Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy

Wu, Wei; Zhou, Qiuping; Masubuchi, Takeya; Shi, Xiaoshan; Li, Hua; Xu, Xiaoxiao; Huang, Min; Li, Meng; He, Xing; Zhu, Hengyu; Gao, Shuaixin; Zhang, Nan; Jing, Ruirui; Sun, Jie; Wang, Haopeng; Hui, Enfu; Wong, Catherine C. L.; Xu, Chenqi

doi:10.1016/j.cell.2020.07.018

Cited by 108 publications

(100 citation statements)

References 70 publications

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“…The molecular mechanism underlying the distinction between the cytolytic and pro‐inflammatory function of T cells is not fully understood. However, a recent study revealed that the alternation of TCR signalling via modulating CD3 subunits can maintain the killing function while reducing the production of pro‐inflammatory cytokines IL‐2, IFN‐γ and TNFα, 26 which were found to be associated with CD25 + PD‐1 + T cells in this study.…”

Section: Discussionmentioning

confidence: 45%

High levels of soluble CD25 in COVID‐19 severity suggest a divergence between anti‐viral and pro‐inflammatory T‐cell responses

et al. 2021

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Objectives We aimed to gain an understanding of the paradox of the immunity in COVID‐19 patients with T cells showing both functional defects and hyperactivation and enhanced proliferation. Methods A total of 280 hospitalised patients with COVID‐19 were evaluated for cytokine profiles and clinical features including viral shedding. A mouse model of acute infection by lymphocytic choriomeningitis virus (LCMV) was applied to dissect the relationship between immunological, virological and pathological features. The results from the mouse model were validated by published data set of single‐cell RNA sequencing (scRNA‐seq) of immune cells in bronchoalveolar lavage fluid (BALF) of COVID‐19 patients. Results The levels of soluble CD25 (sCD25), IL‐6, IL‐8, IL‐10 and TNF‐α were higher in severe COVID‐19 patients than non‐severe cases, but only sCD25 was identified as an independent risk factor for disease severity by multivariable binary logistic regression analysis and showed a positive association with the duration of viral shedding. In agreement with the clinical observation, LCMV‐infected mice with high levels of sCD25 demonstrated insufficient anti‐viral response and delayed viral clearance. The elevation of sCD25 in mice was mainly contributed by the expansion of CD25+CD8+ T cells that also expressed the highest level of PD‐1 with pro‐inflammatory potential. The counterpart human CD25+PD‐1+ T cells were expanded in BALF of COVID‐19 patients with severe disease compared to those with modest disease. Conclusion These results suggest that high levels of sCD25 in COVID‐19 patients probably result from insufficient anti‐viral immunity and indicate an expansion of pro‐inflammatory T cells that contribute to disease severity.

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Section: Discussionmentioning

confidence: 45%

High levels of soluble CD25 in COVID‐19 severity suggest a divergence between anti‐viral and pro‐inflammatory T‐cell responses

et al. 2021

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“…E-cadherin speci cally binds to the NK cell inhibitory receptor KLRG1, which might provide a better solution for NK cell inhibition 30 . A previous study used an elegant design to show that a 28EZ CAR attenuated CAR-T cell activation-induced cell death (AICD) by recapitulating natural CD3ζ dephosphorylation by tethering the CD3ε domain, leading to rapid CD3ζ dephosphorylation and reduced cytokine production 31 . This is in line with our ndings.…”

Section: Discussionmentioning

confidence: 99%

Efficacy-enhanced and cytokine release syndrome-attenuated anti-CD7 universal chimeric antigen receptor-T cell therapy for relapsed/refractory CD7-positive hematological malignancies: A phase I clinical study

Huang¹,

Hu²,

Zhou³

et al. 2021

Preprint

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Chimeric antigen receptor-T cell (CAR-T) therapy in T cell malignancies faces fratricide, T cell aplasia, and product contamination. Here, we successfully developed a universal anti-CD7 CAR-T product (RD13-01). RD13-01 contains a bbzg-CAR comprising an anti-CD7 single-chain variable fragment, a 4-1BB costimulatory domain, a CD3ζ signaling domain, the intracellular domain of the common γ chain, and a natural killer cell inhibitory molecule (E-cadherin). TRAC, CD7 and HLA-II were disrupted to avoid graft versus host disease (GvHD), fratricide and rejection. Bbzg-CAR-T exerted antitumor effects superior to those of conventional CAR-T, while exhibiting reduced cytokine production. Among 11 evaluable relapsed/refractory (r/r) patients, no dose-limited toxicity, GvHD, immune effector cell-associated neurotoxicity or severe cytokine release syndrome (grade≥3) occurred. Nine (82%) showed objective response. For r/r leukemia and NHL, complete response rates were 75% and 33.3% respectively. Outstanding safety and efficacy of this universal CAR-T product was achieved in CD7+ T cell malignancies.

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“…Integration of the cytoplasmic domain of CD3ε with a second-generation CAR could active the anti- tumor effect of CAR-T cells. It is revealed that we could reduce cytokine production of CAR by Csk-recruiting ITAM of CD3ε and produce CAR-T persistence via p85 recruitment of the basic residue rich sequence (BRS) of CD3 (39).…”

Section: Prospectivementioning

confidence: 99%

A narrative review of chimeric antigen receptor-T (CAR-T) cell therapy for lung cancer

Liu¹,

He²

2021

Ann Transl Med

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Lung cancer represents one of the most common and deadliest cancers in the world. Chimeric antigen receptor-T cell (CAR-T) therapy which can recognize antigens in a major histocompatibility complex (MHC)-independent manner provides a new approach for tumor treatment. However, lung cancer, as a solid tumor, faces several formidable barriers to adoptive cell transfer, which includes inhibition of T-cell localization and suppression of T-cell function. Therefore, lung cancer fails to respond significantly to infusions of CAR-T cells in most trials until now. PubMed was researched using the terms "CAR-T" and "lung cancer" only in English from 2000 through June 2020. We also included results presented in international conferences, such as the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO). Besides, we found new progress in CAR-T therapy for solid tumors as a supplement. To enhance the efficacy and conquer the limitations, we collected some applications in lung cancer. In recent years, there have been some improvements in selecting the proper target and reducing toxicity. CAR-T technology provides an excellent way for tumor treatment, which does not depend on MHC molecules and provides a new method for the utilization of tumor targets. Targeting different antigens and overcoming the solid barrier, there are some improvements in responding significantly and reducing toxicity. CAR-T technology will play a decisive role in the treatment of lung cancer.

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Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy

Cited by 108 publications

References 70 publications

High levels of soluble CD25 in COVID‐19 severity suggest a divergence between anti‐viral and pro‐inflammatory T‐cell responses

High levels of soluble CD25 in COVID‐19 severity suggest a divergence between anti‐viral and pro‐inflammatory T‐cell responses

Efficacy-enhanced and cytokine release syndrome-attenuated anti-CD7 universal chimeric antigen receptor-T cell therapy for relapsed/refractory CD7-positive hematological malignancies: A phase I clinical study

A narrative review of chimeric antigen receptor-T (CAR-T) cell therapy for lung cancer

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