CCL19 x IL-7

1

项与 CCL19 x IL-7 相关的临床试验

NCT04381741

/ Enrolling by invitation临床1期IIT

CD19 CAR-T Expressing IL7 and CCL19 Combined With PD1 mAb for Relapsed or Refractory Diffuse Large B Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, accounting for 35% of lymphoma. Chimeric antigen receptor T cell (CAR-T) therapy is a new method to treat DLBCL. KTE-C19, published in the New England Medical Journal in December 2017, was used to treat relapsed and refractory B-cell lymphoma. One year of treatment for 111 patients, the total response rate was 82%, and the complete remission rate was 54%. However, a large number of clinical studies have shown that about 20% of patients with B-ALL and 50% of patients with B-NHL cannot achieve complete remission (CR) after CD19-CAR-T treatment. Targeting tumor microenvironment is an important new method to overcome the drug resistance of CAR-T cells. In this study, IL-7 and CCL19 were connected on the basis of traditional second generation CD19 CAR-T cells to construct novel fourth generation CAR-T cells, which can promote the infiltration, accumulation and survival of CAR-T cells in lymphoma tissue, and further enhance the anti-tumor effect of traditional CAR-T cells. At the same time, combined with four generations of CAR-T cells and PD1 monoclonal antibody, PD1 / PDL1 signal pathway was blocked, anti-tumor effect of CAR-T was improved, and immune response and long-term remission rate of DLBCL were improved.

开始日期2020-06-18

申办/合作机构

浙江大学医学院附属第二医院（浙江省第二医院）

100 项与 CCL19 x IL-7 相关的临床结果

登录后查看更多信息

100 项与 CCL19 x IL-7 相关的转化医学

登录后查看更多信息

0 项与 CCL19 x IL-7 相关的专利（医药）

50

项与 CCL19 x IL-7 相关的文献（医药）

2025-02-01·Clinical Lymphoma Myeloma and Leukemia

Plasma Cytokine and Chemokine Profiles Predict Efficacy and Toxicity of Anti-CD19 CAR-T Cell Therapy in Large B-Cell Lymphoma

Article

作者: Wang, Shuhua ; Koff, Jean L ; Waller, Edmund K ; Abousaud, Aseala I ; Zeng, Fanyuan ; O'Leary, Colin B ; Liu, Yuan ; Funk, Christopher R ; Wyman, Sarah ; Passang, Tenzin ; Rupji, Manali ; Zhang, Hanwen ; Li, Yiwen ; Dhodapkar, Kavita M

BACKGROUNDAnti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising treatment for large B-cell lymphoma (LBCL); however, durable complete responses are achieved in only 30% to 40% of patients. Additionally, CAR-T therapy is frequently associated with significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).PATIENTS AND METHODSWe explored the translational potential of cytokines and chemokines as predictive biomarkers for CAR-T outcomes by analyzing 47 plasma cytokines/chemokines in serial blood samples from 24 LBCL patients undergoing CAR-T therapy. Blood samples were collected at multiple times: prelymphodepletion, day of CAR-T infusion (Day 0), and post-infusion. We investigated the association between cytokine levels and key clinical outcomes using machine learning models, including treatment response at 3 months, CRS, and ICANS.RESULTSHigher day 0 IL-7, day 7 IL-21, and day 0 CCL8 levels correlated with improved remission rates. Conversely, elevated CRS risk was linked to higher day 0 CCL17 and day 3 CCL13, IL-6, and IFN-γ levels. ICANS development was associated with increased day 0 TGF-β1, and day 3 IL-5 and IL-7 levels, while lower day 0 CCL19 and day 3 VIP levels were inversely related to ICANS risk. Additionally, patients who received higher-intensity lymphodepletion had elevated day 0 CCL2 and IL-15 levels.CONCLUSIONThese findings highlight the role of plasma cytokines and chemokines as biomarkers for predicting both the therapeutic efficacy and toxicity of CART, with the potential to guide more personalized, safer, and effective immunotherapies for B cell lymphoma.

