Immuno-Oncology 101 for Emergency Physicians Immune Checkpoint Inhibition in the Treatment of Cancer
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PRACTICE AID
APC: antigen-presenting cell; CD: cluster of differentiation; CTLA-4: cytotoxic T-lymphocyte–associated antigen 4; MHC: major histocompatibility complex; PD-1: programmed cell death protein 1; PD-L1: programmed death ligand 1; TCR: T-cell receptor.
Tumor Microenvironment
Lymphoid Tissue
PD-1 pathway inhibits signaling downstream of TCR
• TCR triggered by antigen presented by tumor cell
• Negative regulatory receptor PD-1 expressed and PD-L1 reactively expressed
• PD-L1 binds to PD-1
block the interaction and negative regulation
Anti–CTLA-4 monoclonal antibodies block negative
regulation by CTLA-4
CTLA-4 is a negative regulator of costimulation required for
activation of an antitumor T cell in a lymph node upon recognition of
tumor antigen
STOP
STOP
GO
GO
GO
Anti–CTLA-4: Ipilimumab
Anti–PD-L1: Atezolizumab Avelumab Durvalumab
• Proteins on T cells or cancer cells that need to be activated/inactivated to start/stop an immune response (eg, PD-1, PD-L1, CTLA-4)
• Serve as “brakes” that help keep immune responses in check; can prevent T-cell response against cancer cells
• Can be blocked by immune checkpoint inhibitors (the “brakes” on the immune system are released and T cells are able to attack and kill cancer cells)
What Are Immune
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PRACTICE AID
What Are irAEs?
• Immune checkpoint inhibitors are associated with important clinical benefits, but general immunologic enhancement can also lead to a unique spectrum of immune-related adverse events (irAEs)
• Pathophysiology of irAEs is not entirely clear, but T-cell, antibody, and cytokine responses may be involved
• irAEs differ significantly from toxicities of chemotherapies and other cancer therapies
• Any organ system can be affected, but more commonly occurring irAEs are pulmonary (pneumonitis), dermatologic (rash, pruritus, blisters, ulcers, vitiligo), gastrointestinal (diarrhea, enterocolitis, transaminitis, hepatitis, pancreatitis), and endocrine (thyroiditis, hypophysitis, adrenal insufficiency) irAEs
• irAEs can have unpredictable onset and can present at any time, but typically start within the first few weeks to months after treatment initiation and can occur after treatment discontinuation
• irAEs can be difficult to differentiate from other etiologies and are often diagnosed by exclusion; other causes should be ruled out, but immunotherapy-related toxicity should always be included in the differential for patients who are receiving or have received immunotherapies
Musculoskeletal
Gastrointestinal
Renal
Hematologic
Neurologic
Pulmonary
Cardiovascular
Ocular
Dermatologic
Endocrine
Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and vasculitis, and venous thromboembolism
Pneumonitis
Inflammatory arthritis, myositis, and polymyalgia-like syndrome
Uveitis/iritis, episcleritis, and blepharitis
and diabetes
cutaneous adverse reactions
and acquired hemophilia
Access the activity, “Best Practices for Recognizing & Managing Immune-Related Adverse Events in the Emergency Department: Become Aware, Stay Alert, Change Your Practice, & Keep Patients With Cancer Safe” at PeerView.com/RQF40.
PRACTICE AID
Change How You Approach the Evaluation, Diagnosis, and Management of Patients With Cancer in the Emergency Department!
Ask about history of cancer treatment, including immunotherapy, from any patient with cancer presenting to an ED in an acutely unwell state
Call the oncology care provider for any moderate or severe (grade 2 or higher) toxicity upon presentation to discuss treatment history, if toxicity could be caused by immunotherapy, and next steps
Patients receiving immunotherapies are often given wallet cards listing their therapies à ask about that
Simplify treatment decisions à consider corticosteroids for frontline management of immune-related toxicities in most cases
Coordinate with the oncology care provider and other specialists, if possible
Modify your differential diagnosis when a patient has received cancer immunotherapy à almost any inflammatory condition could be caused by immune checkpoint inhibitor therapy
Avoid premature closure
A multidisciplinary approach can boost the collective awareness of irAEs and help keep patients safe!
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Access the activity, “Best Practices for Recognizing & Managing Immune-Related Adverse Events in the Emergency Department: Become Aware, Stay Alert, Change Your Practice, & Keep Patients With Cancer Safe” at PeerView.com/RQF40.
