CT scan of the chest shows bilateral patchy nodular infiltrates and no pulmonary embolism. Given the history of immune checkpoint inhibitor treatment, pneumonitis (an immune-related adverse event) is considered. After discussion with oncology and ICU colleagues, intravenous methylprednisone at a dose of 1 mg/kg is started and the patient is admitted to the hospital.

GLOSSARY OF TERMS

CT: computed tomography

CTLA-4: cytotoxic T-lymphocyte-associated protein 4

ICU: intensive care unit

PD-1: programmed cell death protein 1

PD-L1: programmed death ligand 1