Checkpoint Inhibitor Pneumonitis: Updates in Management
Main Article Content
Abstract
Checkpoint inhibitor pneumonitis (CIP) is a potentially life-threatening immune-related adverse event associated with immune checkpoint inhibitors (ICIs). While high-dose corticosteroids remain the first-line treatment, up to 40% of patients experience steroid-refractory or resistant disease, posing significant management challenges. This review synthesizes current evidence on evolving CIP management strategies, highlighting both established therapies and emerging options. Recent guidelines favor mycophenolate mofetil (MMF) and intravenous immunoglobulin (IVIG) as second-line agents, replacing infliximab due to infection concerns in this immunocompromised population. Additional therapies such as cyclophosphamide, calcineurin inhibitors, and pulsed-dose corticosteroids have shown benefit in select cases, though evidence remains limited. Advances in understanding CIP immunopathogenesis have spurred interest in targeted biologics, notably interleukin-6 inhibitors like tocilizumab, which demonstrate promise in early reports. Antifibrotic agents, including nintedanib and pirfenidone, are also under investigation for their potential to manage fibrosis, particularly in patients with underlying interstitial lung disease or progressive fibrotic changes. Experimental strategies such as plasmapheresis, granulocyte-macrophage colony-stimulating factor (GM-CSF) modulation, and Janus kinase (JAK) inhibitors are being explored, with several prospective trials underway. Despite these advances, challenges persist in early diagnosis, risk stratification, and the absence of prospective, biomarker-driven treatment algorithms. This review emphasizes the importance of multidisciplinary, individualized management and highlights promising avenues for future research to improve outcomes in this increasingly encountered complication of cancer immunotherapy.
Article Details
How to Cite
MCCRARY, Myah et al.
Checkpoint Inhibitor Pneumonitis: Updates in Management.
Medical Research Archives, [S.l.], v. 13, n. 7, sep. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6740>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i7.6740.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. Khunger, M., et al., Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials. Chest, 2017. 152(2): p. 271-281.
3. Beattie, J., et al., Success and failure of additional immune modulators in steroid-refractory/ resistant pneumonitis related to immune checkpoint blockade. J Immunother Cancer, 2021. 9(2).
4. Lin, X., et al., Safety and efficacy of immunotherapy rechallenge following checkpoint inhibitor-related pneumonitis in advanced lung cancer patients: a retrospective multi-center cohort study. Transl Lung Cancer Res, 2022. 11(11): p. 2289-2305.
5. Zhang, H., et al., Tumour cell-intrinsic CTLA4 regulates PD-L1 expression in non-small cell lung cancer. J Cell Mol Med, 2019. 23(1): p. 535-542.
6. Balaji, A., et al., Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes. J Immunother Cancer, 2021. 9(1).
7. Chao, Y., et al., Risk factors for immune checkpoint inhibitor-related pneumonitis in non-small cell lung cancer. Transl Lung Cancer Res, 2022. 11(2): p. 295-306.
8. Zhou, P., X. Zhao, and G. Wang, Risk Factors for Immune Checkpoint Inhibitor-Related Pneumonitis in Cancer Patients: A Systemic Review and Meta-Analysis. Respiration, 2022. 101(11): p. 1035-1050.
9. Ichimura, T., et al., Safety of immune checkpoint inhibitors in non-small-cell lung cancer patients with idiopathic interstitial pneumonia: a matched case-control study. Cancer Chemother Pharmacol, 2022. 89(1): p. 21-30.
10. Osaki, M., et al., Immune Checkpoint Inhibitor-Related Pneumonitis in Lung Cancer Patients with Interstitial Lung Disease: Significance of Radiological Pleuroparenchymal Fibroelastosis. Oncology, 2023. 101(5): p. 303-312.
11. Tao, H., et al., Rate and risk factors of recurrent immune checkpoint inhibitor-related pneumonitis in patients with lung cancer. Transl Lung Cancer Res, 2022. 11(3): p. 381-392.
12. Stroud, C.R., et al., Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade. J Oncol Pharm Pract, 2019. 25(3): p. 551-557.
13. Lai, K.C., Y.H. Hsiao, and S.C. Chen, Pulse corticosteroid therapy in the treatment of steroid-refractory immune checkpoint inhibitor-related pneumonitis: Case report and review. Front Immunol, 2022. 13: p. 994064.
14. Wang, P.M., et al., Characterization of immunomodulatory factors and cells in bronchoalveolar lavage fluid for immune checkpoint inhibitor-related pneumonitis. J Cancer Res Clin Oncol, 2023. 149(10): p. 8019-8026.
