Pulmonary Toxicities Associated With the Use of Immune Checkpoint Inhibitors: An Update From the Immuno-Oncology Subgroup of the Neutropenia, Infection & Myelosuppression Study Group of the Multinational Association for Supportive Care in Cancer

Abstract

The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, with agents such as nivolumab, pembrolizumab, and cemiplimab targeting programmed cell death protein-1 (PD-1) and durvalumab, avelumab, and atezolizumab targeting PD-ligand 1 (PD-L1). Ipilimumab targets cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). These inhibitors have shown remarkable efficacy in melanoma, lung cancer, urothelial cancer, and a variety of solid tumors, either as single agents or in combination with other anticancer modalities. Additional indications are continuing to evolve. Checkpoint inhibitors are associated with less toxicity when compared to chemotherapy. These agents enhance the antitumor immune response and produce side- effects known as immune-related adverse events (irAEs). Although the incidence of immune checkpoint inhibitor pneumonitis (ICI-Pneumonitis) is relatively low, this complication is likely to cause the delay or cessation of immunotherapy and, in severe cases, may be associated with treatment-related mortality. The primary mechanism of ICI-Pneumonitis remains unclear, but it is believed to be associated with the immune dysregulation caused by ICIs. The development of irAEs may be related to increased T cell activity against cross-antigens expressed in tumor and normal tissues. Treatment with ICIs is associated with an increased number of activated alveolar T cells and reduced activity of the anti-inflammatory Treg phenotype, leading to dysregulation of T cell activity. This review discusses the pathogenesis of alveolar pneumonitis and the incidence, diagnosis, and clinical management of pulmonary toxicity, as well as the pulmonary complications of ICIs, either as monotherapy or in combination with other anticancer modalities, such as thoracic radiotherapy.

Keywords: anti-CTLA-4 antibodies; anti-PDL-1 monoclonal antibodies; immune checkpoint inhibitors; immune related adverse effects; pneumonitis.

FIGURE 1

Exacerbation of preexisting interstitial lung disease. A 68 year-old man with a history of mild idiopathic pulmonary fibrosis and prostate cancer. Severe dyspnea and cough developed 19 days following cycle 1 of ipilimumab plus hormonal therapy, given per protocol. Chest CT at baseline (A,C) demonstrates subpleural ground glass and reticular opacities consistent IPF. CT imaging at presentation (B,D) shows interval development of poorly marginated scattered consolidative and ground glass opacities consistent with pneumonitis. In addition, there is bilateral diffuse thickening of the interlobular septa associated with architectural distortion suggesting progression of underlying fibrosis. Findings suggest that even mild preexisting lung disease may potentiate severe pneumonitis and worsening fibrotic disease following ICI therapy.

FIGURE 2

Recrudescence of pneumonitis with drug rechallenge. A 47-year-old man presented with dry cough and dyspnea 11 weeks after initiation of Nivolumab for treatment of non-Hodgkin lymphoma. CT scan showed patchy bilateral ground glass changes (A,D). Bronchoscopy with biopsy confirmed organizing pneumonia associated with grade II pneumonitis and the patient was started on high dose steroids. Clinical and radiographic improvement was seen 6 weeks later after tapering off steroids (B,E). Nivolumab was resumed. Three weeks later, the patient returned with increased respiratory symptoms and hypoxia. CT imaging demonstrated bilateral infiltrates which were worse than initial presentation (C,F).

FIGURE 3

ICI-related sarcoid-like reaction. Diffuse lymphadenopathy in paratracheal, bi-hilar, and mediastinal locations (arrows), (A,C), developed after the third cycle of ipilimumab plus nivolumab therapy for bladder cancer. Diffuse interstitial and nodular infiltrates along bronchovascular bundles (arrows), (B,D) were also seen. Transbronchial biopsies and biopsies of the lymph nodes by endobronchial ultrasound (EBUS) demonstrated noncaseating granulomas. The diagnosis of ICI induced sarcoid-like reaction was confirmed once competing diagnoses were excluded.

FIGURE 4

ICI-related radiation recall. A 56-year-old man with metastatic adenocarcinoma of the lung presented with severe shortness of breath and dry cough 3.5 weeks after the first cycle of pembrolizumab for metastatic adenocarcinoma. Radiation therapy to the right chest was completed 13 months prior. Stable subpleural reticular opacities associated with traction bronchiectasis are seen on the baseline CT and consistent with sequelae of prior radiotherapy (A,C). Admitting CT scan demonstrated new ground glass opacities in the right upper and lower lobes (B,D) that conform with the prior radiation portal (E). Centrilobular emphysema is again seen. Findings suggest radiation recall precipitated by pembrolizumab therapy.