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: 9280418
• 负责人: CARL H. JUNE
• 金额: $ 289.74万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280418
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute T Cell Leukemia; Acute leukemia; Address; Adoptive Transfer; B lymphoid malignancy; B-Lymphocytes; Back; Biological; Biometry; CD19 gene; CD22 gene; CRISPR/Cas technology; Cell Therapy; Cells; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Trials; Collaborations; Data; Development; Discipline; Disease; Employee Strikes; 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; clinical investigation; high dimensionality; immune checkpoint; improved; innovation; killings; leukemia; manufacturing facility; 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.

总体汇总 本P01的长期目标是开发下一代嵌合抗原受体免疫疗法 (CAR)T细胞，并将这项研究转化为对血液病患者具有治疗潜力的新疗法。 癌我们中心开发的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）、急性髓细胞性白血病（AML）和慢性骨髓瘤（CML）也是常见的。 淋巴细胞白血病（CLL）仍然是血癌中主要的未满足的医疗需求。我们的核心假设 CAR T细胞和通用CAR T细胞的组合疗法， 编辑将使这种强大的疗法能够覆盖更广泛的血癌患者。我们有 汇集了来自多个学科的杰出调查人员，他们相互合作， 一起出版多年。每一个以疾病为重点的项目都将由一个公认的权威机构领导， 领域为了实现我们的目标，我们开发了三个项目，这些项目将与基本的 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CD 19和CD 22的CAR T细胞将用于解决剩余的未满足的 ALL的医疗需求，这是CD 19逃逸变体的出现;和（ii）通用CAR T细胞靶向 将在CLL患者中检测CD 19，以确定T细胞对治疗的内在抗性的作用。在AML中， CAR-T细胞治疗的中心问题是缺乏AML上存在的已知表面抗原， 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个广阔的治疗窗口。 修饰正常骨髓，使其抵抗抗AML CAR T细胞的杀伤，并提供有效的抗AML CAR T细胞。 对CD 33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疗效将是 通过（i）组合CART-BCMA和CTL 019以消除显性肿瘤PC群体， 和罕见骨髓瘤增殖B细胞，和（ii）修饰CAR T细胞以规避特异性骨髓瘤诱导的 T细胞抑制机制（即，免疫检查点）。 此P01的核心对于我们的进展至关重要，包括提供协作项目管理 和生物统计学，临床安全性和监测，以及财政支持（核心A），一个GMP设施，用于生产 细胞和RNA（核心B），以及最先进的GLP分析平台，以提供细胞和RNA的高维数据 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 将CAR T用于ALL的有效性转化为对所有血液恶性肿瘤的有意义的疗效。