2024-09-01·Cancer Research Communications

Therapeutic Efficacy of IL7/CCL19-Expressing CAR-T Cells in Intractable Solid Tumor Models of Glioblastoma and Pancreatic Cancer

Article

作者: Adachi, Keishi ; Ohta, Keisuke ; Sakoda, Yukimi ; Nakajima, Masao ; Yasuda, Hiroyuki ; Tamada, Koji ; Shinozaki, Taro ; Nagano, Hiroaki

AbstractCancer immunotherapy using immune checkpoint inhibitors and its combination with other anticancer therapies has emerged as a new standard of care because of the encouraging therapeutic effects in various solid cancers. Nonetheless, glioblastoma and pancreatic cancer remain resistant to immunotherapy and represent intractable cancers with the poorest prognosis. We investigated the therapeutic effects of next-generation chimeric antigen receptor (CAR) T cells producing IL7 and chemokine (C–C motif) ligand 19 (CCL19; referred to as 7 × 19 CAR-T) in these intractable cancers. Cytotoxic activities and therapeutic effects of 7 × 19 CAR-T were evaluated in vitro and in vivo, in a model using EGFR variant III (EGFRvIII)–positive glioblastoma and anti-EGFRvIII CAR-T generated from healthy donor peripheral blood mononuclear cells (PBMC), or a model using HER2-positive pancreatic cancer organoids and anti-HER2 CAR-T generated from the same patient’s PBMC. Anti-EGFRvIII 7 × 19 CAR-T exhibited cytotoxic activity specific to EGFRvIII-positive tumor, induced complete rejection of glioblastoma with massive T-cell infiltration and tumor cell death in the tumor tissues, and consequently prolonged mouse survival. Anti-HER2 7 × 19 CAR-T demonstrated a potent cytotoxic activity against autologous HER2-positive pancreatic cancer organoids and induced complete rejection of autologous tumor along with prolonged mouse survival. Our results suggest that 7 × 19 CAR-T could become a therapeutic option for glioblastoma and pancreatic cancer. To the best of our knowledge, this is the first study to demonstrate the therapeutic efficacy of next-generation CAR-T in an autologous model using patient-derived tumor organoids and CAR-T generated from the same patient’s PBMC, in which unwanted allogeneic immune responses are fully excluded.Significance:Despite the clinical development of CAR T-cell therapy, its efficacy in solid cancers has yet to be established. This study explored the therapeutic potential and immunologic mechanisms of IL7/CCL19-producing CAR-T therapy in preclinical solid cancer models of glioblastoma and pancreatic cancer. We found that IL7/CCL19-producing CAR-T cells generated from the patient’s PBMC showed potent therapeutic effects against the solid cancer model established by inoculating organoids from the autologous tumor tissue.

2024-09-01·Journal of Dental Research

The PerioGene North Study Uncovers Serum Proteins Related to Periodontitis

Article

作者: Holm, C.K. ; Lövgren, A. ; Betnér, S. ; Lerner, U.H. ; Isehed, C. ; Wänman, M. ; Hänström, L. ; Lindquist, S. ; Kindstedt, E. ; Palmqvist, P. ; Holmlund, A. ; Esberg, A. ; Lundberg, P.

The sequalae of periodontitis include irreversible degradation of tooth-supporting structures and circulatory spread of inflammatory mediators. However, the serum protein profile in periodontitis is not well described, which is partly attributable to the limited number of studies based on large and well-characterized periodontitis cohorts. This study aims to identify novel, circulating inflammation-related proteins associated with periodontitis within the PerioGene North case-control study, which includes 478 cases with severe periodontitis and 509 periodontally healthy controls. The serum concentrations of high-sensitivity C-reactive protein (hs-CRP) and a panel of 45 inflammation-related proteins were analyzed using targeted proteomics. A distinguishable serum protein profile was evident in periodontitis cases. The protein pattern could separate cases from controls with a sensitivity of 0.81 and specificity of 0.81 (area under the curve = 0.87). Adjusted levels for hs-CRP and 24 of the 45 proteins were different between cases and controls. High levels of hs-CRP and matrix metalloproteinase–12, and low levels of epidermal growth factor (EGF) and oxidized low-density lipoprotein receptor 1 (OLR-1) were detected among the cases. Furthermore, the levels of C-C motif chemokine–19, granulocyte colony-stimulating factor–3 (CSF-3), interleukin-7 (IL-7), and hs-CRP were significantly higher in cases with a high degree of gingival inflammation. The levels of CSF-3 and tumor necrosis factor ligand superfamily member–10 TNFSF-10 were higher in cases with many deep periodontal pockets. The PerioGene North study includes detailed clinical periodontal data and uncovers a distinct serum protein profile in periodontitis. The findings of lower EGF and OLR-1 among the cases are highlighted, as this has not been presented before. The role of EGF and OLR-1 in periodontitis pathogenesis and as possible future biomarkers should be further explored.

