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Year : 2021  |  Volume : 17  |  Issue : 3  |  Page : 808-810

The combination therapy with the cytotoxic T lymphocyte-associated antigen-4 and programmed death 1 antibody-induced asthma in a patient with advanced melanoma

Department of Renal Cancer and Melanoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Research Institute, Beijing, China

Date of Submission12-Mar-2021
Date of Acceptance04-Apr-2021
Date of Web Publication9-Jul-2021

Correspondence Address:
Jun Guo
Department of Renal Cancer and Melanoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Research Institute, Beijing 100142
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_419_21

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 > Abstract 

The combination of programmed death 1 (PD-1) inhibitors and cytotoxic T lymphocyte-associated antigen-(CTLA-4) inhibitors have markedly improved the survival of melanoma patients. We report the case of a patient with advanced melanoma who developed asthma during anti-PD-1 and anti-CTLA-4 combination therapy. The patient was a 57-year-old woman enrolled in a clinical trial regarding novel CTLA-4 antibody and sintilimab treatment. The patient was diagnosed with asthma after three cycles of therapy. Subsequently, she was treated with corticosteroids, shortcostero β2 agonists, and antihistamines. The symptoms were relieved after 7 days. This is the first report of asthma in a patient treated with combination immunotherapy to the best of our knowledge. The mechanism remains to be further explored.

Keywords: Adverse event, immunotherapy, melanoma

How to cite this article:
Xu W, Lian B, Cui C, Guo J. The combination therapy with the cytotoxic T lymphocyte-associated antigen-4 and programmed death 1 antibody-induced asthma in a patient with advanced melanoma. J Can Res Ther 2021;17:808-10

How to cite this URL:
Xu W, Lian B, Cui C, Guo J. The combination therapy with the cytotoxic T lymphocyte-associated antigen-4 and programmed death 1 antibody-induced asthma in a patient with advanced melanoma. J Can Res Ther [serial online] 2021 [cited 2021 Jul 26];17:808-10. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/808/321031

Weiran Xu and Bin Lian contributed equally to this work.

 > Introduction Top

Checkpoint inhibitor therapies such as programmed death 1 (PD-1) inhibitors and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitors have improved the response rate and prolonged the survival rate for advanced melanoma patients. Previous studies have proven that the combination of PD-1 inhibitors and CTLA-4 inhibitors have a higher clinical response rate than that observed for either agent used individually.[1] However, the incidence of immune-related adverse events (irAEs) increases with such a combination scheme.[2] Checkpoint inhibitors may lead to various immune-related adverse effects because of the nonspecific activation of the human immune system. The most common type of pulmonary toxicity is pneumonitis, and immunotherapy-associated asthma is very scarce. Here, we report the case of a patient with metastatic cutaneous melanoma who was diagnosed with asthma during anti-PD-1 and anti-CTLA-4 combined therapy.

 > Case Report Top

The patient was a 57-year-old woman who was diagnosed with malignant melanoma of the right foot in January 2020. There were multiple subcutaneous metastases and lymph node metastases in the mediastinum, left supraclavicular, left axillary, retroperitoneum, pelvis, and double groin identified by contrast-enhanced computed tomography (CT) and magnetic resonance imaging examination. She had no history of asthma and no known medication allergies. The patient signed an informed consent form and enrolled in a study about IBI310, a novel CTLA-4 antibody, combined with sintilimab, a PD-1 antibody. The clinical trial was registered with the Chinese Clinical Trials Registry (CIBI310A101) and ClinicalTrials.gov (NCT03545971). The patient was treated with 3 cycles of IBI310 and sintilimab as the first-line anti-tumor therapy. The last cycle was administered on April 15, 2020.

On April 17, 2020, the patient presented with throat itchiness, wheezing and cough, which worsened at night. She did not start taking any new medications during the course of her treatment and exhibited no clinical signs of heart failure, infection, or acid reflux. Her symptoms were gradually worsening. Two weeks later, she was sent to the emergency department because of dyspnea (May 1, 2020).

The patient vital signs on admission revealed a body temperature of 36.8°C, a pulse rate of 121/min, a respiratory rate of 22/min and a blood pressure of 120/75 mmhg. Her oxygen saturation was 82% in room air. Auscultation of the chest revealed diffuse wheezing in both lungs on expiration. Chest CT showed no changes compared with observations made at the previous evaluation [Figure 1]. Laboratory tests revealed an eosinophilia rate of 17.30% and an eosinophil count of 0.86 × 10^9/L, which had gradually increased during the last 2 weeks.
Figure 1: Computed tomography images of the lungs during the asthma attack

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The patient was diagnosed with asthma due to the above characteristics. She was subsequently treated with corticosteroids (methylprednisolone and budesonide), short-acting β2 agonists (terbutaline) and antihistamines (cetirizine and loratadine). The symptoms were gradually relieved, and the asthma was completely controlled after 7 days. No inhaled or oral medication for asthma was continued. The patient received the next 3 cycles of immunotherapy, and the asthma did not relapse. The best response to the therapy was a partial response, and the cut off follow-up time was September 2020.

