Immune Checkpoint Inhibitor-Related Pulmonary Toxicity: Focus on Nivolumab

Bukamur, Hazim; Katz, Heather; Alsharedi, Mohamed; Alkrekshi, Akram; Shweihat, Yousef; Munn, Nancy

doi:10.14423/smj.0000000000001166

Cited by 29 publications

(28 citation statements)

References 35 publications

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“…At present, immune checkpoint inhibitors represent highly promising therapeutic strategies, also for cSCC. They may, however, not apply for all patients due to limitations because of side effects as well as therapy resistance [ 60 ]. Thus, new and additional anticancer strategies are still needed, which may also be used in combinations to improve efficiency.…”

Section: Discussionmentioning

confidence: 99%

High ROS Production by Celecoxib and Enhanced Sensitivity for Death Ligand-Induced Apoptosis in Cutaneous SCC Cell Lines

Zhu

May

Ulrich

et al. 2021

IJMS

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Incidence of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis has increased worldwide, and non-steroidal anti-inflammatory drugs as celecoxib are considered for treatment. We show here strong anti-proliferative effects of celecoxib in four cSCC cell lines, while apoptosis and cell viability largely remained unaffected. Impeded apoptosis was overcome in combinations with agonistic CD95 antibody or TNF-related apoptosis-inducing ligand (TRAIL), resulting in up to 60% apoptosis and almost complete loss of cell viability. Proapoptotic caspase cascades were activated, and apoptosis was suppressed by caspase inhibition. TRAIL receptor (DR5) and proapoptotic Bcl-2 proteins (Puma and Bad) were upregulated, while anti-apoptotic factors (survivin, XIAP, cFLIP, Mcl-1, and Bcl-w) were downregulated. Strongly elevated levels of reactive oxygen species (ROS) turned out as particularly characteristic for celecoxib, appearing already after 2 h. ROS production alone was not sufficient for apoptosis induction but may play a critical role in sensitizing cancer cells for apoptosis and therapy. Thus, the full therapeutic potential of celecoxib may be better used in combinations with death ligands. Furthermore, the immune response against cSCC/AK may be improved by celecoxib, and combinations with checkpoint inhibitors, recently approved for the treatment of cSCC, may be considered.

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Section: Discussionmentioning

confidence: 99%

High ROS Production by Celecoxib and Enhanced Sensitivity for Death Ligand-Induced Apoptosis in Cutaneous SCC Cell Lines

Zhu

May

Ulrich

et al. 2021

IJMS

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“…Although moist rales/crackles are not very commonly manifested symptoms in the patients with immune checkpoint inhibitor-related pneumonitis, they has been listed as one of the clinical findings suspecting the onset of severe pneumonitis recommending a chest CT (21,22). Furthermore, we demonstrated that in NSCLC patients, the incidence of symptomatic pneumonitis induced by atezolizumab plus chemotherapy was lower in the group also treated with bevacizumab than in the group without bevacizumab.…”

Section: Discussionmentioning

confidence: 62%

Anti-VEGF Antibody Protects against Alveolar Exudate Leakage Caused by Vascular Hyperpermeability, Resulting in Mitigation of Pneumonitis Induced by Immunotherapy

Iwai¹,

Sugimoto²,

Patel³

et al. 2021

Molecular Cancer Therapeutics

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Immune-related pneumonitis is an important toxicity associated with checkpoint inhibitor therapy with anti-PD-1 or anti-PD-L1 antibodies, often necessitating discontinuation of treatment.Development of methods to mitigate checkpoint inhibitor-related pneumonitis is required.The contributions of PD-L1, PD-L2, and VEGF to the pathogenesis of pneumonitis were examined in an IL-2-plus IL-18-induced mouse pneumonitis model (IL pneumonitis model). Furthermore, the incidences of pneumonitis were retrospectively examined in non-small-cell lung cancer patients treated with the anti-PD-L1 monoclonal antibody atezolizumab plus chemotherapy, with or without the anti-VEGF monoclonal antibody bevacizumab, in the phase III IMpower150 trial.PD-1 signal blockade by anti-PD-L1 and anti-PD-L2 antibodies aggravated pneumonitis in the IL pneumonitis model. An anti-VEGF antibody prevented PD-1 signal blockade from aggravating pneumonitis in this model. PD-1 signal blockade induced interstitial T cell infiltration in the lungs, but VEGF blockade did not affect this T cell infiltration. The anti-VEGF antibody protected against vascular-to-alveolar leakage of protein and fluid due to PD-1 signal blockade in a murine model. In the IMpower150 trial, incidence rates of pneumonitis of any grade were 4.3% in the group without bevacizumab and 2.8% in the group with bevacizumab. In patients with pneumonitis, outcomes of "Not recovered / Not Resolved" were reported for 29.4% in the group without bevacizumab compared with 9.1% in the group with bevacizumab.Our findings suggest that anti-VEGF antibodies in combination with checkpoint inhibitors may be a treatment method that can control checkpoint inhibitor-related pneumonitis.Research.

