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工程化细胞因子信号转导以改善 CAR T 细胞效应功能。

Engineered Cytokine Signaling to Improve CAR T Cell Effector Function.

机构信息

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, United States.

Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN, United States.

出版信息

Front Immunol. 2021 Jun 4;12:684642. doi: 10.3389/fimmu.2021.684642. eCollection 2021.


DOI:10.3389/fimmu.2021.684642
PMID:34177932
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8220823/
Abstract

Adoptive immunotherapy with T cells genetically modified to express chimeric antigen receptors (CARs) is a promising approach to improve outcomes for cancer patients. While CAR T cell therapy is effective for hematological malignancies, there is a need to improve the efficacy of this therapeutic approach for patients with solid tumors and brain tumors. At present, several approaches are being pursued to improve the antitumor activity of CAR T cells including i) targeting multiple antigens, ii) improving T cell expansion/persistence, iii) enhancing homing to tumor sites, and iv) rendering CAR T cells resistant to the immunosuppressive tumor microenvironment (TME). Augmenting signal 3 of T cell activation by transgenic expression of cytokines or engineered cytokine receptors has emerged as a promising strategy since it not only improves CAR T cell expansion/persistence but also their ability to function in the immunosuppressive TME. In this review, we will provide an overview of cytokine biology and highlight genetic approaches that are actively being pursued to augment cytokine signaling in CAR T cells.

摘要

过继性免疫疗法采用基因修饰的 T 细胞表达嵌合抗原受体 (CAR),是改善癌症患者预后的一种有前途的方法。虽然 CAR T 细胞疗法对血液系统恶性肿瘤有效,但需要提高该治疗方法对实体瘤和脑肿瘤患者的疗效。目前,正在采取几种方法来提高 CAR T 细胞的抗肿瘤活性,包括:i)靶向多个抗原;ii)改善 T 细胞扩增/持久性;iii)增强向肿瘤部位归巢;以及 iv)使 CAR T 细胞抵抗免疫抑制性肿瘤微环境 (TME)。通过转基因表达细胞因子或工程细胞因子受体来增强 T 细胞激活的信号 3 已成为一种很有前途的策略,因为它不仅改善了 CAR T 细胞的扩增/持久性,而且提高了它们在免疫抑制性 TME 中发挥功能的能力。在这篇综述中,我们将概述细胞因子生物学,并重点介绍正在积极探索的基因方法,以增强 CAR T 细胞中的细胞因子信号。

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Engineered Cytokine Signaling to Improve CAR T Cell Effector Function.

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本文引用的文献

[1]
A Chimeric GM-CSF/IL18 Receptor to Sustain CAR T-cell Function.

Cancer Discov. 2021-7

[2]
Enhanced CAR-T activity against established tumors by polarizing human T cells to secrete interleukin-9.

Nat Commun. 2020-11-19

[3]
JAK-STAT Domain Enhanced MUC1-CAR-T Cells Induced Esophageal Cancer Elimination.

Cancer Manag Res. 2020-10-8

[4]
Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis.

Nat Med. 2020-11

[5]
Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia.

J Immunother Cancer. 2020-9

[6]
Coexpression of IL7 and CCL21 Increases Efficacy of CAR-T Cells in Solid Tumors without Requiring Preconditioned Lymphodepletion.

Clin Cancer Res. 2020-10-15

[7]
Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma.

J Clin Oncol. 2020-11-10

[8]
IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy.

Nature. 2020-6-24

[9]
Cytokine IL-36γ improves CAR T-cell functionality and induces endogenous antitumor response.

Leukemia. 2021-2

[10]
Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity.

Nat Immunol. 2020-5-18

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