The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis

Suresh, Karthik; Naidoo, Jarushka; Zhong, Qian; Xiong, Ye; Mammen, Jennifer S.; Flores, Marcia Villegas De; Cappelli, Laura C.; Balaji, Aanika; Palmer, Tsvi; Forde, Patrick M.; Anagnostou, Valsamo; Ettinger, David S.; Marrone, Kristen A.; Kelly, Ronan J.; Hann, Christine L.; Levy, Benjamin; Feliciano, Josephine; Lin, Cheng Ting; Feller‐Kopman, David; Lerner, Andrew D.; Lee, Hans C.; Shafiq, Mājid; Yarmus, Lonny; Lipson, Evan J.; Soloski, Mark J.; Brahmer, Julie R.; Danoff, Sonye K.; D’Alessio, Franco R.

doi:10.1172/jci128654

Cited by 107 publications

(98 citation statements)

References 43 publications

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“…While the BALF cell characteristics of ICI pneumonitis at initial presentation have been described by us previously, 12 changes in the composition of the BALF cell differential in individual patients with repeated ICI pneumonitis episodes are unknown. In this cohort, all six patients underwent BALF and cell differential assessment at the time of initial ICI pneumonitis development and at re-emergence during steroid taper.…”

Section: Bronchoalveolar Lavage Findingsmentioning

confidence: 86%

“…This extends our earlier observations of increased T-cell subsets in the BALF of patients during the first episode of ICI pneumonitis, prior to initiation of steroids. 12 Clinically, the presence of BALF lymphocytes, ongoing steroid requirement, and steroid dose (10-20 mg of prednisone/equivalent) at which ICI pneumonitis re-emerges is similar to the natural history of refractory cryptogenic organizing pneumonia (COP). Indeed, the overall duration and rate of steroid tapering presented in this study is similar to prior reports of rates of steroid weaning in COP.…”

Section: Pathological Findingsmentioning

confidence: 98%

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Chronic immune checkpoint inhibitor pneumonitis

Naidoo¹,

Cottrell

Lipson³

et al. 2020

J Immunother Cancer

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BackgroundPneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4–6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ≥12 weeks of immunosuppression.MethodsPatients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ≥12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available.ResultsAmong 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0–50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3–12 weeks), with all patients requiring steroid reintroduction when tapered to ≤10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16–43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper.ConclusionsA subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ≥12 weeks, and has distinct clinicopathological features.

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Section: Bronchoalveolar Lavage Findingsmentioning

confidence: 86%

Section: Pathological Findingsmentioning

confidence: 98%

Chronic immune checkpoint inhibitor pneumonitis

Naidoo¹,

Cottrell

Lipson³

et al. 2020

J Immunother Cancer

Self Cite

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show abstract

“…Several studies have demonstrated increased lymphocyte proportion on BAL of patients with ICI pneumonitis. 48,65 Naidoo et al 52 examined the transbronchial biopsies of 11 patients with checkpoint inhibitor pneumonitis and reported the following histopathological findings: cellular interstitial pneumonitis in four patients, OP in three, diffuse alveolar damage in one patient and no abnormalities identified in the other three patients.…”

Section: Radiographic and Histologic Featuresmentioning

confidence: 99%

Pulmonary toxicity of systemic lung cancer therapy

Long

Suresh

2020

Respirology

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Lung cancer is the leading cause of cancer-related deaths worldwide. As new therapies are developed, it is important to understand the pulmonary toxicities associated with systemic lung cancer therapies. Cytotoxic chemotherapy regimens for NSCLC often include taxanes. Pulmonary toxicity from taxanes presents as an ILD-type reaction characterized by increasing dyspnoea, dry cough, fever and bilateral pulmonary interstitial infiltrates. The incidence of taxane-induced pneumonitis is rare, and many patients respond to steroid therapy; however, fatal cases have been reported. Patients with NSCLC are routinely tested for the presence of tumour oncogenes to determine their candidacy for targeted therapies, such as TKI. EGFR-TKI can cause pneumonitis characterized by progressive dyspnoea and hypoxia. EGFR-TKIassociated ILD rarely presents as an AIP with rapidly progressive respiratory failure and high mortality rates. The most recent development in lung cancer therapy has been the discovery of immune checkpoint inhibitor (ICI). ICI pneumonitis has been increasingly recognized as a common complication of ICI therapy, with reported incidence as high as 19% in some clinical settings. Early-grade ICI pneumonitis may be asymptomatic; however, high-grade ICI pneumonitis can result in progressive dyspnoea, hypoxia and respiratory failure. ICI pneumonitis is unique in that only half of the patients will improve with steroid treatment, and mortality rates are high. As treatment of NSCLC evolves, providers must be able to recognize and respond to the development of drug-induced pulmonary toxicities.

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“…and decreased expression in BAL Tregs. 40 Collectively, the data underline the essential and major role of T cells in the ICI-related toxicity.…”

Section: Re-challengementioning

confidence: 96%

Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy

Haanen

Ernstoff

Wang

et al. 2020

J Immunother Cancer

104

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Patients with cancer who developed severe, grade 3 or 4 immune-related adverse events (irAEs) during therapy with immune checkpoint inhibitors are at risk for developing severe toxicities again on rechallenge with checkpoint inhibitors. Consequently, medical oncologists and multidisciplinary teams are hesitant to retreat in this scenario, despite the fact that a number of patients may derive clinical benefit from this approach. Balancing such clinical benefit and treatment-related toxicities for each patient is becoming increasingly challenging as more and more patients with cancer are being treated with checkpoint inhibitors. In this manuscript, we provide an extensive overview of the relevant literature on retreatment after toxicity, and suggest prophylactic approaches to minimize the risk of severe irAE following rechallenge with immune checkpoint blockade, since treatment may be lifesaving in a number of occasions.

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The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis

Cited by 107 publications

References 43 publications

Chronic immune checkpoint inhibitor pneumonitis

Chronic immune checkpoint inhibitor pneumonitis

Pulmonary toxicity of systemic lung cancer therapy

Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy

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