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 这个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 癌症。我们中心开发的 CAR 目前正在进行针对难治性/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）、急性髓性白血病（AML）和慢性 淋巴细胞白血病（CLL）仍然是血癌中未满足的主要医疗需求。我们的中心假设 是结合 CAR T 细胞和通过 CRISPR/Cas9 基因创建的通用 CAR T 细胞的疗法 编辑将使这种强大的疗法能够惠及更广泛的血癌患者。我们有 汇集了一批来自多个学科的杰出研究人员，他们进行了合作和 共同出版多年。每个以疾病为重点的项目都将由该领域公认的权威领导 场地。为了实现我们的目标，我们开发了三个项目，这些项目将与重要的项目密切协调 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 两项临床试验：(i) 靶向 CD19 和 CD22 的 CAR T 细胞将用于解决剩余的未满足问题 ALL 的医疗需求，即 CD19 逃逸变体的出现； (ii) 通用 CAR T 细胞靶向 CD19 将在 CLL 患者中进行测试，以确定 T 细胞对治疗的内在耐药性的作用。在反洗钱中， CAR T 细胞疗法的核心问题是缺乏 AML 上存在的已知表面抗原，但 正常造血功能缺乏。项目2的目标是通过基因治疗打开一个广阔的治疗窗口 修改正常骨髓，使其能够抵抗抗 AML CAR T 细胞的杀伤，并提供有效的抗 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功效将是 通过 (i) 结合 CART-BCMA 和 CTL019 来消除主要的肿瘤性 PC 群体，从而最大化 和罕见的骨髓瘤增殖 B 细胞，以及 (ii) 修改 CAR T 细胞以规避特定的骨髓瘤诱导的 T 细胞抑制机制（即免疫检查点）。 P01 的核心对于我们的进步至关重要，包括提供协作项目管理 和生物统计学、临床安全和监测以及财政支持（核心 A），一个用于制造的 GMP 设施 细胞和 RNA（核心 B），以及最先进的 GLP 分析平台，可提供细胞和 RNA 的高维数据 所有项目（核心 C）中生成的样本。范式转变影响的潜力是改变教训 CAR T for ALL 对所有血液恶性肿瘤具有有意义的疗效。