CD40 配体修饰的嵌合抗原受体 T 细胞通过引发内源性抗肿瘤反应增强抗肿瘤功能。
CD40 Ligand-Modified Chimeric Antigen Receptor T Cells Enhance Antitumor Function by Eliciting an Endogenous Antitumor Response.
机构信息
Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
出版信息
Cancer Cell. 2019 Mar 18;35(3):473-488.e6. doi: 10.1016/j.ccell.2019.02.006.
Abstract
Chimeric antigen receptor (CAR) T cells provide great efficacy in B cell malignancies. However, improved CAR T cell therapies are still needed. Here, we engineered tumor-targeted CAR T cells to constitutively express the immune-stimulatory molecule CD40 ligand (CD40L) and explored efficacy in different mouse leukemia/lymphoma models. We observed that CD40L CAR T cells circumvent tumor immune escape via antigen loss through CD40/CD40L-mediated cytotoxicity and induction of a sustained, endogenous immune response. After adoptive cell transfer, the CD40L CAR T cells displayed superior antitumor efficacy, licensed antigen-presenting cells, enhanced recruitment of immune effectors, and mobilized endogenous tumor-recognizing T cells. These effects were absent in Cd40 mice and provide a rationale for the use of CD40L CAR T cells in cancer treatment.
摘要
嵌合抗原受体 (CAR) T 细胞在 B 细胞恶性肿瘤中具有显著疗效。然而，仍需要改进 CAR T 细胞疗法。在这里，我们设计了靶向肿瘤的 CAR T 细胞，使其持续表达免疫刺激性分子 CD40 配体 (CD40L)，并在不同的小鼠白血病/淋巴瘤模型中探索其疗效。我们观察到 CD40L CAR T 细胞通过 CD40/CD40L 介导的细胞毒性和诱导持续的内源性免疫反应，规避了抗原丢失导致的肿瘤免疫逃逸。在过继细胞转移后，CD40L CAR T 细胞表现出优越的抗肿瘤疗效，许可抗原呈递细胞，增强免疫效应细胞的募集，并动员内源性肿瘤识别 T 细胞。在 Cd40 小鼠中观察不到这些效应，为 CD40L CAR T 细胞在癌症治疗中的应用提供了理论依据。
相似文献
1
CD40 Ligand-Modified Chimeric Antigen Receptor T Cells Enhance Antitumor Function by Eliciting an Endogenous Antitumor Response.CD40 配体修饰的嵌合抗原受体 T 细胞通过引发内源性抗肿瘤反应增强抗肿瘤功能。
Cancer Cell. 2019 Mar 18;35(3):473-488.e6. doi: 10.1016/j.ccell.2019.02.006.
2
CD103 cDC1 and endogenous CD8 T cells are necessary for improved CD40L-overexpressing CAR T cell antitumor function.CD103cDC1 和内源性 CD8 T 细胞对于提高过表达 CD40L 的 CAR-T 细胞抗肿瘤功能是必要的。
Nat Commun. 2020 Dec 2;11(1):6171. doi: 10.1038/s41467-020-19833-3.
3
Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression.通过组成性表达CD40L增强嵌合抗原受体T细胞的抗肿瘤功效。
Mol Ther. 2015 Apr;23(4):769-78. doi: 10.1038/mt.2015.4. Epub 2015 Jan 13.
4
Cytokine IL-36γ improves CAR T-cell functionality and induces endogenous antitumor response.细胞因子 IL-36γ 可改善 CAR T 细胞功能并诱导内源性抗肿瘤反应。
Leukemia. 2021 Feb;35(2):506-521. doi: 10.1038/s41375-020-0874-1. Epub 2020 May 23.
5
Chimeric antigen receptor T cells engineered to secrete CD40 agonist antibodies enhance antitumor efficacy.经基因工程改造以分泌CD40激动剂抗体的嵌合抗原受体T细胞可增强抗肿瘤疗效。
J Transl Med. 2021 Feb 18;19(1):82. doi: 10.1186/s12967-021-02750-4.
6
PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations.PD-L1 靶向高亲和力 NK（t-haNK）细胞可诱导直接抗肿瘤作用，并靶向抑制性 MDSC 群体。
J Immunother Cancer. 2020 May;8(1). doi: 10.1136/jitc-2019-000450.
7
Double Strike Approach for Tumor Attack: Engineering T Cells Using a CD40L:CD28 Chimeric Co-Stimulatory Switch Protein for Enhanced Tumor Targeting in Adoptive Cell Therapy.双管齐下的肿瘤攻击策略：利用 CD40L:CD28 嵌合共刺激开关蛋白工程化 T 细胞，以增强过继细胞治疗中的肿瘤靶向性。
Front Immunol. 2021 Nov 29;12:750478. doi: 10.3389/fimmu.2021.750478. eCollection 2021.
8
Multispecific Targeting with Synthetic Ankyrin Repeat Motif Chimeric Antigen Receptors.多特异性靶向的合成锚蛋白重复序列嵌合抗原受体。
Clin Cancer Res. 2019 Dec 15;25(24):7506-7516. doi: 10.1158/1078-0432.CCR-19-1479. Epub 2019 Sep 23.
9
4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2 Generation Chimeric Antigen Receptor-Modified T Cells.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。
Front Immunol. 2020 Nov 13;11:539654. doi: 10.3389/fimmu.2020.539654. eCollection 2020.
10
Chimeric antigen receptor-engineered T-cell therapy for liver cancer.嵌合抗原受体修饰的 T 细胞治疗肝癌。
Hepatobiliary Pancreat Dis Int. 2018 Aug;17(4):301-309. doi: 10.1016/j.hbpd.2018.05.005. Epub 2018 May 24.
