Abstract
BackgroundThe synergistic effect of radiotherapy (RT) in combination with immunotherapy has been shown in several clinical trials and case reports. The overlapping pulmonary toxicity induced by thoracic RT and programmed death 1/programmed death ligand-1 (PD-1/PD-L1) blockades is an important issue of clinical investigation in combination treatment. Thus far, the underlying mechanism of this toxicity remains largely unknown.Main textIn this review, we discuss the unique pattern of radiation recall pneumonitis (RRP) induced by PD-1 blockade. The clinical presentation is different from common radiation pneumonitis (RP) or RRP induced by cytotoxic drugs. The immune checkpoint inhibitors may evoke an inflammatory reaction in patients’ previously irradiated fields, with infiltrating lymphocytes and potential involvement of related cytokines. All RRP patients have showed durable response to anti-PD-1/PD-L1. RRP is manageable; however, interruption of checkpoint blockades is necessary and immunosuppressive treatment should be started immediately. Further analyses of the predictive factors, including RT dosimetric parameters, tumor-infiltrating lymphocytes (TILs), and PD-L1 expression, are needed given the wide use of immune checkpoint inhibitors and high mortality from lung toxicity with the combination treatment.ConclusionImmune checkpoint inhibitors may evoke an RRP in the patients’ previously irradiated fields. Interactions between immune checkpoint inhibitors and radiotherapy should be studied further.
Highlights
In this review, we discuss the unique pattern of radiation recall pneumonitis (RRP) induced by Programmed death 1 (PD-1) blockade
Several PD-1/programmed death ligand-1 (PD-L1) blockades have been approved by the Food and Drug Administration (FDA) and the European Agency of Medicine (EAM) in the treatment of nonsmall cell lung cancer (NSCLC) [1–7]
Since the potential pulmonary toxicity induced by thoracic RT and PD-1/Programmed death ligand-1 (PDL1) blockades could overlap, pneumonitis is an important point of clinical investigation in combination treatment
Summary
Clinical and patients characteristics Based on the previous trials and meta-analysis, all-grade and grade 3–4 pneumonitis occurred in 3–5% and 1%, respectively, of patients with NSCLC who received PD1/PD-L1 blockades [10, 16, 17]. A study of 148 lung cancer patients who received definitive chemoradiation was reviewed to identify factors that may predict severe radiation pneumonitis (RP) [30]. IL-4 and IL-13 were shown to facilitate fibrosis by promoting TGF-β [63] This finding may explain the associations between RRP and response to anti-PD-1/PD-L1 in our case and previous reports. Immunologic factors Understanding the molecular and cellular processes of RRP helps in finding biomarkers that predict the risk for developing radiation pneumonitis during checkpoint immunotherapy. In addition to steroids and corticosteroids as the mainstay of treatment, angiotensin-converting enzyme inhibitor could potentially reduce the risk of symptomatic radiation pneumonitis in male patients and patients receiving low MLD with NSCLC [85, 86]. Some molecular approaches targeting the intermediates involved in the development of inflammatory response in the lungs, such as DNA intercalator and anti-TGF-β type 1 receptor, were studied in preclinical practice [87, 88]
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