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[1]刘纪乐,郭姝婧,孙瑞,等.溶瘤单纯疱疹病毒联合CD19 CAR-T细胞提升[J].天津医科大学学报,2025,31(04):315-321.[doi:10.20135/j.issn.1006-8147.2025.04.0315]
　LIU Jile,GUO Shujing,SUN Rui,et al.Combination of oncolytic herpes simplex virus and CD19 CAR-T cells enhances the therapeutic effect of diffuse large B-cell lymphoma[J].Journal of Tianjin Medical University,2025,31(04):315-321.[doi:10.20135/j.issn.1006-8147.2025.04.0315]
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溶瘤单纯疱疹病毒联合CD19 CAR-T细胞提升(PDF)

《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:
31卷
期数:
2025年04期
页码:
315-321
栏目:
肿瘤疾病专题
出版日期:
2025-07-10

文章信息/Info

Title:
Combination of oncolytic herpes simplex virus and CD19 CAR-T cells enhances the therapeutic effect of diffuse large B-cell lymphoma
文章编号:
1006-8147(2025)04-0315-07
作者:
刘纪乐1; 郭姝婧1; 孙瑞2; 赵茉含1; 安昱欣1; 张金琳1; 赵明峰3
（1.天津医科大学一中心临床学院，天津 300192；2. 南开大学医学院，天津300071；3.天津市第一中心医院血液科，天津 300192）
Author(s):
LIU Jile1;  GUO Shujing1;  SUN Rui2;  ZHAO Mohan1;  AN Yuxin1;  ZHANG Jinlin1;  ZHAO Mingfeng3
（1. First Center Clinical College， Tianjin Medical University， Tianjin 300192，China；2. School of Medicine， Nankai University， Tianjin 300071， China；3. Department of Hematology， Tianjin First Central Hospital， Tianjin 300192， China）
关键词:
溶瘤单纯疱疹病毒; CD19 CAR-T细胞; B细胞淋巴瘤; 弥漫大B细胞淋巴瘤; 肿瘤微环境
Keywords:
oncolytic herpes simplex virus;  CD19 CAR-T cells;  B-cell lymphoma;  diffuse large B-cell lymphoma;  tumor microenvironment
分类号:
R733.4
DOI:
10.20135/j.issn.1006-8147.2025.04.0315
文献标志码:
A
摘要:
目的：探究溶瘤单纯疱疹病毒（oHSV）和CD19 CAR-T细胞联合治疗弥漫大B细胞淋巴瘤的疗效以及CD19 CAR-T细胞是否为oHSV的良好载体。方法：将oHSV与CD19 CAR-T细胞共培养，制备携带oHSV的CD19 CAR-T细胞（CD19 CAR-ToHSV细胞）。通过细胞增殖实验、细胞杀伤实验以及重要指标如细胞因子、细胞亚群、耗竭表型的测定，评估体外CD19 CAR-ToHSV细胞相较于CD19 CAR-T细胞的抗肿瘤效果和功能。构建弥漫大B肿瘤细胞系小鼠模型，比较未转导T细胞组、CD19 CAR-T细胞组和CD19 CAR-ToHSV细胞组小鼠瘤体变化和重要脏器指标，探究CD19 CAR-ToHSV细胞在体内的安全性和有效性。结果：成功制备出CD19 CAR-ToHSV细胞。体外实验发现，与CD19 CAR-T细胞相比，CD19 CAR-ToHSV细胞表现出更强的抗肿瘤效果（t24 h=2.989，P<0.05；t48 h=8.525，P<0.01）。联合治疗促进了干扰素（IFN）-γ的分泌（t=4.578，P<0.05），并降低CD19 CAR-T细胞表面PD-1的表达（t=2.946，P<0.05）。在小鼠模型中，CD19 CAR-ToHSV只感染肿瘤，不影响其他脏器功能，显示出安全性。同时，CAR-ToHSV细胞组瘤体质量显著小于CD19 CAR-T细胞组（t=6.010，P<0.01）。免疫组化也发现，CD19 CAR-T细胞和oHSV的联合治疗促进了CAR-T细胞向肿瘤的浸润（t=12.68，P<0.001）。结论：CD19 CAR-T细胞可以作为oHSV的良好载体。CD19 CAR-ToHSV细胞治疗可安全且有效提升弥漫大B细胞淋巴瘤治疗效果。
Abstract:
Objective： To explore the efficacy of combined treatment with oncolytic herpes simplex virus （oHSV） and CD19 CAR-T cells in diffuse large B-cell lymphoma（DLBCL）， and determine whether CD19 CAR-T cells can serve as a good carrier for oHSV. Methods： CD19 CAR-T cells were co-cultured with oHSV to prepare CD19 CAR-T cells carrying oHSV（CD19 CAR-ToHSV cells）. The anti-tumor effect and function of CD19 CAR-ToHSV cells were evaluated in vitro compared to CD19 CAR-T cells through cell proliferation assays， cytotoxicity assays， and the determination of important indicators such as cytokines， cell subsets， and exhaustion phenotypes. A mouse model of DLBCL was established to compare the tumor growth and important organ function in mice treated with non-transduced T cells， CD19 CAR-T cells， and CD19 CAR-ToHSV cells， and to investigate the safety and efficacy of CD19 CAR-ToHSV cells in vivo. Results： CD19 CAR-ToHSV cells were successfully prepared. In vitro experiments showed that CD19 CAR-ToHSV cells exhibited stronger anti-tumor effects compared with CD19 CAR-T cells（t24 h=2.989，P<0.05； t48 h=8.525， P<0.01）. The combined treatment promoted the secretion of interferon（IFN）-γ （t=4.578， P<0.05） and reduced the expression of PD-1 on the surface of CD19 CAR-T cells （t=2.946， P<0.05）. In the mouse model， CD19 CAR-ToHSV cells showed safety by only infecting tumors but not affecting the function of other organs， demonstrating safety. Additionally， the tumor weight in the CAR-ToHSV cells group was significantly lower than that in the CD19 CAR-T cells group （t=6.010， P<0.01）. Immunohistochemistry also revealed that the combined treatment of CD19 CAR-T cells and oHSV promoted the infiltration of CAR-T cells into tumors（t=12.68， P<0.001）. Conclusion： CD19 CAR-T cells can serve as a good carrier for oHSV. The treatment with CD19 CAR-ToHSV cells can safely and effectively enhance the therapeutic effect on diffuse large B-cell lymphoma.

