CD147-CAR-NK Cells for Hepatocellular Carcinoma Treatment

CD147-CAR-NK 细胞用于肝细胞癌治疗

• 批准号: 10547810
• 负责人: Dongfang Liu
• 金额: $ 17.53万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547810
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Antibodies; Antigens; Applications Grants; Award; Back; Biological Assay; Biology; CD147 antigen; Cell Line; Cell Proliferation; Cell Therapy; Cells; Clinical Trials; Communication; Data; Development; Effectiveness; Engineering; Extracellular Matrix; Future; GPC3 gene; Goals; Hematopoietic Neoplasms; HepG2; Home; Human; Human Engineering; Immune; Immunotherapeutic agent; Immunotherapy; In Vitro; Knowledge; Logic; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Matrix Metalloproteinases; Molecular; Natural Killer Cells; Nature; Patients; Pharmaceutical Preparations; Phenotype; Primary carcinoma of the liver cells; Production; Proteins; Publishing; Receptor Cell; Receptor Signaling; Refractory; Reporting; Retroviral Vector; S10 grant; Severe Combined Immunodeficiency; Solid Neoplasm; Specificity; Specimen; Surface; T-Lymphocyte; Technology; Testing; Toxic effect; Transgenic Mice; Transgenic Organisms; Translating; Tumor Antigens; Umbilical Cord Blood; Work; Xenograft procedure; cancer immunotherapy; cancer type; cell killing; cellular transduction; chimeric antigen receptor; chimeric antigen receptor T cells; cost; cytokine; effective therapy; efficacy evaluation; efficacy testing; hepatocellular carcinoma cell line; immune activation; immunoengineering; immunological synapse; immunological synapse formation; in vivo; in vivo imaging system; leukemia; liver cancer model; mouse model; neoplastic cell; novel; novel strategies; patient derived xenograft model; peripheral blood; receptor; side effect; success; superresolution imaging; treatment strategy; tumor; ultra high resolution

Project Summary: This project will pursue an ‘off-the-shelf’ immunotherapy liver cancer “living drug” by re- engineering human primary Natural killer (NK) cells derived from a third-party cord blood or peripheral blood to home-in on a specific hepatocellular carcinoma cancer antigen (CD147). Recent clinical trials testing cancer immunotherapies have shown promising results for the treatment of various cancers. One such therapy involves engineering immune cells to express chimeric antigen receptors (CAR), which combine tumor antigen specificity with immune cell activation in a single receptor. The adoptive transfer of these CAR-modified immune cells (especially T cells, CAR T) into patients has shown remarkable success in treating multiple refractory blood cancers. However, CAR T therapy is often associated with significant toxicity, high cost, marginal effects on solid tumors. In order to achieve the promise of CAR cell therapy in treating solid tumor cancers, further advances will be required. One key challenge is identifying a safe and effective solid tumor antigen, as well as development of ‘off-the-shelf’ cell products. We recently devised a novel strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest solid tumor cancers in humans). We report that T and NK cells transduced with a CAR that targets the HCC surface marker, CD147, also known as Basigin (BSG) or extracellular matrix metalloproteinase inducer (EMMPRIN), can effectively kill multiple malignant HCC cell lines (including SK-Hep1 and HepG2 cell lines), primary HCC in vitro and tumors in xenograft and patient-derived xenograft (PDX) mouse models of liver cancer (Tseng, HC., D. et al., Nature Communications., 2020,). Critical gaps in our current knowledge of this immunotherapeutic strategy include the exact mechanism(s) by which the CD147-CAR-NK cells derived from a third-party peripheral or cord blood (CD147-CAR-NKprimary) can control HCC and whether the CD147-CAR-NK cells are safe in vivo. We propose to test the hypothesis that the CD147-CAR-NKprimary targeting HCC is effective and safe. The long- term goal of this project is to develop a novel immunotherapeutic strategy for the treatment of HCC. The objective of this application is to assess the efficacy CD147-CAR-NKprimary in vitro using HCC cell lines and in vivo using a newly created human CD147 transgenic (hCD147TG) mouse model. The proposed work will characterize the biology of CD147-CAR-NKprimary by analyzing surface marker profile, cytokine production, and cellular proliferation (Aim 1), test the efficacy of CD147-CAR-NKprimary both in vitro and in vivo (including severe combined immunodeficiency [SCID], patient-derived xenograft (PDX), and DEN/PB and HDF-induced orthotopic HCC in hCD147TG mouse model) and investigate the molecular mechanisms with a focus on immunological synapse (Aim 2), Future plan includes characterization of the CD147-CAR-NKprimary toxicity in the hCD147TG HCC mouse model. The results of these studies will streamline the path to clinical trials of ‘off- the-shelf’ CD147-CAR-NKprimary cells for adoptive cell therapy for the treatment of HCC.

