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.
Highlights
Since FDA approval of the first ICI, ipilimumab, in 2011, a growing portfolio of monoclonal antibodies targeting the Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1/PD-L1 pathways has emerged, which purport therapeutic advantage over a broad spectrum of cancers (Table 1)
The precise pathophysiologic mechanism of lung injury associated with ICIs remains under rigorous investigation, it is thought that these therapies act as a double-edged sword in which release of regulatory controls is responsible for both the therapeutic efficacy of ICI therapy and the driver of immune-related adverse events (irAEs)
Since the first ICI was FDA-approved in the United States, it has become apparent that the 2–5% incidence of ICI-related lung injury reported in early clinical trials grossly underestimates the real-world experience of 12–19%
Summary
Since FDA approval of the first ICI, ipilimumab, in 2011, a growing portfolio of monoclonal antibodies targeting the CTLA-4 and PD-1/PD-L1 pathways has emerged, which purport therapeutic advantage over a broad spectrum of cancers (Table 1). With the expansion of ICI-targeted therapies and the development of complex combination and multimodal therapies, there has been increasing recognition of a unique spectrum of associated end-organ toxicities, referred to as immune-related adverse events (irAEs). The precise pathophysiologic mechanism of lung injury associated with ICIs remains under rigorous investigation, it is thought that these therapies act as a double-edged sword in which release of regulatory controls is responsible for both the therapeutic efficacy of ICI therapy and the driver of irAEs. The incidence of severe or life-threatening irAEs (grade ≥ 3) ranges from 20 to 30% for patients receiving anti-CTLA-4 and 10–15% for patients treated with anti-PD-1/anti-PD-L1 agents.
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