Exploratory Study to Evaluate the Safety and Preliminary Efficacy of Anti-HER2 CAR-T Cell Injection in Patients With HER2-positive Advanced Malignant Solid Tumors

This is a single-arm, open-label, exploratory clinical study to evaluate the safety and preliminary efficacy of Anti-HER2 CAR-T cell injection in patients with HER2-positive advanced malignant solid tumors.

开始日期2024-11-30

申办/合作机构

上海优替济生生物医药有限公司

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项与 UCLE-802 相关的文献（医药）

2025-10-01·Cancer Immunology Research

Endoglin-Directed CAR T Cells Comprehensively Target Tumors in Advanced Sarcomas

Article

作者: Kurenbekova, Lyazat ; Ozcan, Ada I. ; Major, Angela M. ; Joseph, Sujith K. ; Mirabal, Jeneffer ; Berger, Harrison R. ; Yustein, Jason T. ; Sorensen, Poul H. ; Hicks, M. John ; Seon, Ben K. ; Ahmed, Nabil ; Kerr, Sybrina S. ; McKenna, Mary K. ; Dasgupta, Atreyi ; Baker, Matthew L. ; Maharana, Malina ; Sheha, Mohamed F. ; Delaidelli, Alberto ; Hegde, Meenakshi ; Gad, Ahmed Z. ; Morris, Jessica S.

Abstract:

There are limited therapeutic options for patients with advanced sarcomas, which leads to dismal outcomes for children and adults. Although chimeric antigen receptor (CAR) T cells hold promise for treating advanced sarcomas, this approach is constrained by a paucity of effective targets. Our previous clinical study identified endoglin (ENG/CD105), a TGFβ coreceptor, as a target of the endogenous immune response in a patient with sarcoma who exhibited an exceptional response to HER2-targeted CAR T-cell therapy. ENG is expressed on various sarcomas, cancer-associated fibroblasts, and neoangiogenic vessels and therefore offers comprehensive tumor targeting. Furthermore, ENG knockout in sarcoma cells reduces their invasiveness, highlighting its potential as a therapeutic target. Accordingly, we designed a second-generation human ENG-targeting CAR molecule signaling through the CD28 endodomain and retrovirally transduced primary human T cells with this CAR. ENG CAR T cells exhibited strong antigen-specific cytokine release, robust proliferation, memory formation, and cytotoxic function against various sarcoma cell lines. Their cytotoxicity remained unaffected by the presence of soluble ENG or its natural ligand, bone morphogenetic protein-9. Furthermore, ENG CAR T cells disrupted multicellular tumor spheroids in vitro, overcoming tumor compactness and the stromal barrier created by cancer-associated fibroblasts, which are critical challenges in sarcoma CAR T-cell therapy. In orthotopic xenograft models of sarcomas, ENG CAR T-cell treatment resulted in control of tumor growth and metastasis, leading to survival extension. In summary, our study describes the involvement of ENG in sarcoma metastasis and validates our human ENG CAR T cells as a potential therapeutic for advanced sarcomas.

2023-10-01·Journal of biochemical and molecular toxicology

Cbl induced ubiquitination of HER2 mediate immune escape from HER2‐targeted CAR‐T

Article

作者: Cheng, Hao ; Sun, Qingqing ; Yang, Yanqiu ; Shi, Wencong ; Deng, Zhiping

Abstract:

Breast cancer (BC) with high HER2 expression has higher recurrence rate and worse prognosis, and its immunotherapy is promising. Based on the high expression of HER2, develop Chimeric Antigen Receptor T‐cell (CAR‐T) and PDL‐1 immunotherapy, and study the molecular pathways of related immune cells and recurrence. HER2‐CAR‐T cells were constructed using retroviruses, and their specific recognition and immune effects on HER2+ BC cells were verified by in vivo and in vitro experiments. PDL‐1 was used as adjuvant immunotherapy, knocking down PDL‐1 in tumor cells or dendritic cells, or depleted macrophages to study immune pathways. The negative regulation of HER2 by cbl was determined by IP, ubiquitination experiments, and segmented plasmids, elucidating the molecular mechanism of HER2+ BC recurrence after immunotherapy. HER2‐CAR‐T specifically recognizes HER2‐positive tumor cells and inhibits tumor growth in vivo and in vitro, and anti‐PDL1 treatment enhances the therapeutic effect of HER2‐CAR‐T on tumors. HER2‐CART therapy eradicated solid tumors after PDL1 knockdown in dendritic cells. Immunotherapy of relapsed tumors lost HER2 expression by upregulating cbl. HER2‐CAR‐T shows specific recognition of HER2+ cells and can mediate immune response therapy with the cooperation of PDL‐1.