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“…Respiratory toxicity with checkpoint inhibitors is well documented with a wide range of toxicities reported including dyspnoea, pneumonitis, pleural effusion, pulmonary sarcoidosis, acute fibrinous organizing pneumonia, eosinophilic pneumonia, adult respiratory distress syndrome, and lung cavitation [ 8 , 9 ]. The most common is pneumonitis with a reported incidence of 1.7% of any grade in melanoma with single-agent anti-PD-1 agents [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…The most common is pneumonitis with a reported incidence of 1.7% of any grade in melanoma with single-agent anti-PD-1 agents [ 6 ]. Exacerbation of asthma has been reported and may be fatal [ 8 , 10 ]. Predictive markers for immune checkpoint-related toxicity are lacking.…”

Section: Discussionmentioning

confidence: 99%

Eosinophilic Asthma Secondary to Adjuvant Anti-PD-1 Immune Checkpoint Inhibitor Treatment in a Melanoma Patient

Kissoonsingh

Sutton

Iqbal

et al. 2022

Case Reports in Oncological Medicine

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Background. Adjuvant immune checkpoint inhibitors are a new standard of care in melanoma. However, the immune related toxicity associated with these agents can be serious, and the long-term implications are yet to be defined especially in the adjuvant setting. We report, to our knowledge, the first case of anti-PD-1-induced eosinophilic asthma in a melanoma patient treated with adjuvant pembrolizumab. Case Presentation. A 72-year-old man commenced pembrolizumab in the adjuvant setting after resection of a stage IIIB cutaneous melanoma. The patient experienced episodes of breathlessness 4 weeks after cycle 1. These episodes were nocturnal and caused acute respiratory distress and cough, occasionally waking him up. The episodes progressed, and he was admitted after cycle 2 with a productive cough, wheeze, and breathlessness. Observations showed saturations on air of 94% and a respiratory rate of 19/min. The only laboratory abnormality was a raised eosinophil count of 1.1 × 10 9 . Spirometry showed a FEV1 of 2.57 (91% predicted), FVC of 4.04 (108% predicted), and ratio of 64%. Peak expiratory flow rate was 94% predicted, and corrected gas transfer was 6.29 (78% predicted) with KCO 1.18 (93% predicted). FeNO was raised at 129 indicating inflammation of his airways, and peak flow was 422 l/min. CT of the chest did not show pneumonitis or other lung pathology. A diagnosis of acute eosinophilic asthma was made. Treatment with steroids and beclometasone dipropionate and formoterol inhaler produced rapid resolution of symptoms and normalisation of the eosinophil count. Pembrolizumab was safely recommenced once steroids had discontinued and symptoms had resolved. Conclusions. Specialist respiratory input was needed for optimal patient management and is ongoing. Although a safe rechallenge with pembrolizumab was possible, treatment in the adjuvant setting is curative in intent and long-term safety follow-up is required to assess for delayed toxicity and long-term health implications. This is likely to require large regional/national/international databases to detect, monitor, and educate the wider medical community as these patients are followed up in primary care following initial specialist follow-up.

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Immune Checkpoint Inhibitor-Related Pulmonary Toxicity: Focus on Nivolumab

Cited by 29 publications

References 35 publications

High ROS Production by Celecoxib and Enhanced Sensitivity for Death Ligand-Induced Apoptosis in Cutaneous SCC Cell Lines

High ROS Production by Celecoxib and Enhanced Sensitivity for Death Ligand-Induced Apoptosis in Cutaneous SCC Cell Lines

Anti-VEGF Antibody Protects against Alveolar Exudate Leakage Caused by Vascular Hyperpermeability, Resulting in Mitigation of Pneumonitis Induced by Immunotherapy

Eosinophilic Asthma Secondary to Adjuvant Anti-PD-1 Immune Checkpoint Inhibitor Treatment in a Melanoma Patient

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