15. Hu, X., et al., AntiPD1/PDL1 and antiCTLA4 associated checkpoint inhibitor pneumonitis in nonsmall cell lung cancer: Occurrence, pathogenesis, and risk factors (Review). Int J Oncol, 2023. 63(5).
16. Suresh, K., et al., Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors. J Thorac Oncol, 2018. 13(12): p. 1930-1939.
17. Guo X, C.S., Wang X, Liu X, Immune-Related Pulmonary Toxicities of Checkpoint Inhibitors in Non-Small Cell Lung Cancer: Diagnosis, Mechanism, and Treatment Strategies. Frontiers in Immunology, 2023. 14(1138483).
18. Schneider, B.J., et al., Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol, 2021. 39(36): p. 4073-4126.
19. Kalisz, K.R., et al., Immune Checkpoint Inhibitor Therapy-related Pneumonitis: Patterns and Management. Radiographics, 2019. 39(7): p. 1923-1937.
20. Brahmer, J.R., et al., Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer, 2021. 9(6).
21. Edel, Y., et al., The safety of pulse corticosteroid therapy- Systematic review and meta-analysis. Semin Arthritis Rheum, 2020. 50(3): p. 534-545.
22. Lin, M.X., et al., Immune checkpoint inhibitor-related pneumonitis: research advances in prediction and management. Front Immunol, 2024. 15: p. 126 6850.
23. Brahmer, J.R., et al., Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol, 2018. 36(17): p. 1714-1768.
24. Haanen, J., et al., Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment, and follow-up. Ann Oncol, 2022. 33(12): p. 1217-1238.
25. Li Y, J.X., Zhang Y, et al., Correction: Risk factors and immunomodulators use in steroid-refractory checkpoint inhibitor pneumonitis. J Immunother Cancer, 2023. 11(12).
26. Tan, P., et al., Risk Factors for Refractory Immune Checkpoint Inhibitor-related Pneumonitis in Patients With Lung Cancer. Journal of Immunotherapy, 2023. 46(2): p. 64-73.
27. Montemayor, K., et al., Managing Immune Checkpoint Inhibitor Pneumonitis in the ICU. CHEST Critical Care, 2025. 3(1).
28. Joshi, K.P., et al., Absolute lymphocyte count (ALC) as predictor of Pneumocystis Jiroveci Pneumonia (PCP) infection in patients on immune checkpoint inhibitors (ICPi). Journal of Clinical Oncology, 2019. 37(15_suppl): p. e14255-e14255.
29. Kyi, C., et al., Opportunistic infections in patients treated with immunotherapy for cancer. J Immunother Cancer, 2014. 2: p. 19.
30. Wang, H., et al., Clinical diagnosis and treatment of immune checkpoint inhibitor-associated pneumonitis. Thorac Cancer, 2020. 11(1): p. 191-197.
31. Meng, Y., et al., Extracorporeal Membrane Oxygenation for Treatment of Immune Checkpoint Inhibitor-Related Pneumonia Complicated with Severe ARDS: A Case Report. Int Med Case Rep J, 2025. 18: p. 411-419.
32. Luo, J., et al., Beyond Steroids: Immunosuppressants in Steroid-Refractory or Resistant Immune-Related Adverse Events. J Thorac Oncol, 2021. 16(10): p. 1759-1764.
33. Iyoda, T., et al., Resolution of Infliximab-Refractory Nivolumab-Induced Acute Severe Enterocolitis After Cyclosporine Treatment in a Patient with Non-Small Cell Lung Cancer. Am J Case Rep, 2018. 19: p. 360-364.
34. NCCN, National Comprehensive Cancer Network guidelines version 1. 2025 Management of immunotherapy-related toxicities. National Comprehensive Cancer Network website: National Comprehensive Cancer Network, 2025.
35. Daetwyler, E., et al., Corticosteroid-resistant immune-related adverse events: a systematic review. J Immunother Cancer, 2024. 12(1).
36. Cooksley, T., W. Marshall, and A. Gupta, Early infliximab in life-threatening immune-mediated pneumonitis. QJM: An International Journal of Medicine, 2019. 112(12): p. 929-930.
37. Ortega Sanchez, G., et al., Treatment of mycophenolate-resistant immune-related organizing pneumonia with infliximab. Journal for ImmunoTherapy of Cancer, 2018. 6(1): p. 85.