2023-05-01·Gene therapy

Distinct functions of CAR-T cells possessing a dectin-1 intracellular signaling domain

Article

作者: Chen, Nianyong ; Wang, Wei ; Li, Dan ; Liang, Xiao ; Su, Jinhua ; Zhou, Weilin ; Huang, Yong ; Jiang, Lin ; Yang, Xiao

Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacies in treating hematopoietic malignancies, but not in the solid tumors. Incorporating costimulatory signaling domains, such as ICOS or 4-1BB, can positively influence CAR-T cell functions and then the immune responses. These CAR-engineered T cells have showed their enhanced persistence and effector functions with improved antitumor activities, and provided a new approach for the treatment of solid tumors. Here, we designed novel 2nd generation CARs with a costimulatory signaling molecule, dectin-1. The impacts of dectin-1 signaling domain on CAR-T cells were evaluated in vitro and in vivo. Our data show that in vitro cytokine secretions by HER2 or CD19 specific CAR-T cells increase significantly via incorporating this dectin-1 signaling domain. Additional properties of these novel CAR-T cells are affected by this costimulatory domain. Compared with a popular reference (i.e., anti-HER2 CAR-T cells with 4-1BB), in vitro T cell functions and in vivo antitumor activity of the dectin-1 engineered CAR-T cells are similar to the 4-1BB based, and both are discrete to the mock T cells. Furthermore, we found that the CAR-T cells with dectin-1 show distinct phenotype and exhaustion marker expression. These collective results suggest that the incorporation of this new signaling domain, dectin-1, into the CARs may provide the clinical potential of the CAR-T cells through this signaling domain in treating solid tumors.

