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.

总体总结 P01的长期目标是开发具有嵌合抗原受体的下一代免疫疗法 (CAR)T细胞，并将这项研究转化为对血液患者具有治疗潜力的新疗法 癌症。我们中心开发的CAR目前正在进行难治性/复发性前B细胞急性白血病的国际试验 淋巴细胞白血病(ALL)。然而，多发性骨髓瘤(MM)、急性髓系白血病(AML)和慢性 淋巴细胞性白血病(CLL)仍然是血癌中尚未得到满足的主要医疗需求。我们的中心假设 用CRISPR/Cas9基因创造的CAR T细胞和通用CAR T细胞的组合治疗 编辑将使这一强大的疗法能够覆盖更广泛的血癌患者。我们有 汇聚了一批来自多个学科的杰出调查人员，他们合作并 多年来共同出版。每个以疾病为重点的项目都将由一个公认的权威机构领导 菲尔德。为了实现我们的目标，我们开发了三个项目，这些项目将与Essential密切协调 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 在两项临床试验中：(I)靶向CD19和CD22的CAR T细胞将用于解决剩余的未满足 所有的医疗需要，这是CD19逃逸变体的出现；以及(Ii)普遍的CAR T细胞靶向 CD19将在慢性淋巴细胞性白血病患者中进行检测，以确定T细胞内在抵抗治疗的作用。在AML中， CAR T细胞治疗的中心问题是缺乏一种存在于AML上的已知表面抗原，但 缺乏正常的造血功能。项目2的目标是通过基因治疗打开一扇广阔的治疗之窗 对正常骨髓进行修饰，使其耐受抗AML CAR T细胞的杀伤，并提供有效的抗AML CD33特异性的白血病CAR T细胞。在项目3中，总体假设是抗骨髓瘤的疗效将是 通过以下方式最大化：(I)结合CART-BCMA和CTL019以消除主要的肿瘤PC种群 和罕见的骨髓瘤B细胞，以及(Ii)修改CAR T细胞以避开特定骨髓瘤诱导的 T细胞抑制机制(即免疫检查点)。 P01的核心对于我们的进展至关重要，包括为协作提供项目管理 和生物统计学、临床安全和监测，以及财政支持(核心A)，这是一个GMP设施，用于制造 细胞和RNA(核心B)，以及用于GLP分析的最先进平台，以提供 在所有项目中生成的样本(核心C)。范式转变的潜在影响是改变经验教训 Car T for All对所有血液系统恶性肿瘤都有有意义的疗效。