638 Plasma proteome analysis in patients with immune checkpoint inhibitors related arthritis and pneumonitis
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Background
Immune checkpoint inhibitors (ICIs) have resulted in unprecedented advances in the treatment of cancer. By disinhibiting the immune system, they enhance anti-tumor immunity, but provoke off-target inflammatory and immune-related adverse events (irAEs) which can seriously impact morbidity and mortality. The exact immunobiology of irAEs is not completely understood, but may involve specific immune pathways. To date, there is no validated biomarker test to predict the development of irAEs in patients treated with ICIs.Methods
To identify possible biomarkers of irAEs, we performed in-depth proteomic profiling of blood samples obtained from cancer patients receiving ICIs. The plasmas were processed with Hu-14 immuno-depletion column (Agilent Technologies) and the samples were labeled with TMT (Thermo Scientific). The proteins were next pre-fractionated with HPLC, trypsin digested and analyzed by nanoAQUITY LC coupled Synapt G2-Si ion-mobility mass spectrometry (WATERS).Results
A total of 12 patients were enrolled in the study; all were receiving anti-programmed cell death-1 (PD-1) agents. Cancer types included melanoma (n=9), renal cell carcinoma (n=2), and non-small cell lung cancer (n=1). Eight patients had irAEs with active toxicity symptoms at blood draw (4 with pneumonitis-irAE and 4 with arthritis-irAE); 6 of those patients were receiving corticosteroids (ranging from 5 to 60 mg/d), and 1 was receiving tocilizumab (an anti-IL-6 receptor antibody). Four patients who completed a minimum of one year of anti-PD1 treatments without irAEs were enrolled as control group. Median time from ICI initiation until blood draw was 16 months (range, 4–31) among patients with irAEs and 23 months (range, 17–28) among controls.We identified 925 protein gene products from 2.5 million mass spectra that can cover 107 dynamic range of plasma proteins. Among them, 19 proteins showed statistically significant differences between patients with and without irAEs (P<0.05) (figure 1). Nine proteins including CFB, CLEC3B, ITIH4, HPX, RARRES2, TF, OAF, MYL12A, and MYL12B were significantly upregulated in patients with irAEs; MYL12A and MYL12B are known to be elevated in airway inflammation of lung tissues. While, 10 other proteins including APOC4, AVPR2, B9D1, DPEP2, JCHAIN, LINC00238, PLG, RAB40C, TCF4, and ZFP30 were significantly downregulated in patients with irAEs (figure 2).Conclusions
In-depth plasma proteome analysis identified possible biomarkers of adverse events modulated by ICI treatment. We plan a prospective validation cohort study of melanoma patients initiating treatment with ICIs to further evaluate the potential clinical utility of the identified biomarkers and their association with immune toxicity, and tumor response to ICI therapy.Ethics Approval
The study was approved by The Institutional Review Board at The University of Texas MD Anderson Cancer Center, approval number PA16-0928Consent
Written informed consent was obtained from all patients who agreed to participate in the studyKeywords:
Pneumonitis
Tocilizumab
Abstract Background Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, has shown survival benefit in clinical trials of various malignant tumors. Nivolumab-induced pneumonitis is major immune-related adverse event (irAE) that is occasionally serious and life-threatening. The aim of this study was to examine the association between pre-existing interstitial lung disease (ILD) on chest computed tomography (CT) and nivolumab-induced pneumonitis among different types of solid tumors. Methods We retrospectively collected the clinical data of 311 patients who were diagnosed with non-small cell lung cancer (NSCLC), head and neck cancer (HNC), or gastric cancer (GC), and treated with nivolumab monotherapy. Patients who underwent chest CT immediately before starting nivolumab without previous thoracic radiotherapy or other immune checkpoint inhibitors were eligible. We collected baseline patient characteristics and assessed pre-existing ILD on baseline chest CT. Results Finally, 188 patients were included in the analysis: 96 patients with NSCLC, 43 patients with HNC, and 49 patients with GC. NSCLC patients had a significantly higher rate of pre-existing ILD compared with HNC/GC patients ( P =0.047). Nivolumab-induced pneumonitis occurred in 11.7% (22 of 188), including 14.6% (14 of 96) of NSCLC, and 8.7% (8 of 92) of HNC/GC. Univariate and multivariate logistic regression analyses revealed that pre-existing ILD (odds ratio, 5.92; 95% confidence interval (CI), 2.07–18.54, P =0.0008) and male sex (odds ratio, 5.58; 95% CI, 1.01–104.40, P =0.049) significantly increased the risk of nivolumab-induced pneumonitis. Conclusion Our results indicated that pre-existing ILD and male sex are risk factors for nivolumab-induced pneumonitis in solid tumors.
