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4-1BB 信号增强了嵌合抗原受体修饰的 CD28 整合第二代 T 细胞的抗肿瘤活性。

4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2 Generation Chimeric Antigen Receptor-Modified T Cells.

机构信息

Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, China.

出版信息

Front Immunol. 2020 Nov 13;11:539654. doi: 10.3389/fimmu.2020.539654. eCollection 2020.

DOI:10.3389/fimmu.2020.539654
PMID:33281809
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7691374/
Abstract

While chimeric antigen receptor-modified T (CAR-T) cells have shown great success for the treatment of B cell leukemia, their efficacy appears to be compromised in B cell derived lymphoma and solid tumors. Optimization of the CAR design to improve persistence and cytotoxicity is a focus of the current CAR-T study. Herein, we established a novel CAR structure by adding a full length 4-1BB co-stimulatory receptor to a 28Z-based second generation CAR that targets CD20. Our data indicated that this new 2028Z-4-1BB CAR-T cell showed improved proliferation and cytotoxic ability. To further understand the mechanism of action, we found that constitutive 4-1BB sensing significantly reduced the apoptosis of CAR-T cells, enhanced proliferation, and increased NF-κB pathway activation. Consistent with the enhanced proliferation and cytotoxicity , this new structure of CAR-T cells exhibited robust persistence and anti-tumor activity in a mouse xenograft lymphoma model. This work provides evidence for a new strategy to optimize the function of CAR-T against lymphoma.

摘要

嵌合抗原受体修饰的 T（CAR-T）细胞在治疗 B 细胞白血病方面取得了巨大成功，但在 B 细胞来源的淋巴瘤和实体瘤中的疗效似乎受到了影响。优化 CAR 设计以提高持久性和细胞毒性是当前 CAR-T 研究的重点。在此，我们通过在靶向 CD20 的基于 28Z 的第二代 CAR 上添加全长 4-1BB 共刺激受体，建立了一种新型的 CAR 结构。我们的数据表明，这种新型的 2028Z-4-1BB CAR-T 细胞显示出改善的增殖和细胞毒性能力。为了进一步了解作用机制，我们发现组成型 4-1BB 感应显著降低了 CAR-T 细胞的凋亡，增强了增殖，并增加了 NF-κB 通路的激活。与增强的增殖和细胞毒性一致，这种新型 CAR-T 细胞在小鼠异种移植淋巴瘤模型中表现出强大的持久性和抗肿瘤活性。这项工作为优化 CAR-T 对抗淋巴瘤的功能提供了新的策略证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/a3fb3303c1b5/fimmu-11-539654-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/3666d3fb789b/fimmu-11-539654-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/1680f7c97fbb/fimmu-11-539654-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/77183c53aea8/fimmu-11-539654-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/0dd5474622e4/fimmu-11-539654-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/869b0d740f94/fimmu-11-539654-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/a3fb3303c1b5/fimmu-11-539654-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/3666d3fb789b/fimmu-11-539654-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/1680f7c97fbb/fimmu-11-539654-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/77183c53aea8/fimmu-11-539654-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/0dd5474622e4/fimmu-11-539654-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/869b0d740f94/fimmu-11-539654-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0166/7691374/a3fb3303c1b5/fimmu-11-539654-g006.jpg

相似文献

[1]
4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2 Generation Chimeric Antigen Receptor-Modified T Cells.

Front Immunol. 2020

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[10]
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[3]
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[4]
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[5]
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J Immunother Cancer. 2025-1-25

[6]
[The mechanisms and salvage treatment strategies underlying positive relapse following CD19 CAR-T cell therapy in B-acute lymphoblastic leukemia].

Zhonghua Xue Ye Xue Za Zhi. 2024-10-14

[7]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells.

Cancer Cell. 2020-1-30

[2]
Mechanisms of Relapse After CD19 CAR T-Cell Therapy for Acute Lymphoblastic Leukemia and Its Prevention and Treatment Strategies.

Front Immunol. 2019-11-12

[3]
Production and Application of Multicistronic Constructs for Various Human Disease Therapies.

Pharmaceutics. 2019-11-6

[4]
Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR.

Nat Med. 2019-9-2

[5]
CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity.

Nat Biotechnol. 2019-7-22

[6]
Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity.

Nat Commun. 2019-5-20

[7]
A safe and potent anti-CD19 CAR T cell therapy.

Nat Med. 2019-4-22

[8]
Combined CD28 and 4-1BB Costimulation Potentiates Affinity-tuned Chimeric Antigen Receptor-engineered T Cells.

Clin Cancer Res. 2019-7-1

[9]
CD40 Ligand-Modified Chimeric Antigen Receptor T Cells Enhance Antitumor Function by Eliciting an Endogenous Antitumor Response.

Cancer Cell. 2019-3-18

[10]
Controversies in the Treatment of Classical Hodgkin Lymphoma.

Hemasphere. 2018-10

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