权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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.

整体总结