Pneumonitis
Univariate analysis
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Pulmonary disease associated with rheumatoid arthritis or collagen diseases were noted recently in Japan.Three cases with rheumatoid pneumonitis were reported while the patients with rheumatoid arthritis was treated in our clinic. They were patients with definite or classical rheumatoid arthritis, and had a cough, dyspnea, shortness of breath and sense of a vise. The Co-relation between the stage and the appearance of rheumatoid pneumonitis was not clear. The chest film revealed the fibrosing pneumonitis or diffuse interstitial fibrosis with a strand or nodular shadow. Respiratory examination revealed low function. The treatment using corticosteroid was successful for the rheumatoid pneumonitis.
Pneumonitis
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Abstract Background Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, has shown survival benefit in clinical trials of various malignant tumors. Nivolumab-induced pneumonitis is major immune-related adverse event (irAE) that is occasionally serious and life-threatening. The aim of this study was to examine the association between pre-existing interstitial lung disease (ILD) on chest computed tomography (CT) and nivolumab-induced pneumonitis among different types of solid tumors. Methods We retrospectively collected the clinical data of 311 patients who were diagnosed with non-small cell lung cancer (NSCLC), head and neck cancer (HNC), or gastric cancer (GC), and treated with nivolumab monotherapy. Patients who underwent chest CT immediately before starting nivolumab without previous thoracic radiotherapy or other immune checkpoint inhibitors were eligible. We collected baseline patient characteristics and assessed pre-existing ILD on baseline chest CT. Results Finally, 188 patients were included in the analysis: 96 patients with NSCLC, 43 patients with HNC, and 49 patients with GC. NSCLC patients had a significantly higher rate of pre-existing ILD compared with HNC/GC patients ( P = 0.047). Nivolumab-induced pneumonitis occurred in 11.7% (22 of 188), including 14.6% (14 of 96) of NSCLC, and 8.7% (8 of 92) of HNC/GC. Univariate and multivariate logistic regression analyses revealed that pre-existing ILD (odds ratio, 5.92; 95% confidence interval (CI), 2.07–18.54, P = 0.0008) and male sex (odds ratio, 5.58; 95% CI, 1.01–104.40, P = 0.049) significantly increased the risk of nivolumab-induced pneumonitis. Conclusion Our results indicated that pre-existing ILD and male sex are risk factors for nivolumab-induced pneumonitis in solid tumors.
Pneumonitis
Univariate analysis
Surgical oncology
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Pneumonitis
Cryptogenic Organizing Pneumonia
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Background The risk of developing lung cancer is high in patients with interstitial lung disease (ILD), as few treatment options are available. Immune checkpoint inhibitors (ICI) are used for the treatment of non‐small cell lung cancer (NSCLC) in clinical practice; however, in patients with preexisting ILD, the risk of ICI‐related pneumonitis is unknown. We evaluated the efficacy and lung toxicity of nivolumab in patients with NSCLC and ILD. Methods We retrospectively reviewed the medical records of 216 NSCLC patients who had received nivolumab therapy. The existence of ILD in these patients was determined by lung computed tomography findings; 26 patients had ILD. We evaluated the efficacy of nivolumab by measuring the response rate (RR), progression‐free survival (PFS) duration, and lung toxicity by incidence, severity, and outcome of nivolumab‐related ILD. Results The RR and median PFS of the ILD and non‐ILD groups were 27% versus 13% ( P = 0.078) and 2.7 (95% confidence interval [CI], 1.7–5.3) versus 2.9 months (95% CI 2.1–3.4; P = 0.919), respectively. The incidences of total and severe nivolumab‐related pneumonitis were significantly higher in the ILD group than in the non‐ILD group (31% vs. 12%, P = 0.014 and 19% vs. 5%, P = 0.022, respectively). No death from nivolumab‐related pneumonitis occurred. Over 50% of the patients in both groups with nivolumab‐related pneumonitis showed improvement over time. Conclusion Relative to the non‐ILD group, nivolumab‐related pneumonitis was observed more frequently in the ILD group; however, most cases were manageable.
