Hijacking the T cell machinery for logic-gated CAR T cell control

劫持 T 细胞机器以进行逻辑门控 CAR T 细胞控制

• 批准号: 10246119
• 负责人: Robbie G. Majzner
• 金额: $ 80万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246119
• 关键词: Antigen Targeting; Antigens; Autoimmunity; B lymphoid malignancy; Cancer Etiology; Caring; Cell Therapy; Cessation of life; Clinical; Dangerousness; Disease; Fibrosis; Generations; Immunotherapeutic agent; Logic; Malignant Neoplasms; Mediating; Myeloproliferative disease; Normal tissue morphology; Output; Patients; Refractory; Relapse; Research Personnel; Risk; Safety; Solid; Solid Neoplasm; Surface; System; T cell response; T-Lymphocyte; Technology; Tissues; Toxic effect; Tumor Antigens; Tumor Tissue; United States; cancer immunotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; effective therapy; innovation; neoplastic cell; novel; prevent; programs; receptor; response; tumor; tumor specificity

Project Summary Solid tumors are the most common cause of cancer death in the United States. Chimeric antigen receptor (CAR) T cells have revolutionized the care of relapsed and refractory B cell malignancies but have not yet mediated substantial benefit for patients with solid tumors. CARs redirect the powerful anti-tumor activity of a T cell against a tumor cell by targeting an antigen expressed on its surface. In solid cancers, most target antigens are shared with normal, vital tissues, and therefore CARs can mediate dangerous and potentially fatal toxicity. This has prevented widespread application of CAR T cells to solid tumors. The current generation of CAR T cells is unable to differentiate between tumor tissue and normal tissue largely because they rely on a single input/single output system that activates whenever the T cell finds its target. We have generated a novel mechanism to direct the CAR T cell response only when multiple antigens are present, greatly enhancing our ability to generate a programmed immunotherapeutic response against solid tumors. Optimization and application of this platform will greatly enhance the number of potential targets for CAR T cells, a paradigm shifting technology poised to mediate significant clinical benefit for patients with solid tumors. This strategy will also prove essential to effectively use CAR T cells to treat other cancers, such as myeloid malignancies, and diseases as diverse as autoimmunity and fibrosis. The novel system proposed here has the potential to redefine the landscape for programmable cellular therapies.

项目摘要 实体瘤是美国癌症死亡的最常见原因。嵌合抗原受体 T细胞已经彻底改变了复发性和难治性B细胞恶性肿瘤的治疗，但尚未介导 对实体瘤患者有很大益处。汽车重定向T细胞的强大抗肿瘤活性， 通过靶向肿瘤细胞表面表达的抗原来治疗肿瘤细胞。在实体癌中，大多数靶抗原是共享的， 因此汽车可以介导危险和潜在致命的毒性。这 阻止了CAR T细胞在实体瘤中的广泛应用。目前这一代的CAR T细胞无法 区分肿瘤组织和正常组织很大程度上是因为它们依赖于单输入/单输出 当T细胞找到目标时，这个系统就会激活。我们创造了一种新的机制来引导 只有当存在多种抗原时，CAR T细胞才能应答，这大大增强了我们产生CAR T细胞的能力。 针对实体瘤的程序性免疫应答。该平台的优化和应用， 大大增加了CAR T细胞的潜在靶点数量，这是一种有望介导 对实体瘤患者有显著的临床获益。这一战略也将被证明是至关重要的有效利用 CAR T细胞治疗其他癌症，如骨髓恶性肿瘤，以及各种疾病，如自身免疫和 纤维化这里提出的新系统有可能重新定义可编程蜂窝网络的前景。 治疗