项目概述：该项目将通过重新开发一种现成的免疫治疗肝癌的“活药” 改造来自第三方脐带血或外周血的人类初级自然杀伤(NK)细胞以 在特定的肝细胞癌抗原(CD147)上进行定位。最近的临床试验测试 癌症免疫疗法在治疗各种癌症方面显示出了良好的效果。一种这样的疗法 涉及工程免疫细胞表达嵌合抗原受体(CAR)，该受体结合肿瘤抗原 单一受体中免疫细胞激活的特异性。这些改装车的收养转让 免疫细胞(尤其是T细胞，CART)注入患者在治疗多发性硬化方面显示出显著的成功。 难治性血癌。然而，CAR-T疗法通常与显著的毒性、高昂的费用、 对实体瘤的边际效应。为了实现CAR细胞治疗实体瘤的前景 在癌症方面，将需要进一步的进展。一个关键的挑战是确定安全有效的实体肿瘤 抗原，以及“现成”细胞产品的开发。我们最近设计了一种新的策略来 以肝细胞癌(肝癌，人类最致命的实体肿瘤之一)为靶标。我们报道说 以肝癌表面标志CD147为靶点的CAR转导T和NK细胞，也称为basigin 细胞外基质金属蛋白酶诱导剂(BSG)或EMMPRIN，可有效杀灭多种恶性肿瘤 肝癌细胞系(包括SK-Hep1和HepG2细胞系)、体外原发肝癌、异种移植瘤和 患者来源的异种移植(PDX)小鼠肝癌模型(Tseng，HC，D.等，自然 通讯，2020，)。我们目前对这一免疫治疗策略的认识存在严重差距 包括CD147-CAR-NK细胞来自第三方外周血细胞或 脐血CD147-CAR-NK细胞在体内能否控制肝细胞癌以及CD147-CAR-NK细胞是否安全。我们 建议验证CD147-CAR-NK原代靶向肝癌是有效和安全的假说。长的- 该项目的长期目标是开发一种治疗肝细胞癌的新的免疫治疗策略。这个 该应用的目的是评价CD147-CAR-NK在体外对人肝癌细胞系和人肝癌细胞株的作用。 体内使用新创建的人CD147转基因(HCD147TG)小鼠模型。拟议的工作将 通过分析CD147-CAR-NK原代细胞的表面标志谱、细胞因子的产生和表达来鉴定其生物学特性 细胞增殖(目标1)，检测CD147-CAR-NK原代细胞在体外和体内(包括重症)的效果 联合免疫缺陷[SCID]、患者来源的异种移植(PDX)以及DEN/PB和HDF诱导的 HCD147TG小鼠模型的原位肝细胞癌)，并探讨其分子机制 免疫突触(AIM 2)，未来计划包括CD147-CAR-NK初级毒性的表征 HCD147TG肝癌小鼠模型。这些研究的结果将为临床试验铺平道路。 CD147-CAR-NK原代细胞用于肝癌过继细胞治疗的研究