A Single Infusion of Engineered Long-lived and Multifunctional T Cells Confers Durable Remission of Asthma in Mice

Overview

Journal Nat Immunol

Date 2024 May 27

PMID 38802511

Authors

Gang Jin

Yanyan Liu

Lixia Wang

Zihao He

Xiaocui Zhao

Yuying Ma

Yuting Jia

Zhuoyang Li

Na Yin

Min Peng

Affiliations

Soon will be listed here.

Abstract

Asthma, the most prevalent respiratory disease, affects more than 300 million people and causes more than 250,000 deaths annually. Type 2-high asthma is characterized by interleukin (IL)-5-driven eosinophilia, along with airway inflammation and remodeling caused by IL-4 and IL-13. Here we utilize IL-5 as the targeting domain and deplete BCOR and ZC3H12A to engineer long-lived chimeric antigen receptor (CAR) T cells that can eradicate eosinophils. We call these cells immortal-like and functional IL-5 CAR T cells (5T) cells. 5T cells were further modified to secrete an IL-4 mutein that blocks IL-4 and IL-13 signaling, designated as 5T4 cells. In asthma models, a single infusion of 5T4 cells in fully immunocompetent mice, without any conditioning regimen, led to sustained repression of lung inflammation and alleviation of asthmatic symptoms. These data show that asthma, a common chronic disease, can be pushed into long-term remission with a single dose of long-lived CAR T cells.

Citing Articles

Advances in engineered T cell immunotherapy for autoimmune and other non-oncological diseases.

Huang Q, Zhu X, Zhang Y Biomark Res. 2025; 13(1):23.

PMID: 39901288 PMC: 11792665. DOI: 10.1186/s40364-025-00736-8.

CAR T cells take to the airways.

Bordon Y Nat Rev Drug Discov. 2024; 23(8):579.

PMID: 38898270 DOI: 10.1038/d41573-024-00105-4.

CAR T cells put the brakes on asthma.

Lambrecht B, Hammad H Nat Immunol. 2024; 25(6):935-937.

PMID: 38802513 DOI: 10.1038/s41590-024-01851-8.

References

Hinrichs C, Rosenberg S . Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev. 2013; 257(1):56-71. PMC: 3920180. DOI: 10.1111/imr.12132. View

Neelapu S, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke F . Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2017; 15(1):47-62. PMC: 6733403. DOI: 10.1038/nrclinonc.2017.148. View

Luke J, Flaherty K, Ribas A, Long G . Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. 2017; 14(8):463-482. DOI: 10.1038/nrclinonc.2017.43. View

Kochenderfer J, Wilson W, Janik J, Dudley M, Stetler-Stevenson M, Feldman S . Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010; 116(20):4099-102. PMC: 2993617. DOI: 10.1182/blood-2010-04-281931. View

Israel E, Reddel H . Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017; 377(10):965-976. DOI: 10.1056/NEJMra1608969. View

Papi A, Brightling C, Pedersen S, Reddel H . Asthma. Lancet. 2017; 391(10122):783-800. DOI: 10.1016/S0140-6736(17)33311-1. View

Hammad H, Lambrecht B . The basic immunology of asthma. Cell. 2021; 184(9):2521-2522. DOI: 10.1016/j.cell.2021.04.019. View

Brusselle G, Koppelman G . Biologic Therapies for Severe Asthma. N Engl J Med. 2022; 386(2):157-171. DOI: 10.1056/NEJMra2032506. View

Hearn A, Kent B, Jackson D . Biologic treatment options for severe asthma. Curr Opin Immunol. 2020; 66:151-160. DOI: 10.1016/j.coi.2020.10.004. View

10.

Jacobsen E, Jackson D, Heffler E, Mathur S, Bredenoord A, Pavord I . Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies. Annu Rev Immunol. 2021; 39:719-757. PMC: 8317994. DOI: 10.1146/annurev-immunol-093019-125918. View

11.

Bleecker E, FitzGerald J, Chanez P, Papi A, Weinstein S, Barker P . Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016; 388(10056):2115-2127. DOI: 10.1016/S0140-6736(16)31324-1. View

12.

FitzGerald J, Bleecker E, Nair P, Korn S, Ohta K, Lommatzsch M . 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. Lancet. 2016; 388(10056):2128-2141. DOI: 10.1016/S0140-6736(16)31322-8. View

13.

Wang L, Jin G, Zhou Q, Liu Y, Zhao X, Li Z . Induction of immortal-like and functional CAR T cells by defined factors. J Exp Med. 2024; 221(5). PMC: 10965394. DOI: 10.1084/jem.20232368. View

14.

Cornelis S, Plaetinck G, Devos R, Van der Heyden J, Tavernier J, Sanderson C . Detailed analysis of the IL-5-IL-5R alpha interaction: characterization of crucial residues on the ligand and the receptor. EMBO J. 1995; 14(14):3395-402. PMC: 394406. DOI: 10.1002/j.1460-2075.1995.tb07345.x. View

15.

Dudley M, Wunderlich J, Robbins P, Yang J, Hwu P, Schwartzentruber D . Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002; 298(5594):850-4. PMC: 1764179. DOI: 10.1126/science.1076514. View

16.

Murad J, Tilakawardane D, Park A, Lopez L, Young C, Gibson J . Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity. Mol Ther. 2021; 29(7):2335-2349. PMC: 8261088. DOI: 10.1016/j.ymthe.2021.02.024. View

17.

Amor C, Feucht J, Leibold J, Ho Y, Zhu C, Alonso-Curbelo D . Senolytic CAR T cells reverse senescence-associated pathologies. Nature. 2020; 583(7814):127-132. PMC: 7583560. DOI: 10.1038/s41586-020-2403-9. View

18.

Mackensen A, Muller F, Mougiakakos D, Boltz S, Wilhelm A, Aigner M . Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022; 28(10):2124-2132. DOI: 10.1038/s41591-022-02017-5. View

19.

Rosenberg H, Dyer K, Foster P . Eosinophils: changing perspectives in health and disease. Nat Rev Immunol. 2012; 13(1):9-22. PMC: 4357492. DOI: 10.1038/nri3341. View

20.

Wenzel S, Wilbraham D, Fuller R, Burmeister Getz E, Longphre M . Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007; 370(9596):1422-31. DOI: 10.1016/S0140-6736(07)61600-6. View