24

项与 CCL19 x IL-7 相关的新闻（医药）

2025-04-24

·同写意

邦耀生物刘明耀、杜冰教授团队《Cancer Cell 》重磅综述：CAR-T攻克实体瘤，未来可期！

免疫疗法细胞疗法临床研究临床结果

2025-04-18

·生物世界

Cancer Cell：刘明耀/杜冰团队全面综述CAR-T治疗实体瘤的进展及挑战

编辑丨王多鱼排版丨水成文尽管嵌合抗原受体（CAR）T 细胞疗法在血液系统恶性肿瘤中取得了巨大成功，但在占据癌症患者绝大多数的实体瘤中的疗效却因多种因素而受限，其中包括抗原异质性和肿瘤微环境（TME）的免疫抑制特性。2025 年 4 月 14 日，华东师范大学刘明耀教授、杜冰教授团队在 Cancer Cell 期刊发表了题为：CAR-T therapy in solid tumors 的综述论文，系统介绍了目前 CAR-T 细胞疗法在多种实体瘤临床研究中的突破性进展，探讨了 CAR-T 细胞疗法在实体瘤中面临的挑战，并对突破实体瘤治疗瓶颈的策略进行了全面总结。CAR-T 细胞疗法在实体瘤治疗中的临床进展：肺癌：EGFR-CAR-T 细胞疗法的中位无进展生存期（PFS）为 7.13 个月，总生存期（OS）达到了 15.63 个月；肝癌：GPC3-CAR-T 细胞疗法显示出 90.9% 的疾病控制率（DCR）和 50% 的客观缓解率（ORR）；胃癌：CLDN18.2-CAR-T 细胞疗法显示出 91.8% 疾病控制率（DCR）和 38.8% 的客观缓解率（ORR）；前列腺癌：PSMA-CAR-T 细胞疗法将患者前列腺特异性抗原（PSA）水平降低了 95% 以上；卵巢癌：MSLN-CAR-T 细胞疗法将患者的 6 个月总生存率提高到了 70.2%，无进展生存期为 5.8 个月；脑胶质瘤：鞘内给药 EGFR 和 IL13Rα2 靶向的双特异性 CAR-T 细胞，观察到短暂肿瘤消退；B7-H3-CAR-T 细胞疗法的中位总生存期（OS）达 20.3 个月，12 个月总生存率为 83.3%；GD2-CAR-T 细胞疗法实现了 50% 的部分缓解率（PR）。尽管上述创新性 CAR-T 细胞疗法在少数实体瘤患者中展示出了治疗潜力，但其整体的临床疗效仍有待提升。随后作者分析了 CAR-T 细胞治疗实体瘤面临的挑战，四大瓶颈亟待突破：1、T 细胞耗竭：长期对抗肿瘤导致 CAR-T 细胞抗肿瘤活性下降；2、误伤正常细胞：部分肿瘤靶点在正常组织中也有表达，引起 On-target off-tumor 毒性；3、免疫抑制性的肿瘤微环境：实体瘤微环境缺氧、营养匮乏，且充满抑制免疫的细胞和分子，例如 TGFβ 等抑制 CAR-T 细胞的免疫反应；4、CAR-T 细胞难迁移并浸润：实体瘤具备纤维组织的物理屏障，加之趋化因子表达匮乏，不利于 CAR-T 细胞的定位和浸润。图1. CAR-T疗法在实体瘤中的挑战作者对优化并提升 CAR-T 细胞治疗实体瘤的相关研究进展进行了归纳与总结，系统地提出了 5 大创新升级方案，让 CAR-T 细胞疗法更精准、更安全：1、智能设计 CAR 结构引入“双靶点”技术（例如 GD2+B7-H3），降低误伤风险；整合 CAR-T 和 TCR-T 技术，开发“STAR-T”新型受体，提升肿瘤识别灵敏度。2、增强 CAR-T 细胞功能过表达 IL-10、FOXO1 等因子，增强细胞持久性和杀伤力；基因编辑技术敲除耗竭相关基因（例如 NR4A），延长 CAR-T 细胞存活时间。3、革新 CAR-T 细胞生产工艺现货通用型 CAR-T 可实现“即取即用”，大大缩短制备周期的同时，也有效降低了生产成本。非病毒定点整合技术改造细胞，提升安全性，避免基因插入错误风险。4、瓦解肿瘤免疫微环境装载“定位信号”（例如 IL-7/CCL19），引导细胞深入肿瘤内部，增强对肿瘤细胞的杀伤。改造 CAR-T 分泌 LIGHT、肝素酶，可实现破坏肿瘤外部屏障或重塑肿瘤异常的脉管系统。5、提升 CAR-T 治疗安全性双靶点 CAR-T 细胞的设计与改造，以降低中靶脱瘤毒性；引入“安全开关”及时控制副作用，阻断细胞因子风暴（CRS）关键通路。图2. 克服实体瘤障碍的策略总的来说，在这篇综述中，作者探讨了针对实体瘤的 CAR-T 细胞疗法在临床研究方面取得的进展以及所面临的挑战。为了提高 CAR-T 细胞在实体瘤中的疗效，研究人员探索了诸如增强 T 细胞持久性和细胞毒性、靶向多种抗原以及利用创新的同种异体 CAR-T 细胞制造等策略。此外，该综述还强调了将 CAR-T 细胞疗法与免疫检查点抑制剂及其他治疗手段相结合的潜在益处，以克服肿瘤微环境（TME）的限制。最后，作者表示，对于 CAR-T 细胞疗法在实体瘤中的未来持乐观态度，但还需要持续开展研究以优化治疗方案，并满足癌症患者的临床需求。原文链接：https://www-cell-com.libproxy1.nus.edu.sg/cancer-cell/abstract/S1535-6108(25)00120-5设置星标，不错过精彩推文开放转载欢迎转发到朋友圈和微信群微信加群为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。点在看，传递你的品味