参考文献/References:

[1] SHAH N N， LEE D W， YATES B， et al. Long-term follow-up of CD19-CAR T-cell therapy in children and young adults with B-ALL [J]. J Clin Oncol， 2021， 39（15）： 1650-1659.
[2] QI Y， ZHAO M， HU Y， et al. Efficacy and safety of CD19-specific CAR T cell-based therapy in B-cell acute lymphoblastic leukemia patients with CNSL [J]. Blood， 2022， 139（23）： 3376-3386.
[3] ABRAMSON J S， PALOMBA M L， GORDON L I， et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas （TRANSCEND NHL 001）： a multicentre seamless design study [J]. Lancet， 2020， 396（10254）： 839-852.
[4] TESTA U， LEONE G， PELOSI E， et al. CAR-T Cell therapy in large B cell lymphoma [J]. Mediterr J Hematol Infect Dis， 2023， 15（1）： e2023066.
[5] LOCKE F L， FILOSTO S， CHOU J， et al. Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemoth-erapy and transplant in large B cell lymphoma [J]. Nat Med， 2024， 30（2）： 507-518.
[6] AUTIO M， LEIVONEN S K， BR?譈CK O， et al. Clinical impact of immune cells and their spatial interactions in diffuse large B-cell lymphoma microenvironment [J]. Clin Cancer Res， 2022， 28（4）： 781-792.
[7] KLINE J， GODFREY J， ANSELL S M. The immune landscape and response to immune checkpoint blockade therapy in lymphoma[J]. Blood， 2020， 135（8）： 523-533.
[8] LAN Q， XIA S， WANG Q， et al. Development of oncolytic virotherapy： from genetic modification to combination therapy[J]. Front Med， 2020， 14（2）： 160-184.
[9] SAMSON A， SCOTT K J， TAGGART D， et al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade[J]. Sci Transl Med， 2018， 10（422）：eaam7577.
[10] LI L， LIU S， HAN D， et al. Delivery and biosafety of oncolytic virotherapy[J]. Front Oncol， 2020， 10： 475.
[11] FARES J， AHMED A U， ULASOV I V， et al. Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant gli-oma： a first-in-human， phase 1， dose-escalation trial[J]. Lancet Oncol， 2021， 22（8）： 1103-1114.
[12] QIAO J， WANG H， KOTTKE T， et al. Loading of oncolytic vesicular stomatitis virus onto antigen-specific T cells enhances the efficacy of adoptive T-cell therapy of tumors [J]. Gene Ther， 2008， 15（8）： 604-616.
[13] CHASTKOFSKY M I， PITUCH K C， KATAGI H， et al. Mesenchymal Stem cells successfully deliver oncolytic virotherapy to diffuse intrinsic pontine glioma [J]. Clin Cancer Res， 2021， 27（6）： 1766-1777.
[14] EVGIN L， KOTTKE T， TONNE J， et al. Oncolytic virus-mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice [J]. Sci Transl Med， 2022， 14（640）： eabn2231.
[15] ZHENG N， FANG J， XUE G， et al. Induction of tumor cell autosis by myxoma virus-infected CAR-T and TCR-T cells to overcome primary and acquired resistance[J]. Cancer cell， 2022， 40（9）： 973-985.
[16] VANSEGGELEN H， TANTALO D G， AFSAHI A， et al. Chimeric antigen receptor-engineered T cells as oncolytic virus carriers[J]. Mol Ther Oncolytics， 2015， 2： 15014.

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备注/Memo

备注/Memo:
基金项目:国家自然科学基金面上项目（81970180）
作者简介:刘纪乐（2000-），男，硕士在读，研究方向：血液系统恶性肿瘤的细胞免疫疗法；通信作者：赵明峰，E-mail：mingfengzhao@sina.com。
更新日期/Last Update: 2025-07-10