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干细胞记忆 EBV 特异性 T 细胞控制 EBV 肿瘤生长并在体内持续存在。

Stem cell memory EBV-specific T cells control EBV tumor growth and persist in vivo.

机构信息

Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.

Cellular Immunotherapy, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.

出版信息

Sci Adv. 2024 Aug 23;10(34):eado2048. doi: 10.1126/sciadv.ado2048.

DOI:10.1126/sciadv.ado2048
PMID:39178248
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11343021/
Abstract

Adoptive T cell therapy (ACT), the therapeutic transfer of defined T cell immunity to patients, offers great potential in the fight against different human diseases including difficult-to-treat viral infections, but persistence and longevity of the cells are areas of concern. Very-early-differentiated stem cell memory T cells (T) have superior self-renewal, engraftment, persistence, and anticancer efficacy, but their potential for antiviral ACT remains unknown. Here, we developed a clinically scalable protocol for expanding Epstein-Barr virus (EBV)-specific T-enriched T cells with high proportions of CD4 T cells and broad EBV antigen coverage. These cells showed tumor control in a xenograft model of EBV-induced lymphoma and were superior to previous ACT protocols in terms of tumor infiltration, in vivo proliferation, persistence, proportion of functional CD4 T cells, and diversity of EBV antigen specificity. Thus, our protocol may pave the way for the next generation of potent unmodified antigen-specific cell therapies for EBV-associated diseases, including tumors, and other indications.

摘要

过继性 T 细胞疗法（ACT），即将特定的 T 细胞免疫转移给患者的治疗方法，在对抗包括难以治疗的病毒感染在内的各种人类疾病方面具有巨大的潜力，但细胞的持久性和寿命是人们关注的领域。非常早期分化的干细胞记忆 T 细胞（T 细胞）具有优越的自我更新、植入、持久性和抗癌功效，但它们在抗病毒 ACT 中的潜力尚不清楚。在这里，我们开发了一种临床可扩展的方案，用于扩增 EBV 特异性 T 细胞富集的 T 细胞，其中包含高比例的 CD4 T 细胞和广泛的 EBV 抗原覆盖范围。这些细胞在 EBV 诱导的淋巴瘤异种移植模型中显示出肿瘤控制作用，并且在肿瘤浸润、体内增殖、持久性、功能性 CD4 T 细胞比例和 EBV 抗原特异性多样性方面优于先前的 ACT 方案。因此，我们的方案可能为下一代针对 EBV 相关疾病（包括肿瘤和其他适应症）的未经修饰的抗原特异性细胞疗法铺平道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/b8f99faa9417/sciadv.ado2048-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/5d2274f54950/sciadv.ado2048-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/7992a188268a/sciadv.ado2048-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/0413916505da/sciadv.ado2048-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/d01b8e7b3eeb/sciadv.ado2048-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/f8a338e8c80b/sciadv.ado2048-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/626b9ed9da46/sciadv.ado2048-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/edd7fb4bbce3/sciadv.ado2048-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/b8f99faa9417/sciadv.ado2048-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/5d2274f54950/sciadv.ado2048-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/7992a188268a/sciadv.ado2048-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/0413916505da/sciadv.ado2048-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/d01b8e7b3eeb/sciadv.ado2048-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/f8a338e8c80b/sciadv.ado2048-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/626b9ed9da46/sciadv.ado2048-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/edd7fb4bbce3/sciadv.ado2048-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d0/11343021/b8f99faa9417/sciadv.ado2048-f8.jpg

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[1]
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引用本文的文献

[1]
Epstein-Barr virus-specific T-cell response in pediatric liver transplant recipients: a cross-sectional study by multiparametric flow cytometry.

Front Immunol. 2024

本文引用的文献

[1]
Third-party virus-specific T cells for the treatment of double-stranded DNA viral reactivation and posttransplant lymphoproliferative disease after solid organ transplant.

Am J Transplant. 2024-9

[2]
Cotargeting EBV lytic as well as latent cycle antigens increases T-cell potency against lymphoma.

Blood Adv. 2024-7-9

[3]
Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial.

Lancet Oncol. 2024-3

[4]
A method for polyclonal antigen-specific T cell-targeted genome editing (TarGET) for adoptive cell transfer applications.

Mol Ther Methods Clin Dev. 2023-6-19

[5]
Naive T cells inhibit the outgrowth of intractable antigen-activated memory T cells: implications for T-cell immunotherapy.

J Immunother Cancer. 2023-4

[6]
Posoleucel, an Allogeneic, Off-the-Shelf Multivirus-Specific T-Cell Therapy, for the Treatment of Refractory Viral Infections in the Post-HCT Setting.

Clin Cancer Res. 2023-1-17

[7]
Immunocompromised host section: Adoptive T-cell therapy for dsDNA viruses in allogeneic hematopoietic cell transplant recipients.

Curr Opin Infect Dis. 2022-8-1

[8]
Stem cell like memory T cells: A new paradigm in cancer immunotherapy.

Clin Immunol. 2022-8

[9]
Rapid single-cell identification of Epstein-Barr virus-specific T-cell receptors for cellular therapy.

Cytotherapy. 2022-8

[10]
Clonal dynamics of tumor-infiltrating T-cell receptor beta-chain repertoires in the peripheral blood in response to concurrent chemoradiotherapy for Epstein-Barr virus-associated nasopharyngeal carcinoma.

Oncoimmunology. 2021

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