项与 UCLE-802 相关的新闻（医药）

2025-12-08

·生物制药小编

CAR-T：肿瘤Vs.自免

CAR-T 细胞疗法作为一种革命性的免疫治疗手段，在肿瘤和自身免疫性疾病领域均展现出潜力，但因治疗目标、疾病机制不同，两者在设计、靶点选择、疗效评估等方面存在显著差异，以下从核心维度展开对比分析。治疗目标与作用机制（一）肿瘤领域：清除恶性细胞核心目标精准识别并杀伤表达特定抗原的肿瘤细胞，根除或控制肿瘤进展，例如治疗急性淋巴细胞白血病（ALL）、淋巴瘤等血液系统肿瘤，或尝试突破实体瘤治疗瓶颈。作用机制通过基因工程改造 T 细胞，使其表达能特异性结合肿瘤相关抗原（TAAs）的嵌合抗原受体（CAR）。CAR-T 细胞输注后，可直接识别肿瘤细胞表面抗原，激活自身杀伤功能，释放细胞因子（如 IL-2、IFN-γ），同时招募其他免疫细胞（如 NK 细胞、巨噬细胞），形成协同抗肿瘤免疫反应。例如，CD19 CAR-T 细胞通过识别 B 细胞肿瘤表面的 CD19 抗原，高效清除 B 系恶性肿瘤细胞。（二）自身免疫性疾病领域：重建免疫耐受核心目标抑制过度激活的自身反应性免疫细胞（如自身反应性 B 细胞、T 细胞），调节免疫失衡状态，实现疾病缓解，而非 “杀伤” 目标细胞，例如治疗系统性红斑狼疮（SLE）、1 型糖尿病（T1D）等。作用机制 CAR-T 细胞多靶向自身反应性免疫细胞表面标志物，如 CD19（针对 B 细胞介导的自身免疫病），通过清除过度活化的 B 细胞，减少自身抗体产生，缓解炎症反应。例如，CD19 CAR-T 细胞可降低 SLE 患者体内的自身抗体水平，改善肾脏损伤。CAR-Treg 细胞通过基因工程改造调节性 T 细胞（Treg），使其表达靶向自身抗原或免疫细胞标志物的 CAR。输注后，CAR-Treg 细胞可通过分泌抑制性细胞因子（如 TGF-β、IL-10）、抑制抗原提呈细胞功能、直接接触抑制效应 T 细胞活化等方式，重建免疫耐受。例如，针对胰岛 β 细胞自身抗原的 CAR-Treg 细胞，可抑制自身反应性 T 细胞对胰岛 β 细胞的攻击，保护胰岛素分泌功能。CAR 设计差异（一）肿瘤 CAR-T：强化杀伤与增殖能力抗原识别域多选择高亲和力的单链可变片段（scFv），以确保高效识别肿瘤抗原。但需平衡亲和力，避免过高亲和力导致 “脱靶效应”（攻击正常低抗原表达细胞）。例如，针对 CD19 的 CAR 多采用中等亲和力 scFv，在保证杀伤肿瘤细胞的同时，减少对正常 B 细胞的过度损伤。共刺激域常整合多个共刺激信号（如 CD28、4-1BB、OX40），增强 CAR-T 细胞的活化、增殖和体内持久性。例如，第二代 CD19 CAR-T 细胞（如 Kymriah）含 CD28 或 4-1BB 共刺激域，相比第一代（仅含 CD3ζ 信号域），可显著延长 CAR-T 细胞在体内的存活时间，提升抗肿瘤疗效；第三代 CAR-T 细胞（如 CD3ζ-CD28-4-1BB 结构）则通过双共刺激域进一步强化杀伤功能。功能优化部分新一代 CAR-T（如第四代 TRUCKs）整合细胞因子（如 IL-12）表达元件，在肿瘤微环境（TME）中释放细胞因子，招募 innate 免疫细胞，克服 TME 的免疫抑制（如 Treg 细胞、髓系抑制细胞浸润）。（二）自身免疫性疾病 CAR-T：侧重调控与安全性抗原识别域多选择低亲和力或特异性靶向自身反应性细胞抗原的 scFv，避免过度激活免疫反应。例如，针对自身反应性 B 细胞的 CAR，其 scFv 亲和力较低，仅清除过度活化的 B 细胞，对正常 B 细胞影响较小。共刺激域以 “温和调节” 为目标，较少使用强共刺激信号（如 CD28），常选择可调控的共刺激域或仅保留基础信号（如 CD3ζ+ 单一弱共刺激域），防止 CAR-T 细胞过度增殖引发炎症。例如，CAR-Treg 细胞的共刺激域多选择 ICOS（诱导性共刺激分子），可增强 Treg 细胞的免疫抑制功能，同时避免过度活化。“安全开关” 设计更注重安全性控制，部分 CAR-T（如 CAAR-T 细胞）引入 “条件性激活” 机制。例如，嵌合自身抗体受体（CAAR-T）的抗原识别域来自自身抗原，仅在识别自身反应性 B 细胞表面的自身抗体时激活，避免非特异性免疫抑制。靶点选择差异（一）肿瘤 CAR-T：聚焦肿瘤特异性 / 高表达抗原靶点需满足 “肿瘤细胞高表达、正常细胞低表达或不表达” 的特点，以降低脱靶毒性，常见靶点如下。