 > Discussion Top

The combined therapy with the PD-1 antibody and the CTLA-4 antibody exhibited a better survival benefit than single-agent immunotherapy for advanced melanoma. One clinical trial, NCT01844505, found that the median progression-free survival following treatment with ipilimumab plus nivolumab was 11.5 months, which was much longer than that of nivolumab monotherapy (6.9 months) or ipilimumab monotherapy (2.9 months).[3] However, in terms of safety, the combination regimen seems to be associated with a higher probability for irAEs. A retrospective study demonstrated an overall incidence of irAEs of 95% for the combination of ipilimumab plus nivolumab, 78% for nivolumab alone and 86% for ipilimumab alone. The combination regimen was also associated with more frequent severe adverse events than observed with nivolumab or ipilimumab monotherapy.[4]

The most common irAE in the respiratory system is pneumonitis, which occurs in <10% of patients.[5] Acute asthma requiring hospitalization is rare. Our case is the first report of acute asthma in a patient treated with combination immunotherapy to the best of our knowledge. The case of a patient who developed asthma after 6 weeks of nivolumab treatment has been reported. This patient, similar to our patient, recovered rapidly after treatment with bronchodilators and glucocorticoids.[6]

Asthma is a disease of chronic airway inflammation that is associated with airway hyperresponsiveness, reversible airflow obstruction and airway remodeling. These pathophysiological changes may be related to the increased presence of eosinophils, Th2 lymphocytes, and Group 2 innate lymphoid cells (ILC2s) in the airways and smooth muscle.[7] These mechanisms later result in the increased release of Th2-type inflammatory cytokines, such as IL-4, IL-5, IL-9, and IL-13, which play important roles in the pathogenesis of asthma.[8] A previous study demonstrated that PD-1 could limit the viability of ILC2s, downregulate their effector functions and control lung inflammation.[9] Therefore, blocking PD-1 may lead to Th2-type inflammation. Moreover, in a mouse experiment, enhanced Th2 sensitization after anti-CTLA-4 mAb injections led to increased bronchial eosinophilia and increased IL-4 and IL-5 levels in bronchoalveolar lavage fluid following repeated inhalation of allergens, which can lead to more severe airway inflammation.[10]

Our patient developed asthma within the 4th month of combined immunotherapy. Asthma may be associated with immunotherapy. The early clinical symptoms that this patient presented with were throat itchiness, typical wheezing, and cough. CT examination was performed, and other organic diseases were ruled out. The symptoms were rapidly resolved and did not relapse after rechallenge immunotherapy. Clinicians should pay attention to this rare irAE of the respiratory tract. When the patient was treated appropriately, restarting immunotherapy was possible.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This work was supported by grants from Beijing Municipal Administration of Hospitals' Youth Programme (QML20181101), Beijing Municipal Administration of Hospitals Incubating Program (PX2017042), Natural Science Foundation of China (81672696) and Beijing Municipal Administration of Hospitals' Ascent Plan (DFL20181101).

Conflicts of interest

There are no conflicts of interest.

 > References Top

Forschner A, Battke F, Hadaschik D, Schulze M, Weißgraeber S, Han CT, et al. Tumor mutation burden and circulating tumor DNA in combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma-Results of a prospective biomarker study. J Immunother Cancer 2019;7:180.  Back to cited text no. 1
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010;107:4275-80.  Back to cited text no. 2
Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017;377:1345-56.  Back to cited text no. 3
Hassel JC, Heinzerling L, Aberle J, Bähr O, Eigentler TK, Grimm MO, et al. Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. Cancer Treat Rev 2017;57:36-49.  Back to cited text no. 4
Kähler KC, Hassel JC, Heinzerling L, Loquai C, Mössner R, Ugurel S, et al. Management of side effects of immune checkpoint blockade by antiation and management of adverse drug reactions.in B16 melanoma. J Dtsch Dermatol Ges 2016;14:662-81.  Back to cited text no. 5
Maeno K, Fukuda S, Oguri T, Niimi A. Nivolumab-induced asthma in a patient with non-small-cell lung cancer. Ann Oncol 2017;28:2891.  Back to cited text no. 6
Cohn L, Elias JA, Chupp GL. Asthma: Mechanisms of disease persistence and progression. Annu Rev Immunol 2004;22:789-815.  Back to cited text no. 7
Gurram RK, Zhu J. Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses. Cell Mol Immunol 2019;16:225-35.  Back to cited text no. 8
Helou DG, Shafiei-Jahani P, Lo R, Howard E, Hurrell BP, Galle-Treger L, et al. PD-1 pathway regulates ILC2 metabolism and PD-1 agonist treatment ameliorates airway hyperreactivity. Nat Commun 2020;11:3998.  Back to cited text no. 9
Hellings PW, Vandenberghe P, Kasran A, Coorevits L, Overbergh L, Mathieu C, et al. Blockade of CTLAi4 enhances allergic sensitization and eosinophilic airway inflammation in genetically predisposed mice. Eur J Immunol 2002;32:585-94.  Back to cited text no. 10


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