GPC3-CAR-T Cells for Immunotherapy of Cancer With GPC3 Expression

Официальное название

CAR-T Cell Targeting GPC3 for Immunotherapy of Hepatocellular Carcinoma: Phase I Clinical Trial

Обзор

The third/fourth generation of CAR-T cells that target GPC3 (GPC3-CART cell) and/or soluble TGFβ (GPC3/TGFβ-CART )have been constructed and their anti-HCC function has been verified by multiple in vitro and in vivo studies. Clinical studies will be performed to test the anti-cancer function by the GPC3/TGFβ-CAR-T cells in human HCC patients with GPC3 expression. In this phase I study, the safety, tolerance, and preliminary efficacy of the GPC3/TGFβ-CAR-T cell immunotherapy on human will firstly be tested.

Подробное описание

1. Choose appropriate patients with advanced hepatocellular carcinoma,with written consent for this study; 2. Perform biopsy to determine the expression of GPC3 of the tumor by western blotting or IHC; 3. Collect blood from the patients and isolate mononuclear cells, activate the T cells and transfect the T cells with GPC3/TGFβ targeting CAR (or/and scfv/cytokines-secreting), amplify the number of transfected T cells as needed, test the quality and killing activity of the GPC3/TGFβ-CART cells and then transplant back the patients via systemic or local infusions (via artery or intra-tumor), and follow up closely to collect related results as needed; 4. To enhance the killing capability, CD4+ T cells are genetically engineered to express TGFβ-CAR and secret IL7/CCL19 and/or SCFVs against PD1/CTLA4/Tigit; CD8+T cells are constructed to express GPC3-DAP10-CAR with knockdown of PD1/HPK1; 5. Evaluate the clinical results as needed. 6. Will also perform the similar clinical trial on lung squamous carcinoma with the GPC3 expression.

Вмешательства

• Биопрепарат GPC3 and/or TGFβ targeting CAR-T cells
  Engineering GPC3 or/and TGFβ targeting CAR combined with/or without IL7/CCL19 and/or scfv against PD1/CTLA4/Tigit secreting vector into T cells with knockdown of PD1/HPK1, which are isolated from patients with advanced HCC, and then transfusing them back the patients.

Первичные конечные точки

• Number of Patients with Dose Limiting Toxicity [Срок оценки: three months]

Вторичные конечные точки (2)

• Percent of Patients with best response as either complete remission or partial remission. [Срок оценки: three months]
• Median CAR-T cell persistence [Срок оценки: Five years]

Критерии участия

Критерии включения

• patients with advanced HCC,which express GPC3 protein.
• Life expectancy >12 weeks
• Child-Pugh-Turcotte score <7
• Adequate heart,lung,liver,kidney function
• Available autologous transduced T cells with greater than or equal to 20% expression of GPC3 CAR determined by flow-cytometry and killing of GPC3-positive targets greater than or equal to 20% in cytotoxicity assay
• Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent. -

Критерии исключения

• Had accepted gene therapy before;
• Tumor size more than 25cm;
• Severe virus infection such as HBV,HCV,HIV,et al
• Known HIV positivity
• History of liver transplantation
• Active infectious disease related to bacteria, virus,fungi,et al
• Other severe diseases that the investigators consider not appropriate;
• Pregnant or lactating women
• Systemic steroid treatment (greater than or equal to 0.5 mg prednisone equivalent/kg/day)
• Other conditions that the investigators consider not appropriate. -

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 2 центра

• The First Affiliated Hospital of Sun Yat-sen University — Гуанчжоу
• The Second Affiliated Hospital of Guangzhou Medical University — Гуанчжоу

Публикации

• Jiang Z, Jiang X, Chen S, Lai Y, Wei X, Li B, Lin S, Wang S, Wu Q, Liang Q, Liu Q, Peng M, Yu F, Weng J, Du X, Pei D, Liu P, Yao Y, Xue P, Li P. Anti-GPC3-CAR T Cells Suppress the Growth of Tumor Cells in Patient-Derived Xenografts of Hepatocellular Carcinoma. Front Immunol. 2017 Jan 11;7:690. doi: 10.3389/fimmu.2016.00690. eCollection 2016. PMID 28123387
• Pang N, Shi J, Qin L, Chen A, Tang Y, Yang H, Huang Y, Wu Q, Li X, He B, Li T, Liang B, Zhang J, Cao B, Liu M, Feng Y, Ye X, Chen X, Wang L, Tian Y, Li H, Li J, Hu H, He J, Hu Y, Zhi C, Tang Z, Gong Y, Xu F, Xu L, Fan W, Zhao M, Chen D, Lian H, Yang L, Li P, Zhang Z. IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. J Hematol Oncol. 2021 Jul 29;14(1):11 PMID 34325726

Идентификаторы

NCT: NCT03198546 · ZZCART-003

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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