Novel synthetic receptors with improved antigen specificity and specificity for cancer therapy

具有改进的抗原特异性和癌症治疗特异性的新型合成受体

• 批准号: 10601316
• 负责人: STANLEY R. RIDDELL
• 金额: $ 37.93万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601316
• 关键词: Address; Adoptive Cell Transfers; Antibodies; Antigen Targeting; Antigens; B lymphoid malignancy; CD19 gene; CD22 gene; CD28 gene; CD3 Antigens; CD8-Positive T-Lymphocytes; Cell Differentiation process; Cell physiology; Cell surface; Cells; Chronic Lymphocytic Leukemia; Clinic; Clinical Data; Data; Development; Disease remission; FDA approved; Foundations; Functional disorder; Funding; Gene Transfer; Grant; Hematopoietic Neoplasms; Heterogeneity; Hybrids; Immunoglobulin Constant Region; Infiltration; Knock-in; Knock-out; Ligands; Light; Link; Logic; MS4A1 gene; Major Histocompatibility Complex; Malignant Neoplasms; Modality; Multiple Myeloma; Normal Cell; Outcome; Patients; Peptides; Population; Pre-Clinical Model; Progress Reports; Property; Proteins; ROR1 gene; Receptor Signaling; Refractory; Relapse; Sensitivity and Specificity; Signal Pathway; Signal Transduction; Solid; Solid Neoplasm; Specific qualifier value; Specificity; Surface; T cell therapy; T-Cell Immunologic Specificity; T-Cell Receptor; T-Lymphocyte; TRA@ gene cluster; TRB@ gene cluster; Toxic effect; Tumor Antigens; Tumor Escape; Tumor-infiltrating immune cells; Universities; Washington; Work; base; cancer cell; cancer therapy; cancer type; chimeric antigen receptor; chimeric antigen receptor T cells; clinically relevant; curative treatments; cytokine; density; design; engineered T cells; exhaustion; gamma secretase; genomic locus; improved; in vitro Assay; in vivo; in vivo Model; inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; neoplastic cell; next generation; novel; pre-clinical; prevent; receptor; synaptogenesis; targeted treatment; tumor; tumor heterogeneity; tumor microenvironment

Abstract Adoptive cell therapy using T cells modified by gene transfer to express T cell receptors or synthetic chimeric antigen receptors (CARs) that specify T cell recognition of tumor associated antigens can be effective in patients with refractory malignancies. Clinical data has shown that tumor cells that express low levels of antigen or that have heterogeneous antigen expression can escape and cause relapse. To address the barrier of low antigen density on tumor cells, we have designed novel synthetic hybrid receptors based on principles of T cell receptor signaling that have superior properties and may be capable of eliminating tumor cells with low antigen levels. To address the barrier of heterogeneous antigen expression on tumor cells, we designed colocalization-dependent orthogonal protein switches that perform ‘AND’, ‘OR’, and ‘NOT’ Boolean logic at the cell surface. In principle, this approach can instruct T cells to eliminate heterogeneous tumor cell populations and spare normal antigen positive cells, extending the constellation of antigens that can be safely targeted. The studies in this application will advance these two classes of next generation synthetic receptors for multiple clinically relevant target antigens to achieve more effective and safe elimination of tumors with low and/or heterogeneous antigen expression. The specific aims are: Aim 1: To evaluate signaling and function of novel CAR/TCR hybrid receptors in primary T cells. Signaling, synapse formation, antigen sensitivity, and in vivo function and fate of T cells expressing CAR-TCR hybrid receptors introduced by lentiviral transduction or by knock-in to the T cell receptor alpha gene locus, will be compared to T cells expressing CD28/CD3z and 4-1BB/CD3z CARs targeting the same antigens. Aim 2: To evaluate chimeric costimulatory receptors for T cells engineered with CAR/TCRs. We will evaluate whether the addition of costimulation in CAR/TCR engineered T cells by co-expressing chimeric molecules that engage a tumor associated ligand will enhance antitumor function. Aim 3 To design OR and AND gated CARS specific for multiple myeloma (MM) antigens and evaluate their ability to prevent tumor escape. Multiple myeloma is responsive to T cell therapy targeting single antigens, but tumor cell heterogeneity allows escape. Co-localization dependent protein switches that can perform OR and AND logic gated recognition of heterogeneous tumor cells will be developed and evaluated for targeting multiple myeloma antigens.

摘要 使用通过基因转移修饰的T细胞以表达T细胞受体或合成的嵌合T细胞受体的免疫细胞疗法 特异性T细胞识别肿瘤相关抗原的抗原受体（CAR）可以有效地 难治性恶性肿瘤患者。临床数据表明，表达低水平的 抗原或具有异质性抗原表达的细胞可逃逸并引起复发。解决障碍 由于肿瘤细胞上抗原密度低，我们设计了基于以下原理的新型合成杂合受体： T细胞受体信号传导具有上级特性，并且可能能够以低的细胞毒性消除肿瘤细胞。 抗原水平。为了解决肿瘤细胞上异质性抗原表达的障碍，我们设计了 共定位依赖的正交蛋白质开关，其在所述蛋白质开关处执行"与"、"或"和"非"布尔逻辑。 细胞表面原则上，这种方法可以指导T细胞消除异质性肿瘤细胞群 并保留正常的抗原阳性细胞，从而扩大了可以安全靶向的抗原群。 本申请中的研究将推进这两类下一代合成受体， 多种临床相关的靶抗原，以实现更有效和安全的肿瘤消除， 和/或异质抗原表达。具体目标是： 目的1：评估新型CAR/TCR杂合受体在原代T细胞中的信号传导和功能。 表达CAR-TCR的T细胞的信号传导、突触形成、抗原敏感性以及体内功能和命运 通过慢病毒转导或通过敲入T细胞受体α基因座引入的杂合受体将 与表达靶向相同抗原的CD28/CD3z和4 - 1BB/CD3z CAR的T细胞相比。 目的2：评估嵌合共刺激受体的T细胞工程与CAR/TCR。我们将 评估是否通过共表达嵌合抗原在CAR/TCR工程化T细胞中添加共刺激， 与肿瘤相关配体结合的分子将增强抗肿瘤功能。 目的3设计特异性针对多发性骨髓瘤（MM）抗原的OR门控和AND门控CARS， 防止肿瘤逃逸的能力。多发性骨髓瘤对靶向单个 抗原，但肿瘤细胞的异质性允许逃逸。共定位依赖性蛋白质开关， 将开发和评价异质性肿瘤细胞的OR和AND逻辑门控识别， 靶向多发性骨髓瘤抗原。