Journal of Shandong University (Health Sciences) ›› 2024, Vol. 62 ›› Issue (5): 35-42.doi: 10.6040/j.issn.1671-7554.0.2024.0144

• Precision medicine in chronic airway diseases—Expert Overview • Previous Articles    

Research progress on biological and cellular therapies for severe asthma

XU Fang1, TIAN Guoxiong1,2, SUN Beibei1, CHEN Xinyi1, CHEN Gaoying1,2, ZHANG Ruiqi2, YING Songmin1,2, WU Miaolian2, ZHANG Chao1, WU Youqian2   

  1. 1. Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China;
    2. Zhejiang-Denmark Joint Laboratory of Regeneration and Aging Medicine, Department of Pharmacy, Center for Regeneration and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, Zhejiang, China
  • Published:2024-05-29

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Abstract: Asthma is a highly heterogeneous disease with multiple effector cells and cytokines involved in its development. In severe asthma, conventional high-dose inhaled glucocorticoid therapy is usually difficult to control symptoms, and patients may present with persistent airflow limitation and worsening symptoms, leading to decreased quality of life and increased healthcare burden. Currently, the exploration of biological therapies targeting effector cells or cytokines offers novel treatment options as add-on therapies for severe asthma. In recent years, studies have also pioneered the application of novel cellular therapies, such as stem cell therapy or chimeric antigen receptor T(CAR-T)cell therapy, to the treatment of severe asthma. In this article, we will review the research progress of biological agents for severe asthma and novel cellular therapies as potential therapeutic strategies, describe promising biological therapies and their mechanisms of action, efficacy and safety, and on the basis of which, we will look forward to the future development of biological and cellular therapies as a strategy for the treatment of severe asthma in terms of long-term efficacy and safety, precision medicine, patient accessibility, and interdisciplinary cooperation.

Key words: Severe asthma, Biological therapy, Cellular therapy, Monoclonal antibody, Stem cell therapy, CAR-T cell therapy

CLC Number: 

