CD147-CAR-NK Cells for Hepatocellular Carcinoma Treatment

CD147-CAR-NK 细胞用于肝细胞癌治疗

• 批准号: 10356640
• 负责人: Dongfang Liu
• 金额: $ 21.56万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356640
• 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; Image; Immune; Immunotherapeutic agent; Immunotherapy; In Vitro; Knowledge; Logic; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Matrix Metalloproteinases; Molecular; Mus; Natural Killer Cells; Nature; Patients; Pharmaceutical Preparations; Phenotype; Primary carcinoma of the liver cells; Production; Proteins; Publishing; Receptor Cell; Receptor Signaling; Refractory; Reporting; Resolution; Retroviral Vector; S10 grant; Severe Combined Immunodeficiency; Solid Neoplasm; Specificity; Specimen; Surface; T-Lymphocyte; Technology; Testing; Toxic effect; 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; liver cancer model; mouse model; neoplastic cell; novel; novel strategies; patient derived xenograft model; peripheral blood; receptor; side effect; success; treatment strategy; tumor

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：该项目将通过重新设计，寻求一种“现成”的免疫治疗肝癌“活药”。 工程化源自第三方脐带血或外周血的人原代自然杀伤（NK）细胞， 特异性肝细胞癌癌抗原（CD 147）的归巢。近期临床试验检测 癌症免疫疗法已经显示出治疗各种癌症的有希望的结果。一种这样的疗法 涉及工程化免疫细胞以表达嵌合抗原受体（CAR），其联合收割机结合肿瘤抗原 在单个受体中具有免疫细胞活化的特异性。这些CAR修饰的细胞的过继转移 免疫细胞（特别是T细胞，CAR T）进入患者体内，在治疗多种疾病方面取得了显着的成功。 难治性血癌然而，CAR T疗法通常与显著的毒性、高成本、 对实体瘤的边际效应。为了实现CAR细胞治疗实体瘤的前景， 癌症，需要进一步的进展。一个关键挑战是识别安全有效的实体肿瘤 抗原，以及“现成”细胞产品的开发。我们最近设计了一个新的策略， 靶向肝细胞癌（HCC，人类最致命的实体瘤癌症之一）。我们报告 用靶向肝癌表面标志物CD 147（也称为Basigin）的CAR转导的T细胞和NK细胞 (BSG)或细胞外基质金属蛋白酶诱导剂（EMMPRIN），可有效杀死多种恶性肿瘤 HCC细胞系（包括SK-Hep 1和HepG 2细胞系）、体外原发性HCC和异种移植物中的肿瘤， 肝癌的患者来源的异种移植（PDX）小鼠模型（Tseng，HC.，D.例如，性质 通讯，2020年，）。我们目前对这种免疫策略的认识存在重大差距 包括CD 147-CAR-NK细胞来源于第三方外周血细胞的确切机制， 脐带血（CD 147-CAR-NK primary）是否可以控制HCC以及CD 147-CAR-NK细胞在体内是否安全。我们 提出验证CD 147-CAR-NK原发性靶向HCC有效且安全的假设。很长的- 本项目的长期目标是开发一种新的免疫策略用于治疗HCC。的 本申请的目的是评估使用HCC细胞系的体外CD 147-CAR-NK原代的功效，以及使用CD 147-CAR-NK原代的体外CD 147-CAR-NK原代的功效。 使用新创建的人CD 147转基因（hCD 147 TG）小鼠模型在体内进行。拟议的工作将 通过分析表面标志物特征、细胞因子产生和 细胞增殖（目的1），测试CD 147-CAR-NK原代在体外和体内（包括严重的 联合免疫缺陷[SCID]、患者来源的异种移植物（PDX）、DEN/PB和HDF诱导的 hCD 147 TG小鼠模型中的原位HCC），并研究分子机制，重点是 免疫突触（目标2），未来计划包括表征CD 147-CAR-NK的原发性毒性， hCD 147 TG HCC小鼠模型。这些研究的结果将简化“关闭”临床试验的路径， 用于过继性细胞疗法以治疗HCC的“货架”CD 147-CAR-NK原代细胞。