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Enhancing Chimeric Antigen Receptor T Cell Therapies for HematologicMalignancies: 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：
10713199
负责人：
CARL H. JUNE
金额：
$ 278.23万
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 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713199
关键词：
Acute Myelocytic Leukemia Acute T Cell Leukemia Acute leukemia Address Adoptive Transfer Authorization documentation Autoimmune Diseases B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia Back Biological Biometry Blood CAR T cell therapy CD19 gene CRISPR/Cas technology CTLA4 gene Cell Therapy Cells Chronic Lymphocytic Leukemia Clinic Clinical Clinical Trials Collaborations Development Discipline Disease Engineering FDA approved Funding Future Generations Genes Genetic Genetic Engineering Gills Goals Hematologic Neoplasms Hematopoiesis Hematopoietic Neoplasms Hematopoietic System Human Genome Immune Immunologics Immunotherapy In complete remission Individual Interleukin-2 International Joints Journals Laboratories Licensing Lymphoblastic Leukemia Lymphoma Malignant Neoplasms Marrow Mediating Medical Medicine Messenger RNA Modification Monitor Multiple Myeloma Mutate Myeloid Leukemia New England PTPRC gene Paper Patients Persons Publications Publishing Refractory Relapse Research Research Personnel Resistance Resource Sharing Safety Sampling Services Small-Cell Lymphoma Solid Source Surface Antigens T-Lymphocyte Technology Testing Therapeutic Toxic effect Translating United States Vaccines antitumor effect authority base editing bench to bedside cancer cell cancer immunobiology cancer immunotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical investigation efficacy testing engineered T cells gene therapy genome editing improved indexing innovation leukemia leukemia/lymphoma lipid nanoparticle manufacturing facility multidimensional data next generation novel novel therapeutics overexpression preclinical study programs rational design standard of care synthetic biology tool tumor

项目摘要

OVERALL PROJECT SUMMARY / ABSTRACT The long-term goals of this renewal P01 are 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 was the first cell and gene therapy to ever receive approval from the FDA, initially for refractory/relapsed pre-B cell acute lymphocytic leukemia (ALL) in 2017 and lymphoma in 2018. 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 advanced forms of human genome 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 recognized authorities in the field. To achieve our goals, we have three Projects that build on progress during the previous funding period and will continue to coordinate 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 will be tested with genetic disruption of CD5, CTLA- 4 and TET2 to address CLL and lymphoma, which is lack of sustained effector CAR T function in these patients. 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 for AML 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 CD45. Engineered HSC that are genetically edited to install a hematopoietic system facilitating non-toxic therapy with these potent CAR T cells will be developed. In Project 3, the overall hypothesis is that anti-myeloma efficacy will be maximized by (i) testing the efficacy of marrow- derived CAR T compared to current standard of care blood-derived CAR T (ii) improving persistence of BCMA CAR T with orthogonally mutated IL-2/IL-2R technology and mRNA/lipid-nanoparticle vaccine technology to overcome suboptimal persistence and efficacy of current BCMA T cells. The Scientific and Administrative 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 identification of new binders for CAR targets (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). Our renewal application has the potential for paradigm-shifting impact to transform the lessons of CAR T for ALL into meaningful efficacy against all hematologic malignancies, solid cancers and provides direction for extending beyond cancer to autoimmune disorders.

整体项目摘要/摘要

项目成果

期刊论文数量（72）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adoptive T-cell therapy for Hodgkin lymphoma.

DOI：
10.1182/bloodadvances.2021005304
发表时间：
2021-10-26
期刊：
Blood advances
影响因子：
7.5
作者：
Ho C;Ruella M;Levine BL;Svoboda J
通讯作者：
Svoboda J

Chimeric Antigen Receptor Therapy.

DOI：
10.1056/nejmra1706169
发表时间：
2018-07-05
期刊：
The New England journal of medicine
影响因子：
0
作者：
June CH;Sadelain M
通讯作者：
Sadelain M

Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia.

DOI：
10.1200/jco.19.01892
发表时间：
2020-02-10
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
0
作者：
Frey NV;Shaw PA;Hexner EO;Pequignot E;Gill S;Luger SM;Mangan JK;Loren AW;Perl AE;Maude SL;Grupp SA;Shah NN;Gilmore J;Lacey SF;Melenhorst JJ;Levine BL;June CH;Porter DL
通讯作者：
Porter DL

Acute Kidney Injury Following Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma in a Kidney Transplant Recipient.

DOI：
10.1016/j.xkme.2021.03.011
发表时间：
2021-07
期刊：
Kidney medicine
影响因子：
3.9
作者：
Melilli E;Mussetti A;Linares GS;Ruella M;La Salette C;Savchenko A;Taco MDR;Montero N;Grinyo J;Fava A;Gomà M;Meneghini M;Manonelles A;Cruzado J;Sureda A;Bestard O
通讯作者：
Bestard O

Born to survive: how cancer cells resist CAR T cell therapy.