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一种用于治疗 T 细胞血液系统恶性肿瘤的现成型抗自杀 CAR-T。

An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies.

机构信息

Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Department of Internal Medicine, Division of Dermatology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

出版信息

Leukemia. 2018 Sep;32(9):1970-1983. doi: 10.1038/s41375-018-0065-5. Epub 2018 Feb 20.

DOI:10.1038/s41375-018-0065-5
PMID:29483708
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6102094/
Abstract

T cell malignancies represent a group of hematologic cancers with high rates of relapse and mortality in patients for whom no effective targeted therapies exist. The shared expression of target antigens between chimeric antigen receptor (CAR) T cells and malignant T cells has limited the development of CAR-T because of unintended CAR-T fratricide and an inability to harvest sufficient autologous T cells. Here, we describe a fratricide-resistant "off-the-shelf" CAR-T (or UCART7) that targets CD7+ T cell malignancies and, through CRISPR/Cas9 gene editing, lacks both CD7 and T cell receptor alpha chain (TRAC) expression. UCART7 demonstrates efficacy against human T cell acute lymphoblastic leukemia (T-ALL) cell lines and primary T-ALL in vitro and in vivo without the induction of xenogeneic GvHD. Fratricide-resistant, allo-tolerant "off-the-shelf" CAR-T represents a strategy for treatment of relapsed and refractory T-ALL and non-Hodgkin's T cell lymphoma without a requirement for autologous T cells.

摘要

T 细胞恶性肿瘤是一组血液系统癌症，患者复发率和死亡率高，目前尚无有效的靶向治疗方法。嵌合抗原受体 (CAR) T 细胞和恶性 T 细胞之间共同表达的靶抗原限制了 CAR-T 的发展，因为意外的 CAR-T 自相残杀和无法收获足够的自体 T 细胞。在这里，我们描述了一种抗自相残杀的“现成”CAR-T（或 UCART7），它靶向 CD7+T 细胞恶性肿瘤，并通过 CRISPR/Cas9 基因编辑，缺乏 CD7 和 T 细胞受体α链 (TRAC) 的表达。UCART7 在体外和体内均对人 T 细胞急性淋巴细胞白血病 (T-ALL) 细胞系和原发性 T-ALL 有效，而不会诱导异种移植物抗宿主病 (GvHD)。抗自相残杀、同种异体耐受的“现成”CAR-T 代表了一种治疗复发和难治性 T-ALL 和非霍奇金淋巴瘤的策略，而无需自体 T 细胞。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/689539212721/nihms939559f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/c00dd3094085/nihms939559f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/2ba41661370f/nihms939559f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/0ac6b31ca524/nihms939559f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/9aac2bb4702f/nihms939559f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/2066bbc5d8d9/nihms939559f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/689539212721/nihms939559f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/c00dd3094085/nihms939559f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/2ba41661370f/nihms939559f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/0ac6b31ca524/nihms939559f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/9aac2bb4702f/nihms939559f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/2066bbc5d8d9/nihms939559f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3cf/6102094/689539212721/nihms939559f6.jpg

相似文献

[1]
An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies.

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[2]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
production of CAR T cell: Opportunities and challenges.

Genes Dis. 2025-3-25

[2]
CD7 CAR-T therapy: current developments, improvements, and dilemmas.

Blood Sci. 2025-8-5

[3]
Surface downmodulation of TIM3 safeguards healthy cells but not acute myeloid leukemia from CAR T-cell therapy.

Hemasphere. 2025-7-13

[4]
CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia.

J Hematol Oncol. 2025-7-1

[5]
The Problem of Molecular Target Choice for CAR-T Cells in Acute Myeloid Leukemia Therapy.

Int J Mol Sci. 2025-6-6

[6]
HPV-driven cancers: a looming threat and the potential of CRISPR/Cas9 for targeted therapy.

Virol J. 2025-5-22

[7]
CAR-T Cell Therapy: Managing Side Effects and Overcoming Challenges.

Adv Biomed Res. 2025-4-30

[8]
Addressing graft-versus-host disease in allogeneic cell-based immunotherapy for cancer.

Exp Hematol Oncol. 2025-5-2

[9]
CAR T-cells for acute leukemias in children: current status, challenges, and future directions.

Cancer Metastasis Rev. 2025-4-23

[10]
Clinical development of allogeneic chimeric antigen receptor αβ-T cells.

Mol Ther. 2025-6-4

本文引用的文献

[1]
Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies.

Blood Adv. 2017-11-21

[2]
CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies.

Blood. 2017-7-20

[3]
Integration of a CD19 CAR into the TCR Alpha Chain Locus Streamlines Production of Allogeneic Gene-Edited CAR T Cells.

Mol Ther. 2017-4-5

[4]
Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection.

Nature. 2017-3-2

[5]
Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells.

Sci Transl Med. 2017-1-25

[6]
T-cell lymphomas, a challenging disease: types, treatments, and future.

Int J Clin Oncol. 2017-2

[7]
Pediatric T-cell acute lymphoblastic leukemia.

Genes Chromosomes Cancer. 2017-2

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CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date.

Blood. 2016-6-30

[9]
High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects.

Nature. 2016-1-28

[10]
Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells.

Leukemia. 2015-11-3

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