38. Verheijden, R.J., et al., Association of Anti-TNF with Decreased Survival in Steroid Refractory Ipilimumab and Anti-PD1-Treated Patients in the Dutch Melanoma Treatment Registry. Clin Cancer Res, 2020. 26(9): p. 2268-2274.
39. Morisset, J., et al., Use of Mycophenolate Mofetil or Azathioprine for the Management of Chronic Hypersensitivity Pneumonitis. Chest, 2017. 151(3): p. 619-625.
40. Tashkin, D.P., et al., Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med, 2016. 4(9): p. 708-719.
41. Shioiri, N., et al., Effective treatment of steroid-resistant immune checkpoint inhibitor pneumonitis with mycophenolate mofetil. Respirology Case Reports, 2024. 12(4): p. e01356.
42. Hallowell, R.W., D. Amariei, and S.K. Danoff, Intravenous Immunoglobulin as Potential Adjunct Therapy for Interstitial Lung Disease. Ann Am Thorac Soc, 2016. 13(10): p. 1682-1688.
43. Petri, C.R., et al., Severe pulmonary toxicity from immune checkpoint inhibitor treated successfully with intravenous immunoglobulin: Case report and review of the literature. Respir Med Case Rep, 2019. 27: p. 100834.
44. Nunes, N.S. and C.G. Kanakry, Mechanisms of Graft-versus-Host Disease Prevention by Post-transplantation Cyclophosphamide: An Evolving Understanding. Front Immunol, 2019. 10: p. 2668.
45. Davis T, F.K., Gregos PS, Shapiro LC, Shastri A, et al., High Dose Cyclophosphamide for the Treatment of Severe Immune Checkpoint Inhibitor Related Adverse Events. J Oncol Res Ther, 2023. 8: p. 10194.
46. Camard, M., et al., Prevalence and outcome of steroid-resistant/refractory pneumonitis induced by immune checkpoint inhibitors. Respir Med Res, 2022. 82: p. 100969.
47. Zhang, E., et al., Calcineurin inhibitors in steroid and anti-TNF-alpha refractory immune checkpoint inhibitor colitis. JGH Open, 2021. 5(5): p. 558-562.
48. Utsumi, H., et al., Successful treatment of steroid-refractory immune checkpoint inhibitor-related pneumonitis with triple combination therapy: a case report. Cancer Immunol Immunother, 2020. 69(10): p. 2033-2039.
49. Deng, J., et al., Cyclosporine successfully treats steroid-resistant checkpoint inhibitor-related pneumonitis: a case report. BMC Pulmonary Medicine, 2024. 24(1): p. 577.
50. Lin, X., et al., Peripheral Blood Biomarkers for Early Diagnosis, Severity, and Prognosis of Checkpoint Inhibitor-Related Pneumonitis in Patients With Lung Cancer. Front Oncol, 2021. 11: p. 698832.
51. Singh, K.P., et al., Regulatory Role of IL6 in Immune-Related Adverse Events during Checkpoint Inhibitor Treatment in Melanoma. Int J Mol Sci, 2024. 25(19).
52. Campochiaro, C., et al., Tocilizumab for the treatment of immune-related adverse events: a systematic literature review and a multicentre case series. Eur J Intern Med, 2021. 93: p. 87-94.
53. Gradone, A., Bi, X., Gorman, T., Bao, A., O’Hara, W., Filicko-O'Hara, J., Grosso, D., Toor, A.., Gergis, U., Tocilizumab Mitigates the Risk of Severe Cytokine Release Syndrome in HLA Mismatched Allogeneic Hematopoietic Stem Cell Transplantation. Transplantation and Cellular Therapy, 2025. 31(2): p. S156-S157.
54. Dimitriou, F., et al., Interleukin-6 blockade for prophylaxis and management of immune-related adverse events in cancer immunotherapy. Eur J Cancer, 2021. 157: p. 214-224.
55. Singh, J.A., S. Beg, and M.A. Lopez-Olivo, Tocilizumab for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol, 2011. 38(1): p. 10-20.
56. Nagpal, C., et al., Re-challenge of immune checkpoint inhibitor pembrolizumab with concurrent tocilizumab after prior grade 3 pneumonitis. Ecancermedicalscience, 2023. 17: p. 1644.
57. Distler, O., et al., Nintedanib for Systemic Sclerosis–Associated Interstitial Lung Disease. New England Journal of Medicine, 2019. 380(26): p. 2518-2528.
58. Wollin, L., et al., Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J, 2015. 45(5): p. 1434-45.
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