Enhancing Chimeric Antigen Receptor T Cell Therapies for Hematologic Malignancies: Beyond CART 19

增强嵌合抗原受体 T 细胞治疗血液恶性肿瘤：超越 CART 19

• 批准号: 10245062
• 负责人: CARL H. JUNE
• 金额: $ 219.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245062
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute T Cell Leukemia; Acute leukemia; Address; Adoptive Transfer; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Back; Biological; Biometry; CAR T cell therapy; CD19 gene; CD22 gene; CRISPR/Cas technology; Cells; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Trials; Collaborations; Development; Discipline; Disease; Genetic; Genetic Engineering; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Neoplasms; Immunologics; Immunotherapy; In complete remission; International; Journals; Laboratories; Lymphoblastic Leukemia; Malignant Neoplasms; Marrow; Mediating; Medical; Medicine; Monitor; Multiple Myeloma; Myeloid Leukemia; New England; Paper; Patients; Population; Publishing; RNA; Refractory; Relapse; Research; Research Personnel; Resistance; Resource Sharing; Role; Safety; Sampling; Surface Antigens; T-Lymphocyte; Technology; Testing; Therapeutic; Translating; United States; Variant; antitumor effect; authority; bench to bedside; cancer immunotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; clinical investigation; engineered T cells; immune checkpoint; improved; innovation; leukemia; manufacturing facility; multidimensional data; neoplastic; next generation; novel therapeutics; preclinical study; programs; success; synthetic biology; therapy resistant

OVERALL SUMMARY The long-term goal of this P01 is to develop next generation immunotherapy with chimeric antigen receptor (CAR) T cells and to translate this research into new therapies with curative potential for patients with blood cancer. The CAR developed at our center is now in international trials for refractory/relapsed pre-B cell acute lymphocytic leukemia (ALL). However, multiple myeloma (MM), acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) remain as the major unmet medical need in blood cancers. Our central hypothesis is that therapies with combination of CAR T cells and universal CAR T cells created with CRISPR/Cas9 genetic editing will enable this powerful therapy to reach a broader spectrum of patients with blood cancer. We have brought together a cadre of exceptional investigators from multiple disciplines who have collaborated and published together for many years. Each disease-focused project will be led by a recognized authority in the field. To achieve our goals, we have developed three Projects, which will coordinately closely with essential shared resource cores. In Project 1, we will determine the clinical and immunological impact of treating patients on two clinical trials: (i) CAR T cells targeting CD19 and CD22 will be used to address the remaining unmet medical need in ALL, which is the emergence of CD19 escape variants; and (ii) universal CAR T cells targeting CD19 will be tested in patients with CLL to determine the role of T cell intrinsic resistance to therapy. In AML, the central problem in CAR T cell therapy is the lack of a known surface antigen that is present on AML but lacking from normal hematopoiesis. The goal of Project 2 is to open a wide therapeutic window by genetically modifying normal marrow to make it resistant to killing by anti-AML CAR T cells, and delivering potent anti- leukemic CAR T cells specific for CD33. In Project 3, the overall hypothesis is that anti-myeloma efficacy will be maximized by (i) combining CART-BCMA and CTL019 to eliminate both the dominant neoplastic PC population and rare myeloma-propagating B cells, and (ii) modifying CAR T cells to circumvent specific myeloma-induced T-cell-inhibitory mechanisms (i.e., immune checkpoints). The Cores for this P01 are essential for our progress including provision of project management for collaboration and biostatistics, clinical safety and monitoring, and fiscal support (Core A), a GMP facility for manufacture of cells and RNA (Core B), and a state-of-the-art platform for GLP analysis to provide high dimensional data of the samples generated in all Projects (Core C). The potential for paradigm shifting impact is to transform the lessons of CAR T for ALL into meaningful efficacy against all hematologic malignancies.

总结 该P01的长期目标是用嵌合抗原受体开发下一代免疫疗法 （CAR）T细胞，并将这项研究转化为血液患者具有治愈潜力的新疗法 癌症。在我们中心开发的汽车现在正在国际耐火/复发前B细胞急性试验中 淋巴细胞性白血病（全部）。但是，多发性骨髓瘤（MM），急性髓性白血病（AML）和慢性 淋巴细胞性白血病（CLL）仍然是血液癌的主要未满足医疗需求。我们的中心假设 是用CRISPR/CAS9遗传的CAR T细胞和通用汽车T细胞组合的疗法 编辑将使这种强大的疗法能够达到更广泛的血液癌患者。我们有 从合作和 一起出版了很多年。每个以疾病为中心的项目将由公认的权威领导 场地。为了实现我们的目标，我们开发了三个项目，这些项目将与必不可少 共享资源核心。在项目1中，我们将确定治疗患者的临床和免疫学影响 在两个临床试验中：（i）针对CD19和CD22的CAR T细胞将用于解决其余的未完成 医疗需求总共是CD19逃生变体的出现； （ii）靶向的通用汽车T细胞 CD19将在CLL患者中进行测试，以确定T细胞对治疗的固有耐药性的作用。在AML， 汽车T细胞疗法中的主要问题是缺乏AML上存在的已知表面抗原，但 缺乏正常的造血。项目2的目标是通过遗传开放一个宽的治疗窗口 修饰正常骨髓以使其具有抗AML CAR T细胞杀死的能力，并提供有效的抗 白血病汽车T细胞特有的CD33。在项目3中，总体假设是抗肌瘤功效将是 最大化（i）结合CART-BCMA和CTL019以消除两种主要的肿瘤PC种群 和罕见的骨髓瘤B细胞，以及（ii）修饰CAR T细胞以绕过特定的骨髓瘤诱导 T细胞抑制机制（即免疫检查点）。 该P01的核心对于我们的进度至关重要，包括提供协作项目管理 以及生物统计学，临床安全和监测以及财政支持（核心A），用于制造的GMP设施 细胞和RNA（核心B），以及用于GLP分析的最新平台，可提供高维数据 在所有项目（核心C）中生成的样本。范式转移影响的潜力是改变课程 对所有血液学恶性肿瘤的有意义的疗效。