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Mechanisms regulating chimeric antigen receptor T-cell activity in cancer

癌症中嵌合抗原受体 T 细胞活性的调节机制

基本信息

批准号：
10460171
负责人：
Nathan Singh
金额：
$ 23.81万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460171
关键词：
AKT inhibition Acute Lymphocytic Leukemia Aftercare Allogenic Antibodies Antigens Apoptosis B-Cell Neoplasm Biological Biological Markers Biology CD19 Antigens CD19 gene CD95 Antigens Cell Surface Proteins Cell Therapy Cell physiology Cells Cellular immunotherapy Cessation of life Chemicals Clinical Clinical Trials Computational Biology Cytotoxin Data Defect Development Ectopic Expression Environment Failure Fellowship Foundations Future Genes Genetic Goals Hematologic Neoplasms Hematology Hematopoietic Neoplasms Hybrids Immunologic Memory Immunologist Immunology Immunotherapy Impairment In Vitro Innovative Therapy Internal Medicine International Investigation Knock-out Knowledge Lead Ligands Ligation Light Lymphoma cell Malignant Neoplasms Mediating Membrane Proteins Memory Memory impairment Mentors Mentorship Molecular Molecular Biology Molecular Immunology Molecular Profiling Non-Hodgkin&apos s Lymphoma Oncology Outcome Pathway interactions Patient-Focused Outcomes Patients Pennsylvania Physicians Positioning Attribute Proteins Proteomics Proto-Oncogene Proteins c-akt Receptor Activation Receptor Cell Receptor Signaling Research Research Personnel Residencies Resistance Role Sampling Science Scientist Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Surface T cell regulation T memory cell T-Cell Receptor T-Lymphocyte TNFSF10 gene Techniques Toxin Training Training Programs Tumor Escape Tumor Immunity Universities Vocational Guidance Work Xenograft Model Xenograft procedure base cancer immunotherapy cancer therapy career chemotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical practice cohesion curative treatments cytotoxicity design engineered T cells genome editing genome-wide hematopoietic cell transplantation human model improved improved outcome in vivo inhibitor insight knockout gene leukemia leukemia relapse leukemia/lymphoma mouse model neoplastic cell novel perforin phosphoproteomics predictive signature prevent programs receptor receptor expression research clinical testing responders and non-responders response skills success tumor

项目摘要

PROJECT SUMMARY The proposed research focuses on defining the molecular regulators of chimeric antigen receptor (CAR) T- cell activity against cancer. CAR therapy has generated great enthusiasm in light of its efficacy in the treatment of B-cell neoplasms, however significant limitations still prevent its broader success. Approximately ½ of patients with non-Hodgkin lymphoma do not respond, reflecting a failure of cytotoxicity, and many patients with acute lymphoblastic leukemia relapse after treatment due to a failure of CAR T-cell persistence. The studies proposed aim to determine how these essential T-cell functions are regulated in CAR T cells. Preliminary data suggest that death receptors, surface proteins that initiate apoptosis, are essential in CAR T- cell cytotoxicity. Using molecular profiling and gene editing of T-cell and tumor samples from Penn's CAR clinical trials, I will define the mechanistic role of death receptors in CAR-driven cytotoxicity and tumor escape. Persistence is mediated by the formation of immune memory, and data show that CARs activate cellular programs that suppress memory formation. The studies outlined in this proposal will utilize xenograft mouse models of human leukemia to determine how CAR activation of the PI3K signaling pathway impedes formation of memory cells and impairs CAR T-cell persistence. Using clinical trial samples, this work will further aim to identify additional molecular pathways that limit persistence using proteomic and phosphoproteomic analysis. The goal of the proposed five-year training program is the development of my independent research career as a physician-scientist focused on cellular immunotherapies. I completed residency training in Internal Medicine and am in my final year of fellowship training in Hematology/Oncology. I am now expanding my scientific expertise in molecular biology and immunology, as well as clinical expertise in allogeneic hematopoietic cell transplantation. My goal for the near future is to develop the skills necessary to drive a distinctive program of scientific investigation. Specifically, I seek to gain expertise in genome editing, proteomics and computational biology through didactic and practical training in order to augment my scientific skillset and establish independence. My long-term goal is to enhance the efficacy of T-cell immunotherapy and improve outcomes for patients with hematologic cancers. I will be mentored by Dr. Carl June, an international leader in cellular immunotherapy who is well equipped to provide me with the mentorship I need to succeed. To add breadth and depth to my scientific and career guidance, I have assembled a Mentoring Committee composed of exceptional scientists. The University of Pennsylvania had led the field of cellular immunotherapy science and clinical practice, and provides the ideal environment for my training as a cell therapy investigator. The proposed studies have the potential to provide critical insight into CAR biology. The application of cutting-edge techniques to interrogate clinical trial samples and dissect the mechanisms limiting CAR activity will identify features that predict success and directly inform the design of more effective CAR therapies.

项目总结