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

项目摘要 实体瘤是美国最常见的癌症死亡原因。嵌合抗原受体(CAR) T细胞使复发和难治性B细胞恶性肿瘤的治疗发生了革命性变化，但尚未介导 对实体肿瘤患者有实质性的好处。CARS将T细胞强大的抗肿瘤活性重新定向到 靶向肿瘤细胞表面表达的抗原。在实体癌中，大多数靶抗原是共享的 与正常的，重要的组织，因此汽车可以调解危险的和潜在的致命毒性。这有 阻止了CAR T细胞在实体瘤中的广泛应用。当前一代的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单一输入/单一输出 当T细胞找到它的目标时激活的系统。我们已经产生了一种新的机制来指导 只有当存在多种抗原时，CAR T细胞才会做出反应，极大地增强了我们产生 针对实体瘤的程序性免疫治疗反应。该平台的优化和应用将 大大增加CAR T细胞的潜在靶点数量，这是一种有望实现范式转换的技术 对实体瘤患者有显著的临床益处。这一战略也将被证明是有效利用 CAR T细胞用于治疗其他癌症，如髓系恶性肿瘤，以及各种疾病，如自身免疫和 纤维化症。这里提出的新系统有可能重新定义可编程蜂窝的前景 治疗。

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.