  • R256.12
[1] Brusselle GG, Koppelman GH. Biologic therapies for severe asthma[J]. N Engl J Med, 2022, 386(2): 157-171.
[2] Global Initiative for Asthma. GINA report, global strategy for asthma management and prevention(2023 update)[EB/OL].(2023-07-10)[2024-02-01] , https://ginasthma.org/reports/.
[3] Yu X, Yu L, Guo BX, et al. A narrative review of research advances in mesenchymal stem cell therapy for asthma[J]. Ann Transl Med, 2020, 8(21): 1461. doi:10.21037/atm-20-6389.
[4] Chen SS, Chen GY, Xu F, et al. Treatment of allergic eosinophilic asthma through engineered IL-5-anchored chimeric antigen receptor T cells[J]. Cell Discov, 2022, 8(1): 80. doi:10.1038/s41421-022-00433-y.
[5] Skuljec J, Chmielewski M, Happle C, et al. Chimeric antigen receptor-redirected regulatory T cells suppress experimental allergic airway inflammation, a model of asthma[J]. Front Immunol, 2017, 8: 1125. doi:10.3389/fimmu.2017.01125.
[6] Hammad H, Lambrecht BN. The basic immunology of asthma[J]. Cell, 2021, 184(6): 1469-1485.
[7] Coquet JM, Schuijs MJ, Smyth MJ, et al. Interleukin-21-producing CD4(+)T cells promote type 2 immunity to house dust mites[J]. Immunity, 2015, 43(2): 318-330.
[8] Peters MC, Ringel L, Dyjack N, et al. A transcriptomic method to determine airway immune dysfunction in T2-high and T2-low asthma[J]. Am J Respir Crit Care Med, 2019, 199(4): 465-477.
[9] Lambrecht BN, Hammad H, Fahy JV. The cytokines of asthma[J]. Immunity, 2019, 50(4): 975-991.
[10] Cardet JC, Casale TB. New insights into the utility of omalizumab[J]. J Allergy Clin Immunol, 2019, 143(3): 923-926.e1.
[11] Kanda A, Yasutaka Y, van Bui D, et al. Multiple biological aspects of eosinophils in host defense, eosinophil-associated diseases, immunoregulation, and homeostasis: is their role beneficial, detrimental, regulator, or bystander?[J]. Biol Pharm Bull, 2020, 43(1): 20-30.
[12] Porsbjerg C, Melén E, Lehtimäki L, et al. Asthma[J]. Lancet, 2023, 401(10379): 858-873.
[13] Gauvreau GM, Sehmi R, Ambrose CS, et al. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma[J]. Expert Opin Ther Targets, 2020, 24(8): 777-792.
[14] Raundhal M, Morse C, Khare A, et al. High IFN-γ and low SLPI mark severe asthma in mice and humans[J]. J Clin Invest, 2015, 125(8): 3037-3050.
[15] Reddel HK, Bacharier LB, Bateman ED, et al. Global initiative for asthma strategy 2021: executive summary and rationale for key changes[J]. Am J Respir Crit Care Med, 2022, 205(1): 17-35.
[16] Mavissakalian M, Brady S. The current state of biologic therapies for treatment of refractory asthma[J]. Clin Rev Allergy Immunol, 2020, 59(2): 195-207.
[17] MacGlashan DW Jr, Bochner BS, Adelman DC, et al. Down-regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody[J]. J Immunol, 1997, 158(3): 1438-1445.
[18] Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial[J]. Ann Intern Med, 2011, 154(9): 573-582.
[19] Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab(anti-IgE)for asthma in inner-city children[J]. N Engl J Med, 2011, 364(11): 1005-1015.
[20] Humbert M, Bourdin A, Taillé C, et al. Real-life omalizumab exposure and discontinuation in a large nationwide population-based study of paediatric and adult asthma patients[J]. Eur Respir J, 2022, 60(5): 2103130. doi:10.1183/13993003.03130-2021.
[21] Harris JM, Maciuca R, Bradley MS, et al. A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma[J]. Respir Res, 2016, 17: 29. doi:10.1186/s12931-016-0347-2.
[22] Trischler J, Bottoli I, Janocha R, et al. Ligelizumab treatment for severe asthma: learnings from the clinical development programme[J]. Clin Transl Immunology, 2021, 10(3): e1255. doi:10.1002/cti2.1255.
[23] Mitchell PD, OByrne PM. Epithelial-derived cytokines in asthma[J]. Chest, 2017, 151(6): 1338-1344.
[24] Porsbjerg CM, Sverrild A, Lloyd CM, et al. Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics[J]. Eur Respir J, 2020, 56(5): 2000260. doi:10.1183/13993003.00260-2020.