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Nivolumab, an antiprogrammed death-1 checkpoint inhibitor, has been approved for use in unresectable/metastatic renal cell carcinoma (RCC). Nivolumab-induced pneumonitis, a rare, but often severe and potentially life-threatening immune-related adverse event, has been reported, typically, early during the treatment. Due to its low incidence, more studies are needed to better elucidate this condition and its possible effects on cancer progression. We now present a 57-year-old Hispanic male patient with metastatic RCC-clear cell type who, after his 34 th cycle of nivolumab (16 months after being on nivolumab), developed a late-onset, immune-related adverse event (IRAE) including a grade 3 pneumonitis, which resolved completely, clinically, and on serial lung imaging with steroids and drug discontinuation. His cancer remained stable with no progression for 18 months despite discontinuation of nivolumab which showed tumor progression resistance. This case report is aimed at providing further information regarding the rare phenomena of a late-onset IRAE, in particular, a grade 3 nivolumab-induced pneumonitis which also responded rapidly to treatment, as well as at discussing this immunotherapy’s durable tumor suppressive effect and a possible associated factor to this phenomenon.
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Results Forty-two SJIA patients, 131 blood samplings were included in this study. Seventeen patients (40%) were treated with tocilizumab during the study. Serum IL-6 levels in patients without tocilizumab treatment significantly elevated in active disease with systemic features and arthritis [median (IQR) = 101.8 (303.2) pg/mL] when compared to active disease with only arthritis [median (IQR) = 4.5 (23) pg/mL], and remission on medication [median (IQR) = 1.5 (0.55) pg/mL], whereas serum IL-6 levels in patients with tocilizumab treatment were not different between groups but there were significantly different when compared to healthy children (p < 0.05). In addition, the correlation between serum IL-6 levels and JADAS-71 in patients without tocilizumab treatment (r = 0.71, p < 0.001) was stronger than patients with tocilizumab treatment (r = 0.42, p = 0.01). Serum sIL-6R levels in SJIA patients with and without tocilizumab treatment were significantly higher when compared to healthy children (p < 0.05). Interestingly, in patients with tocilizumab treatment, serum sIL-6R levels were extremely higher [median (IQR) = 1,110.3 (840.2) ng/mL] than patients without tocilizumab treatment [median (IQR) = 94.2 (82.7) ng/mL]. Conclusion The correlation between serum IL-6 levels and disease activity in patients without tocilizumab treatment was stronger than patients with tocilizumab treatment. In addition, serum sIL-6R levels in patients with tocilizumab treatment were extremely higher than patients without tocilizumab treatment.
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The introduction of immune checkpoint inhibitors heralded a new era in the treatment of non-small cell lung cancer. However, nivolumab, an anti-PD-1 antibody, can cause serious adverse events that are mostly autoimmune related.A 58-year-old woman was treated with nivolumab as second-line therapy for stage IV adenocarcinoma. The patient developed a nivolumab-induced recurrent pneumonitis preceding durable clinical remission after seven cycles of nivolumab. Although high-dose glucocorticosteroids were tapered to conform to contemporary guidelines, recurring episodes of pneumonitis occurred without nivolumab rechallenge. In addition, carcinoembryonic antigen (CEA) serum levels were associated with treatment response, since CEA decline correlated with a near complete radiological response and, conversely, elevated CEA serum levels were associated with progressive disease.In this case, we described recurrence of nivolumab-induced pneumonitis as a serious adverse event in immune checkpoint inhibitors. Our case illustrates that immune-related adverse events may correlate with antitumour activity, even after treatment discontinuation. In addition, this case suggests the possible clinical utility of CEA serum levels for the assessment of (durable) effects of immunotherapy.
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Pneumonitis
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Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody used as an immune checkpoint inhibitor, is commonly employed for its anti-tumor effects against various types of malignant tumors. However, its administration is complicated by immune-related adverse events (irAEs), including pneumonitis. We present a case series of four patients with malignant melanoma, non-small cell lung cancer, and hypopharyngeal carcinoma who demonstrated pneumonitis induced by nivolumab, and further review clinicopathological characteristics of these patients in comparison with those of previously reported patients with nivolumab-induced pneumonitis. In our series, 20% of patients who were treated with nivolumab developed pneumonitis, all of which occurred approximately 2 weeks after the initiation of nivolumab treatment. Prompt recognition of the nivolumab-induced pneumonitis allowed for successful resolution. Computed tomography scan images of the patients demonstrated predominantly cryptogenic organizing pneumonia patterns. All patients were males, who had been heavily treated with antitumor drugs prior to nivolumab. Our case series showed that nivolumab had a high incidence of drug-induced pneumonitis with early onset, supporting the need for renewed attention to nivolumab-induced pneumonitis, particularly in patients with a history of heavy antitumor treatments.
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