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Treatment of allergic eosinophilic asthma through engineered IL-5-anchored chimeric antigen receptor T cells.

ABSTRACT: Severe eosinophilic asthma (SEA) is a therapy-resistant respiratory condition with poor clinical control. Treatment efficacy and patient compliance of current therapies remain unsatisfactory. Here, inspired by the remarkable success of chimeric antigen receptor-based cellular adoptive immunotherapies demonstrated for the treatment of a variety of malignant tumors, we engineered a cytokine-anchored chimeric antigen receptor T (CCAR-T) cell system using a chimeric IL-5-CD28-CD3ζ receptor to trigger T-cell-mediated killing of eosinophils that are elevated during severe asthma attacks. IL-5-anchored CCAR-T cells exhibited selective and effective killing capacity in vitro and restricted eosinophil differentiation with apparent protection against allergic airway inflammation in two mouse models of asthma. Notably, a single dose of IL-5-anchored CCAR-T cells resulted in persistent protection against asthma-related conditions over three months, significantly exceeding the typical therapeutic window of current mAb-based treatments in the clinics. This study presents a cell-based treatment strategy for SEA and could set the stage for a new era of precision therapies against a variety of intractable allergic diseases in the future.

SUBMITTER: Chen S

PROVIDER: S-EPMC9381771 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Treatment of allergic eosinophilic asthma through engineered IL-5-anchored chimeric antigen receptor T cells.

Chen Sisi S Chen Gaoying G Xu Fang F Sun Beibei B Chen Xinyi X Hu Wei W Li Fei F Syeda Madiha Zahra MZ Chen Haixia H Wu Youqian Y Wu Peng P Jing Ruirui R Geng Xinwei X Zhang Lingling L Tang Longguang L Li Wen W Chen Zhihua Z Zhang Chao C Sun Jie J Chen Wei W Shen Huahao H Ying Songmin S

Cell discovery 20220816 1

Severe eosinophilic asthma (SEA) is a therapy-resistant respiratory condition with poor clinical control. Treatment efficacy and patient compliance of current therapies remain unsatisfactory. Here, inspired by the remarkable success of chimeric antigen receptor-based cellular adoptive immunotherapies demonstrated for the treatment of a variety of malignant tumors, we engineered a cytokine-anchored chimeric antigen receptor T (CCAR-T) cell system using a chimeric IL-5-CD28-CD3ζ receptor to trigge ...[more]

PMID: 35973984

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Project description:BackgroundChimeric antigen receptor engineered T cells (CAR-T) have demonstrated promising clinical efficacy in B-cell malignancies, and the approach has been extended to T-cell malignancies. However, the use of allogeneic T cells in CAR therapy poses a challenge due to the risk of graft-versus-host disease. Recently, natural killer (NK) cells have exhibited "off‑the‑shelf" availability. The nanobody-based CAR structures have attracted much attention for their therapeutic potential owing to the advantages of nanobody, including small size, optimal stability, high affinity and manufacturing feasibility. CD5, a common surface marker of malignant T cells, has three scavenger receptor cysteine-rich domains (D1-D3) in the extracellular region. The present study aims to construct "off‑the‑shelf" CAR-NK cells targeting the membrane-proximal domain of CD5 derived from nanobody against T-cell malignancies.MethodsAnti-CD5-D3 nanobody was screened by phage display technology, followed by constructing fourth-generation CAR plasmids ectopically producing IL-15 to generate CD5 CAR-NK cells derived from peripheral blood. And the second-generation CD5 CAR-T cells based on nanobody were generated, referred to as 5D.b CAR-T and 12 C.b CAR-T. Furthermore, CAR-NK cells without IL-15 (IL-15△ CAR-NK) were generated to assess the impact on cytotoxicity of CAR-NK cells. Cytotoxic activity against CD5+ hematologic malignant cell lines and normal T cells was exerted in vitro and NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt mouse model transplanted with Jurkat-Luc cells was used to evaluate the antitumor efficacy of CD5 CAR-NK cells in vivo.ResultsTwo nanobodies (5D and 12 C) competed for binding to the epitope of CD5-D3. 12 C CAR-NK cells were superior to 5D CAR-NK cells in antitumor potential and 12 C.b CAR-T cells exhibited superior cytotoxic activity than 5D CAR-T cells ex vivo. So, 12 C was regarded as the optimal nanobody. 12 C CAR-NK cells and IL-15△ CAR-NK cells exhibited robust cytotoxicity against CD5+ malignant cell lines and controlled disease progression in xenograft mouse model. 12 C CAR-NK cells demonstrated greater antitumor activity compared to that of IL-15△ CAR-NK cells in vitro and in vivo.ConclusionsTaken together, the fourth-generation nanobody-derived anti-CD5 CAR-NK cells may be a promising therapeutic against T-cell malignancies.

Dataset Information

Treatment of allergic eosinophilic asthma through engineered IL-5-anchored chimeric antigen receptor T cells.

Publications

Treatment of allergic eosinophilic asthma through engineered IL-5-anchored chimeric antigen receptor T cells.

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