肿瘤靶点作用机制血液肿瘤 CD19 靶向 B 细胞肿瘤（如 ALL、淋巴瘤），清除 B 系恶性细胞 BCMA 靶向多发性骨髓瘤细胞表面的 B 细胞成熟抗原，特异性杀伤骨髓瘤细胞实体瘤 HER2 靶向乳腺癌、胃癌等实体瘤表面的人表皮生长因子受体 2，尝试突破实体瘤治疗瓶颈 mesothelin 靶向间皮瘤、胰腺癌等实体瘤，通过局部输注（如胸腔注射）提升肿瘤部位 CAR-T 细胞浓度（二）自身免疫性疾病 CAR-T：靶向免疫细胞标志物或自身抗原靶点选择以 “调节免疫失衡” 为核心，多针对自身反应性免疫细胞或疾病相关自身抗原，常见靶点如下：疾病类型常见靶点作用机制系统性红斑狼疮（SLE） CD19 清除过度活化的 B 细胞，减少自身抗体（如抗核抗体）产生，缓解全身炎症 1 型糖尿病（T1D）胰岛 β 细胞自身抗原（如胰岛素、GAD65）改造 CAR-Treg 细胞，使其识别胰岛 β 细胞自身抗原，抑制自身反应性 T 细胞攻击胰岛 β 细胞类风湿关节炎（RA）瓜氨酸化波形蛋白（CV）靶向 RA 患者滑膜组织中的 CV 抗原，通过 CAR-Treg 细胞抑制局部炎症反应多发性硬化症（MS）髓鞘少突胶质细胞糖蛋白（MOG）改造 CAR-Treg 细胞，靶向中枢神经系统中的 MOG 抗原，抑制自身反应性 T 细胞对髓鞘的损伤疗效与安全性评估指标（一）肿瘤 CAR-T：以 “肿瘤清除” 为核心指标疗效评估血液系统肿瘤常用完全缓解率（CR）、微小残留病（MRD）阴性率、无进展生存期（PFS）、总生存期（OS）等指标。例如，CD19 CAR-T 治疗复发难治性 ALL 的 CR 率可达 70%-90%，MRD 阴性患者的长期生存率显著提升。实体瘤因肿瘤微环境复杂，疗效评估更关注客观缓解率（ORR）、疾病控制率（DCR），目前实体瘤 CAR-T 的 ORR 多在 20%-50%，远低于血液系统肿瘤。安全性风险细胞因子释放综合征（CRS）因 CAR-T 细胞大量激活释放细胞因子引发，表现为发热、低血压、器官衰竭等，血液系统肿瘤 CAR-T 的 CRS 发生率较高（约 30%-60%），需使用 IL-6 受体拮抗剂（如托珠单抗）治疗。神经毒性（ICANS）表现为意识障碍、癫痫等，常见于 CD19、BCMA CAR-T 治疗，发生率约 10%-30%。脱靶效应如 HER2 CAR-T 治疗乳腺癌时，可能攻击正常心肌细胞表面的低表达 HER2，引发心脏毒性。（二）自身免疫性疾病 CAR-T：以 “免疫平衡与疾病缓解” 为核心指标疗效评估临床症状改善如 SLE 患者的皮疹、关节痛缓解，T1D 患者的胰岛素用量减少。免疫指标调节自身抗体滴度（如抗核抗体、抗 dsDNA 抗体）下降、炎症因子（如 IL-6、TNF-α）水平降低、Treg / 效应 T 细胞比例恢复正常。长期缓解关注疾病无复发缓解期（如 SLE 的 DORIS 缓解标准、RA 的 DAS28 缓解标准），而非 “肿瘤清除” 相关指标。安全性风险免疫抑制过度可能导致感染风险升高（如细菌、病毒感染），因 CAR-Treg 细胞或 CAR-T 细胞过度抑制免疫功能。例如，CD19 CAR-T 治疗自身免疫病时，长期清除 B 细胞可能增加感染风险。脱靶免疫抑制如 CAR-Treg 细胞靶向抗原选择不当，可能抑制正常免疫反应，影响机体对病原体的清除。CRS/ICANS 发生率低因自身免疫病 CAR-T 的活化强度较低，CRS 发生率通常 < 10%，且多为轻度（1-2 级），无需特殊治疗。自身免疫性疾病 CAR-T：处于临床早期，以探索为主目前自身免疫性疾病 CAR-T 治疗多处于 Ⅰ/Ⅱ 期临床试验阶段，聚焦于 SLE、RA、T1D 等疾病。 CD19 CAR-T 针对 SLE 的临床试验显示，患者自身抗体水平显著下降，部分患者实现长期缓解（如 2 年无复发），且 CRS 发生率低（<5%）。CAR-Treg 针对 T1D 的临床前研究表明，靶向胰岛 β 细胞自身抗原的 CAR-Treg 细胞可保护胰岛功能；针对移植后排斥反应的 CAR-Treg 临床试验（如 NCT04817774）正在开展，探索其诱导免疫耐受的效果。参考资料 Kong Y, Li J, Zhao X, Wu Y and Chen L (2025) CAR-T cell therapy: developments, challenges and expanded applications from cancer to autoimmunity. Front. Immunol. 15:1519671. doi: 10.3389/fimmu.2024.1519671 Bulliard Y, Freeborn R, Uyeda MJ, Humes D, Bjordahl R, de Vries D and Roncarolo MG (2024) From promise to practice: CAR T and Treg cell therapies in autoimmunity and other immune-mediated diseases. Front. Immunol. 15:1509956. doi: 10.3389/fimmu.2024.1509956 Cheever A, Kang CC, O’Neill KL and Weber KS (2024) Application of novel CAR technologies to improve treatment of autoimmune disease. Front. Immunol. 15:1465191. doi: 10.3389/fimmu.2024.1465191

免疫疗法细胞疗法基因疗法

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