细胞疗法免疫疗法临床结果临床研究

2025-04-18

·brlmed.com

邦耀生物刘明耀、杜冰教授团队《Cancer Cell 》重磅综述：CAR-T攻克实体瘤，未来可期！

近年来，嵌合抗原受体T细胞疗法（CAR-T）在恶性血液肿瘤中展现出的强大实力，使其逐渐成为最有前景的肿瘤免疫疗法，然而血液肿瘤（非实体瘤）仅仅是众多癌症中较小的一部分。根据2024年世界卫生组织国际癌症研究机构（IARC）在学术期刊CA: A Cancer Journal for Clinicians发布的2022年全球癌症负担数据显示，约90%的癌症发病率都是由实体瘤引起，全球癌症发病率和死亡率排名TOP5的癌症也均为实体肿瘤，而关于实体瘤的细胞治疗临床试验却相对较少，可见实体瘤未被满足的临床治疗需求巨大。 2025年4月18日，聚焦于基因和细胞治疗的上海邦耀生物科技有限公司（以下简称“邦耀生物”）宣布，邦耀生物联合华东师范大学刘明耀教授、杜冰教授领衔的科研团队近日在国际顶级期刊Cancer Cell上发表了题为“CAR-T therapy in solid tumors”的综述文章，系统总结了CAR-T细胞疗法在实体瘤领域的突破性进展，深入剖析当前挑战，并提出多维度创新策略。该综述为全球实体瘤免疫治疗研究提供了重要方向，标志着CAR-T技术向实体瘤全面进军迈出关键一步。突破性成果：从实验室到临床，实体瘤治疗曙光初现 CAR-T疗法在血液肿瘤中已创造“治愈奇迹”，但在实体瘤中仍面临巨大挑战。在本综述中，研究团队首先汇总了全球多种实体瘤临床数据，并阐述了多项针对不同靶点的CAR-T细胞在治疗实体瘤中所取得的突破性进展：肺癌：相较于传统治疗手段，靶向EGFR的CAR-T细胞将患者的中位生存期提升至15.63个月。肝癌、胃癌：分别接受GPC3-CAR-T和CLDN18.2-CAR-T治疗后，实现了90%疾病控制率。前列腺癌：PSMA-CAR-T治疗后，可将患者前列腺特异性抗原（PSA）水平下降超95%以上。卵巢癌、脑胶质瘤：MSLN-CAR-T和GD2-CAR-T分别治疗后，实现70.2%（6个月生存率）和83.3%（12个月生存率）的显著疗效。肺癌：相较于传统治疗手段，靶向EGFR的CAR-T细胞将患者的中位生存期提升至15.63个月。肝癌、胃癌：分别接受GPC3-CAR-T和CLDN18.2-CAR-T治疗后，实现了90%疾病控制率。前列腺癌：PSMA-CAR-T治疗后，可将患者前列腺特异性抗原（PSA）水平下降超95%以上。卵巢癌、脑胶质瘤：MSLN-CAR-T和GD2-CAR-T分别治疗后，实现70.2%（6个月生存率）和83.3%（12个月生存率）的显著疗效。尽管这些创新性CAR-T疗法在少数实体瘤患者中展示出了治疗潜力，但其整体的临床疗效仍有待提升。随后研究团队分析了CAR-T细胞治疗实体瘤面临的挑战，四大瓶颈亟待突破：（1）T细胞“疲劳”：长期对抗肿瘤导致CAR-T细胞活性下降。（2）误伤正常细胞：部分肿瘤靶点与正常组织相似，可能引发副作用。（3）免疫抑制的肿瘤环境：实体瘤微环境缺氧、营养匮乏，且充满抑制免疫的细胞和分子，如TGFβ等抑制CAR-T细胞的免疫反应。（4）CAR-T细胞难迁移并浸润：实体瘤具备纤维组织的物理屏障，加之趋化因子表达匮乏，不利于CAR-T细胞的定位和浸润。图1. CAR-T疗法在实体瘤中的挑战最后，研究团队对优化并提升CAR-T细胞治疗实体瘤的相关研究进展进行了归纳与总结，系统地提出了5大创新升级方案，让CAR-T疗法更精准、更安全：智能设计CAR结构引入“双靶点”技术（如GD2+B7-H3），降低误伤风险。