[25] Corren J, Parnes JR, Wang LW, et al. Tezepelumab in adults with uncontrolled asthma[J]. N Engl J Med, 2017, 377(10): 936-946.
[26] Diver S, Khalfaoui L, Emson C, et al. Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma(CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial[J]. Lancet Respir Med, 2021, 9(11): 1299-1312.
[27] Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma[J]. N Engl J Med, 2021, 384(19): 1800-1809.
[28] Hoy SM. Tezepelumab: first approval[J]. Drugs, 2022, 82(4): 461-468.
[29] Wechsler ME, Ruddy MK, Pavord ID, et al. Efficacy and safety of itepekimab in patients with moderate-to-severe asthma[J]. N Engl J Med, 2021, 385(18): 1656-1668.
[30] Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma[J]. N Engl J Med, 2014, 371(13): 1198-1207.
[31] Castro M, Zangrilli J, Wechsler ME. Corrections. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials[J]. Lancet Respir Med, 2015, 3(4): e15. doi:10.1016/S2213-2600(15)00119-8.
[32] Chupp GL, Bradford ES, Albers FC, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma(MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial[J]. Lancet Respir Med, 2017, 5(5): 390-400.
[33] Khatri S, Moore W, Gibson PG, et al. Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma[J]. J Allergy Clin Immunol, 2019, 143(5): 1742-1751.
[34] Laviolette M, Gossage DL, Gauvreau G, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia[J]. J Allergy Clin Immunol, 2013, 132(5): 1086-1096.e5.
[35] FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma(CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial[J]. Lancet, 2016, 388(10056): 2128-2141.
[36] Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists(SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial[J]. Lancet, 2016, 388(10056): 2115-2127.
[37] Busse WW, Bleecker ER, FitzGerald JM, et al. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial[J]. Lancet Respir Med, 2019, 7(1): 46-59.
[38] Kavanagh JE, Hearn AP, Dhariwal J, et al. Real-world effectiveness of benralizumab in severe eosinophilic asthma[J]. Chest, 2021, 159(2): 496-506.
[39] Scott G, Asrat S, Allinne J, et al. IL-4 and IL-13, not eosinophils, drive type 2 airway inflammation, remodeling and lung function decline[J]. Cytokine, 2023, 162: 156091. doi:10.1016/j.cyto.2022.156091.
[40] Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma[J]. N Engl J Med, 2018, 378(26): 2486-2496.
[41] Castro M, Rabe KF, Corren J, et al. Dupilumab improves lung function in patients with uncontrolled, moderate-to-severe asthma[J]. ERJ Open Res, 2020, 6(1): 00204-02019.
[42] Dupin C, Belhadi D, Guilleminault L, et al. Effectiveness and safety of dupilumab for the treatment of severe asthma in a real-life French multi-centre adult cohort[J]. Clin Exp Allergy, 2020, 50(7): 789-798.
[43] Busse WW, Brusselle GG, Korn S, et al. Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma[J]. Eur Respir J, 2019, 53(2): 1800948. doi:10.1183/13993003.00948-2018.
[44] Xie Y, Abel PW, Casale TB, et al. TH17 cells and corticosteroid insensitivity in severe asthma[J]. J Allergy Clin Immunol, 2022, 149(2): 467-479.
[45] Nakagawa H, Niiro H, Ootaki K, et al. Brodalumab, a human anti-interleukin-17-receptor antibody in the treatment of Japanese patients with moderate-to-severe plaque psoriasis: efficacy and safety results from a phase II randomized controlled study[J]. J Dermatol Sci, 2016, 81(1): 44-52.
[46] Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis[J]. N Engl J Med, 2012, 366(13): 1181-1189.
[47] Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma[J]. Am J Respir Crit Care Med, 2013, 188(11): 1294-1302.
[48] Brightling CE, Nair P, Cousins DJ, et al. Risankizumab in severe asthma - a phase 2a, placebo-controlled trial[J]. N Engl J Med, 2021, 385(18): 1669-1679.
