CD147-CAR-NK Cells for Hepatocellular Carcinoma Treatment

CD147-CAR-NK 细胞用于肝细胞癌治疗

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：该项目将通过重新开发一种“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类原代自然杀伤 (NK) 细胞最近的临床试验测试了一种特定的肝细胞癌抗原（CD147）。癌症免疫疗法已显示出治疗各种癌症的有希望的结果。涉及改造免疫细胞来表达嵌合抗原受体（CAR），它结合了肿瘤抗原这些 CAR 修饰的过继转移具有免疫细胞激活的特异性。将免疫细胞（特别是 T 细胞，CAR T）注入患者体内，在治疗多种疾病方面取得了显著成功然而，CAR T 疗法通常具有显着的毒性、高成本、以实现CAR细胞疗法治疗实体瘤的承诺。癌症方面，一个关键的挑战是确定一种安全有效的实体瘤。抗原，以及“现成”细胞产品的开发，我们最近制定了一项新策略。我们报告说，针对肝细胞癌（HCC，人类最致命的实体瘤癌症之一）。 T 细胞和 NK 细胞用针对 HCC 表面标记物 CD147（也称为 Basigin）的 CAR 转导 (BSG)或细胞外基质金属蛋白酶诱导剂(EMMPRIN)，可有效杀灭多种恶性肿瘤 HCC 细胞系（包括 SK-Hep1 和 HepG2 细胞系）、体外原发性 HCC 以及异种移植和肿瘤患者来源的肝癌异种移植 (PDX) 小鼠模型（Tseng, HC., D. 等人，Nature Communications.，2020，）。包括源自第三方外设或的 CD147-CAR-NK 细胞的确切机制脐带血（CD147-CAR-NKprimary）能否控制HCC以及CD147-CAR-NK细胞在体内是否安全。提议检验 CD147-CAR-NK 主要靶向 HCC 有效且安全的假设。该项目的长期目标是开发一种治疗 HCC 的新型免疫治疗策略。本申请的目的是使用 HCC 细胞系和在体外评估 CD147-CAR-NKprimary 的功效体内使用新创建的人类 CD147 转基因（hCD147TG）小鼠模型。通过分析表面标记谱、细胞因子产生和细胞增殖（目标1），测试CD147-CAR-NKprimary的体外和体内功效（包括严重的联合免疫缺陷 [SCID]、患者来源的异种移植物 (PDX) 以及 DEN/PB 和 HDF 诱导的 hCD147TG 小鼠模型中的原位 HCC）并研究其分子机制，重点是免疫突触（目标 2），未来计划包括 CD147-CAR-NK 主要毒性的表征 hCD147TG HCC 小鼠模型将简化“off-”临床试验的路径。用于治疗 HCC 的过继细胞疗法的现成 CD147-CAR-NK 原代细胞。