TARGETING ROR1 WITH CHIMERIC ANTIGEN RECEPTOR MODIFIED T CELLS

用嵌合抗原受体修饰的 T 细胞靶向 ROR1

基本信息

批准号：
9514861
负责人：
STANLEY R. RIDDELL
金额：
$ 45.87万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9514861
关键词：
Acute Lymphocytic Leukemia Adipose tissue Adoptive Cell Transfers Adoptive Transfer Adult Antibodies Autologous B-Lymphocytes Blood Bone Marrow CD19 gene CD28 gene CD3 Antigens CD4 Positive T Lymphocytes CD8B1 gene Cancer cell line Cause of Death Cell surface Cells Chronic Lymphocytic Leukemia Clinic Clinical Clinical Trials Diagnosis Embryonic Development Engineered Gene Engineering Epidermal Growth Factor Receptor Epithelial Epitopes Formalin Funding Gene Transfer Grant Hematologic Neoplasms Homologous Gene Human Immunize Immunodeficient Mouse Immunoglobulins Immunohistochemistry Immunosuppressive Agents Immunotherapy In Vitro Lentivirus Vector Macaca mulatta Malignant Neoplasms Malignant neoplasm of lung Mantle Cell Lymphoma Mediating Messenger RNA Modeling Monoclonal Antibodies Mus Neural Cell Adhesion Molecule L1 Non-Hodgkin&apos s Lymphoma Non-Small-Cell Lung Carcinoma Normal tissue morphology Orphan Oryctolagus cuniculus PDCD1LG1 gene Pancreas Paraffin Embedding Patients Pattern Phenotype ROR1 gene Receptor Cell Receptor Protein-Tyrosine Kinases Refractory Resistance Safety Signal Transduction Site Solid Solid Neoplasm Specimen Subfamily lentivirinae T cell therapy T memory cell T-Cell Receptor T-Lymphocyte Tissue Embedding Tissues Transcript Translating Translations Tumor Antigens Variant Work base cancer cell cellular engineering cellular transduction chemotherapy chimeric antigen receptor clinical development clinical translation cohort companion diagnostics design first-in-human genetically modified cells immune checkpoint improved in vivo knock-down malignant breast neoplasm mesothelin neoplastic cell next generation nonhuman primate novel outcome forecast preclinical study public health relevance receptor safety and feasibility small hairpin RNA suicide gene trafficking triple-negative invasive breast carcinoma tumor tumor eradication tumor microenvironment tumor xenograft

项目摘要

PROJECT SUMMARY/ABSTRACT Adoptive cell therapy (ACT) with tumor-reactive T cells isolated from the blood or tumor, or engineered with T cell receptors (TCRs) or chimeric antigen receptors (CARs) by gene transfer, is providing new treatment options for patients with chemotherapy refractory malignancies. Developing effective ACT for common cancers such as breast and lung cancer represents an urgent unmet need, but has posed several obstacles. These include the identification of molecules expressed on tumor cells that can be targeted safely and the design of optimal CARs that both redirect T cells to recognize tumors and overcome the immunosuppressive local tumor microenvironment that interferes with T cell mediated tumor eradication. We have identified the receptor tyrosine kinase-like orphan receptor ROR1 as a promising target for CAR-T cell therapy of human malignancies, including refractory chronic lymphocytic leukemia, mantle cell lymphoma, triple negative breast cancer and non small cell lung cancer. We designed and optimized ROR1-specific CARs for recognition of ROR1 positive tumors in vitro and for efficacy in immunodeficient mice engrafted with human tumor xenografts, and demonstrated that transferring autologous ROR1 CAR-T cells in non-human primates was safe. We have developed a monoclonal antibody to identify patients that have ROR1 positive tumors and produced a clinical grade ROR1 CAR lentiviral vector. Thus, we are now poised to perform a first-in-human clinical trial targeting ROR1 in both hematologic malignancies and solid tumors and to develop next generation ROR1 CARs designed to improve safety and for superior function in the tumor microenvironment. The specific aims are: Aim 1: To determine the feasibility and safety of targeting ROR1 with autologous CD8+ and CD4+ T cells engineered with a ROR1/4-1BB/CD3 CAR and formulated in a defined composition for patients with hematologic malignancies (Cohort A) and solid tumors (Cohort B). Aim 2: To evaluate CAR-T cell phenotype, function and trafficking to tumor sites in vivo, and determine potential mechanisms of tumor resistance. Aim 3: To evaluate novel ROR1 CAR designs that enhance selective tumor cell recognition and/or overcome negative signaling by PDL1.

项目概要/摘要过继细胞疗法 (ACT) 使用从血液或肿瘤中分离的肿瘤反应性 T 细胞，或用通过基因转移的 T 细胞受体 (TCR) 或嵌合抗原受体 (CAR) 正在提供新的治疗方法为化疗难治性恶性肿瘤患者提供治疗选择，针对常见癌症开发有效的 ACT 疗法。乳腺癌和肺癌等癌症代表了迫切的未满足需求，但也带来了一些障碍。包括识别肿瘤细胞上表达的可安全靶向的分子以及设计最佳 CAR 既能重定向 T 细胞识别肿瘤，又能克服局部肿瘤的免疫抑制我们已经鉴定出干扰 T 细胞介导的肿瘤根除的微环境。酪氨酸激酶样孤儿受体 ROR1 作为人类 CAR-T 细胞治疗的有希望的靶点恶性肿瘤，包括难治性慢性淋巴细胞白血病、套细胞淋巴瘤、三阴性乳腺癌我们设计并优化了 ROR1 特异性 CAR 来识别癌症和非小细胞肺癌。 ROR1 阳性肿瘤体外试验以及对移植人类肿瘤异种移植物的免疫缺陷小鼠的疗效，并证明在非人类灵长类动物中转移自体 ROR1 CAR-T 细胞是安全的。开发了一种单克隆抗体来识别患有 ROR1 阳性肿瘤的患者，并产生了临床因此，我们现在准备进行首次人体临床试验。 ROR1 在血液系统恶性肿瘤和实体瘤中的作用，并开发下一代 ROR1 CAR 旨在提高肿瘤微环境的安全性和卓越功能，具体目标是：目标 1：确定用自体 CD8+ 和 CD4+ T 细胞靶向 ROR1 的可行性和安全性采用 ROR1/4-1BB/CD3 CAR 进行设计，并配制为针对患有以下疾病的患者的特定组合物：血液系统恶性肿瘤（A 组）和实体瘤（B 组）。目标 2：评估 CAR-T 细胞的表型、功能和体内肿瘤部位的运输，并确定肿瘤耐药的潜在机制。目标 3：评估新型 ROR1 CAR 设计，以增强选择性肿瘤细胞识别和/或克服 PDL1 的负信号传导。