[49] Choy DF, Hart KM, Borthwick LA, et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma[J]. Sci Transl Med, 2015, 7(301): 301ra129. doi:10.1126/scitranslmed.aab3142.
[50] Nair P, Surette MG, Virchow JC. Neutrophilic asthma: misconception or misnomer?[J]. Lancet Respir Med, 2021, 9(5): 441-443.
[51] Kimbrel EA, Lanza R. Next-generation stem cells—ushering in a new era of cell-based therapies[J]. Nat Rev Drug Discov, 2020, 19(7): 463-479.
[52] Mazid MA, Ward C, Luo ZW, et al. Rolling back human pluripotent stem cells to an eight-cell embryo-like stage[J]. Nature, 2022, 605(7909): 315-324.
[53] Weiss DJ. Cell-based therapy for chronic obstructive pulmonary disease. rebuilding the lung[J]. Ann Am Thorac Soc, 2018, 15(Suppl 4): S253-S259.
[54] Boldrini-Leite LM, Michelotto PV Jr, de Moura SAB, et al. Lung tissue damage associated with allergic asthma in BALB/c mice could be controlled with a single injection of mesenchymal stem cells from human bone marrow up to 14 d after transplantation[J]. Cell Transplant, 2020, 29: 963689720913254. doi:10.1177/0963689720913254.
[55] Dai RR, Yu YC, Yan GF, et al. Intratracheal administration of adipose derived mesenchymal stem cells alleviates chronic asthma in a mouse model[J]. BMC Pulm Med, 2018, 18(1): 131. doi:10.1186/s12890-018-0701-x.
[56] Halim NSS, Chng ES, Kardia E, et al. Aerosolised mesenchymal stem cells expressing angiopoietin-1 enhances airway repair[J]. Stem Cell Rev Rep, 2019, 15(1): 112-125.
[57] Dalouchi F, Falak R, Bakhshesh M, et al. Human amniotic membrane mesenchymal stem cell-conditioned medium reduces inflammatory factors and fibrosis in ovalbumin-induced asthma in mice[J]. Exp Physiol, 2021, 106(2): 544-554.
[58] Zhong H, Fan XL, Fang SB, et al. Human pluripotent stem cell-derived mesenchymal stem cells prevent chronic allergic airway inflammation via TGF-β1-Smad2/Smad3 signaling pathway in mice[J]. Mol Immunol, 2019, 109: 51-57. doi:10.1016/j.molimm.2019.02.017.
[59] Yamaguchi S, Marumoto T, Nii T, et al. Characterization of common marmoset dysgerminoma-like tumor induced by the lentiviral expression of reprogramming factors[J]. Cancer Sci, 2014, 105(4): 402-408.
[60] Hur J, Kang JY, Kim YK, et al. Evaluation of human MSCs treatment frequency on airway inflammation in a mouse model of acute asthma[J]. J Korean Med Sci, 2020, 35(23): e188. doi:10.3346/jkms.2020.35.e188.
[61] Zhang LB, He M. Effect of mesenchymal stromal(stem)cell(MSC)transplantation in asthmatic animal models: a systematic review and meta-analysis[J]. Pulm Pharmacol Ther, 2019, 54: 39-52. doi:10.1016/j.pupt.2018.11.007.
[62] Sharan J, Barmada A, Band N, et al. First report in a human of successful treatment of asthma with mesenchymal stem cells: a case report with review of literature[J]. Curr Stem Cell Res Ther, 2023, 18(7): 1026-1029.
[63] June CH, Sadelain M. Chimeric antigen receptor therapy[J]. N Engl J Med, 2018, 379(1): 64-73.
[64] Schett G, Mackensen A, Mougiakakos D. CAR T-cell therapy in autoimmune diseases[J]. Lancet, 2023, 402(10416): 2034-2044.
[65] Qu CR, Zhang H, Cao H, et al. Tumor buster - where will the CAR-T cell therapy ‘missile’ go?[J]. Mol Cancer, 2022, 21(1): 201. doi:10.1186/s12943-022-01669-8.
[66] Seumois G, Ramírez-Suástegui C, Schmiedel BJ, et al. Single-cell transcriptomic analysis of allergen-specific T cells in allergy and asthma[J]. Sci Immunol, 2020, 5(48): eaba6087. doi:10.1126/sciimmunol.aba6087.
[67] Ward DE, Fay BL, Adejuwon A, et al. Chimeric antigen receptors based on low affinity mutants of FcεRI re-direct T cell specificity to cells expressing membrane IgE[J]. Front Immunol, 2018, 9: 2231. doi:10.3389/fimmu.2018.02231.
[68] Schubert ML, Schmitt M, Wang L, et al. Side-effect management of chimeric antigen receptor(CAR)T-cell therapy[J]. Ann Oncol, 2021, 32(1): 34-48.
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