整合CAR-T和TCR-T技术，开发“STAR-T”新型受体，提升肿瘤识别灵敏度。引入“双靶点”技术（如GD2+B7-H3），降低误伤风险。整合CAR-T和TCR-T技术，开发“STAR-T”新型受体，提升肿瘤识别灵敏度。增强CAR-T细胞功能过表达IL-10、FOXO1等因子，增强细胞持久性和杀伤力。基因编辑技术敲除耗竭相关基因（如NR4A），延长CAR-T存活时间。过表达IL-10、FOXO1等因子，增强细胞持久性和杀伤力。基因编辑技术敲除耗竭相关基因（如NR4A），延长CAR-T存活时间。革新CAR-T细胞生产工艺现货通用型CAR-T可实现“即取即用”，大大缩短制备周期的同时，也有效降低了生产成本。非病毒定点整合技术改造细胞，提升安全性，避免基因插入错误风险。现货通用型CAR-T可实现“即取即用”，大大缩短制备周期的同时，也有效降低了生产成本。非病毒定点整合技术改造细胞，提升安全性，避免基因插入错误风险。瓦解肿瘤免疫微环境装载“定位信号”（如IL-7/CCL19），引导细胞深入肿瘤内部，增强对肿瘤细胞的杀伤。改造CAR-T分泌LIGHT、肝素酶，可实现破坏肿瘤外部屏障或重塑肿瘤异常的脉管系统。装载“定位信号”（如IL-7/CCL19），引导细胞深入肿瘤内部，增强对肿瘤细胞的杀伤。改造CAR-T分泌LIGHT、肝素酶，可实现破坏肿瘤外部屏障或重塑肿瘤异常的脉管系统。提升CAR-T治疗安全性双靶点CAR-T细胞的设计与改造，以降低中靶脱瘤毒性。引入“安全开关”及时控制副作用，阻断细胞因子风暴（CRS）关键通路。双靶点CAR-T细胞的设计与改造，以降低中靶脱瘤毒性。引入“安全开关”及时控制副作用，阻断细胞因子风暴（CRS）关键通路。图2. 克服实体瘤障碍的策略从“可能”到“可行”，CAR-T开启实体瘤治疗新时代作为本篇综述共同作者，邦耀生物创始人&董事长刘明耀教授表示：“随着基因编辑、合成生物学与临床转化的深度融合，CAR-T完全有望成为实体瘤治疗的‘终极武器’。” 邦耀生物作为全球领先的细胞基因药企，在细胞治疗实体瘤领域也实现了多项突破性进展，不但打造了具有自主知识产权的增强型T细胞平台（HyperTCell®），其主要通过T细胞的基因改造来攻克实体瘤治疗的世界难题。于2025年1月，邦耀生物科研团队还在Molecular Therapy杂志最新发文，开发出了一种创新型CAR-T细胞“GITRL-PSMA-CAR-T”不仅可以直接增强CAR-T细胞的抗肿瘤活性，还可以促进其在实体肿瘤微环境中的持久性，进一步提升了CAR-T对实体肿瘤的治疗效果，有望加速实现实体瘤CAR-T疗法的开发与应用。不得不说，近年来随着对肿瘤免疫微环境以及T细胞功能调控机制认识的不断深入，对于CAR-T细胞的改造也越来越系统化、多样化，使CAR-T细胞在实体肿瘤的临床治疗中不断取得突破性的进展，CAR-T治疗实体瘤的时代已经到来。未来，邦耀生物将不断加强技术开发，克服行业壁垒进行多管线战略布局和技术整合，力求解决基因和细胞治疗中遇到的核心问题和卡脖子的技术难题，从而为更多遗传疾病、肿瘤疾病（特别是实体肿瘤）及自身免疫疾病等患者带来福音。 Cancer Cell综述原文链接：https://doi-org.libproxy1.nus.edu.sg/10.1016/j.ccell.2025.03.019

免疫疗法细胞疗法临床研究临床结果

基本信息

关联

分析