PRACTICE AID
irAEs are often diagnosed by exclusion;
other causes should be ruled out (including
AEs of other therapies used), but
immunotherapy-related toxicity should always be included in the differential
There should be a high level of suspicion that
new symptoms are treatment related; early recognition, evaluation, and treatment of irAEs plus patient education are essential for the
best outcome
management may require
of therapy
recover from irAEs
Grade 2
Mild-to-moderate symptoms; grade 2 diagnostic abnormalities • Hold treatment; provide supportive care • Methylprednisolone 0.5-1.0 mg/kg/d until stable (or oral equivalent)
If improving: transition to oral steroid at start of taper • Dose suggested: 60 mg prednisone daily x 2 wk • Taper over 4 wk or more to reduce recurrence of symptoms • May consider reinitiation of immunotherapy
If progressing: treat as grade 3/4 • Consider hospitalization of patient; multidisciplinary evaluation
of toxicity
Refractory
If no improvement or progression, additional immunosuppressant treatment may be needed • Infliximab 5 mg/kg (except if contraindicated) • Mycophenolate mofetil 1 g twice daily • Cyclosporine or IV immunoglobulin
Grade Assessment and Management
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PRACTICE AID
Pneumonitis
increased oxygen requirement, hypoxia,
and tachycardia
O2 saturation levels, CT of chest; rule out progression of disease, lymphangitic spread,
pulmonary embolism, and pleural effusion
O2 support, bronchoscopy ± BAL, steroids, and
antibiotic prophylaxis
loose stools, and altered frequency of stools
Rule out infectious causes; stool cultures; rule out
perforation; abdominal CT and lactoferrin and calprotectin levels
If steroid refractory: infliximab; antispasmodic,
antidiarrheal, and fluid support
Rule out other causes; total body exam (include mucous
membranes); measure distribution and skin biopsy
Topical moderate-to-high– dose steroids; IV steroids; consult dermatology and
infectious disease; if mucosa, consult gynecology, ophthalmology, and urology;
admission: burn unit
Endocrine— adrenal insufficiency
More common with anti–PD-1; monitor ACTH and cortisol
Corticosteroids (must start prior to any other hormone replacement) and stress
dosing in trauma
Headache, fatigue, and visual changes
CMP, glucose, cortisol, ACTH, pituitary panel (TSH, FSH, LH, ACTH, and prolactin); testosterone/estradiol; and
MRI of brain with sellar cuts
Hormone replacement
beta-blockers
Endocrine— hypothyroidism
Severe fatigue, sluggishness, anorexia, and weight gain Monitor TSH and T4 Levothyroxine;
usually permanent
consciousness Blood glucose Insulin
Access the activity, “Best Practices for Recognizing & Managing Immune-Related Adverse Events in the Emergency Department: Become Aware, Stay Alert, Change Your Practice, & Keep Patients With Cancer Safe” at PeerView.com/RQF40.
PRACTICE AID
Organ-Specific Summary of Presentation, Assessment, and Management of irAEs1 (Cont’d)
Note: This irAE list is not all inclusive
Hepatic
bleeding, bruising, dark skin, and drowsiness
Liver enzymes (AST, ALT, ALK, total and direct bilirubin),
liver ultrasound, GI consult, and rule out viral syndrome
Hold hepatotoxic drugs; mycophenolate 2 mg/kg/d; if refractory: no infliximab
Renal/nephritis
blood in urine, and ankle swelling
Serum creatinine and urinalysis; nephrology consult, renal ultrasound, and biopsy
Limit nephrotoxic drugs, antibiotics, NSAIDs, and
contrast dye; identify high-risk patients (CRF);
and hydration
VTE, fluid retention, pericarditis, myocarditis, effusion, and vasculitis
ECG, echocardiogram, CXR, and cardiology consult
Blood pressure support and heart rate regulation
Neurologic
neuropathy, altered gait, memory difficulties,
seizures, aseptic meningitis, myasthenia gravis,
Guillain-Barré, encephalitis, and transverse myelitis
Neurology consult, MRI of brain to rule out CVA and brain
metastases; MRI spine; LP; rule out infection
Permanent discontinuation; rehab services;
inflammation; pain; iritis; uveitis; blepharitis;
episcleritis; and conjunctivitis
Lubricating eye drops; topical corticosteroid eye
drops; decrease local irritants: contact lens,
eye makeup, etc.
Musculoskeletal Inflammatory arthritis,
RF, anti-CCP, ESR, CK, and CRP); imaging and EMG
NSAIDs, corticosteroid joint injections, DMARDs, methotrexate, and PT/OT
System Signs & Symptoms Assessment Management