引用本文的文献
1
The spontaneous neoantigen-specific CD4 T-cell response to a growing tumor is functionally and phenotypically diverse.对生长中的肿瘤的自发新抗原特异性CD4 T细胞反应在功能和表型上是多样的。
J Immunother Cancer. 2025 Sep 4;13(9):e012209. doi: 10.1136/jitc-2025-012209.
2
Anti-Her2 CAR-NK92 Cells and Their Exosomes: Generation, Characterization, and Selective Cytotoxicity Against Her2-Positive Tumor Cells.抗Her2嵌合抗原受体自然杀伤细胞系NK92及其外泌体：生成、表征及对Her2阳性肿瘤细胞的选择性细胞毒性
Int J Mol Sci. 2025 Aug 7;26(15):7648. doi: 10.3390/ijms26157648.
3
Off-target effects in CRISPR-Cas genome editing for human therapeutics: Progress and challenges.用于人类治疗的CRISPR-Cas基因组编辑中的脱靶效应：进展与挑战。
Mol Ther Nucleic Acids. 2025 Jul 17;36(3):102636. doi: 10.1016/j.omtn.2025.102636. eCollection 2025 Sep 9.
4
Advances and obstacles of T cell-based immunotherapy in gynecological malignancies.基于T细胞的免疫疗法在妇科恶性肿瘤中的进展与障碍
Mol Cancer. 2025 Jul 26;24(1):207. doi: 10.1186/s12943-025-02411-w.
5
Resistance Mechanisms to BCMA Targeting Bispecific Antibodies and CAR T-Cell Therapies in Multiple Myeloma.多发性骨髓瘤中针对BCMA的双特异性抗体和CAR T细胞疗法的耐药机制
Cells. 2025 Jul 15;14(14):1077. doi: 10.3390/cells14141077.
6
Novel immunotargets in multiple myeloma: biological relevance and therapeutic potential.多发性骨髓瘤中的新型免疫靶点：生物学相关性与治疗潜力
Biomark Res. 2025 Jul 1;13(1):92. doi: 10.1186/s40364-025-00799-7.
7
Tumour-associated vasculature in T cell homing and immunity: opportunities for cancer therapy.肿瘤相关血管在T细胞归巢与免疫中的作用：癌症治疗的机遇
Nat Rev Immunol. 2025 Jun 27. doi: 10.1038/s41577-025-01187-w.
8
Innovative approaches to CAR-T cell therapy: the role of lipid metabolism pathways.嵌合抗原受体T细胞（CAR-T）疗法的创新方法：脂质代谢途径的作用
J Transl Med. 2025 Jun 17;23(1):670. doi: 10.1186/s12967-025-06718-6.
9
Application and recent advances in conventional biomarkers for the prognosis of papillary thyroid carcinoma.传统生物标志物在甲状腺乳头状癌预后评估中的应用及最新进展
Front Oncol. 2025 May 21;15:1598934. doi: 10.3389/fonc.2025.1598934. eCollection 2025.
10
Unraveling the role of M2 TAMs in ovarian cancer dynamics: a systematic review.解析M2肿瘤相关巨噬细胞在卵巢癌动态变化中的作用：一项系统综述
J Transl Med. 2025 Jun 3;23(1):623. doi: 10.1186/s12967-025-06643-8.
本文引用的文献
1
Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity.Fc 工程化抗 CD40 抗体的毒性通过瘤内注射被消除，导致持久的抗肿瘤免疫。
Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):11048-11053. doi: 10.1073/pnas.1810566115. Epub 2018 Oct 8.
2
CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.嵌合抗原受体 T 细胞引起的细胞因子释放综合征是由巨噬细胞介导的，并可通过白细胞介素-1 阻断来减轻。
Nat Med. 2018 Jun;24(6):731-738. doi: 10.1038/s41591-018-0041-7. Epub 2018 May 28.
3
Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System.工程化的肿瘤靶向 T 细胞通过直接作用和激活内源性免疫系统来增强抗肿瘤疗效。
Cell Rep. 2018 May 15;23(7):2130-2141. doi: 10.1016/j.celrep.2018.04.051.
4
Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia.急性淋巴细胞白血病中CD19嵌合抗原受体疗法的长期随访
N Engl J Med. 2018 Feb 1;378(5):449-459. doi: 10.1056/NEJMoa1709919.
5
Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia.替沙格赛定用于治疗儿童和年轻成人B细胞淋巴细胞白血病
N Engl J Med. 2018 Feb 1;378(5):439-448. doi: 10.1056/NEJMoa1709866.
6
Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation.通过 ICOS 和 4-1BB 共刺激增强 CAR T 细胞的持久性。
JCI Insight. 2018 Jan 11;3(1). doi: 10.1172/jci.insight.96976.
7
TIM-3 Regulates CD103 Dendritic Cell Function and Response to Chemotherapy in Breast Cancer.TIM-3 调节乳腺癌树突状细胞的功能和对化疗的反应。
Cancer Cell. 2018 Jan 8;33(1):60-74.e6. doi: 10.1016/j.ccell.2017.11.019.
8
Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.阿基仑赛注射液嵌合抗原受体T细胞疗法治疗难治性大B细胞淋巴瘤
N Engl J Med. 2017 Dec 28;377(26):2531-2544. doi: 10.1056/NEJMoa1707447. Epub 2017 Dec 10.
9
Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18.人源化和鼠源嵌合抗原受体 T 细胞分泌白细胞介素-18 增强抗肿瘤免疫
Cell Rep. 2017 Sep 26;20(13):3025-3033. doi: 10.1016/j.celrep.2017.09.002.
10
Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment.装甲 CAR T 细胞增强抗肿瘤疗效并克服肿瘤微环境。
Sci Rep. 2017 Sep 5;7(1):10541. doi: 10.1038/s41598-017-10940-8.
Zotero 插件