التفاصيل البيبلوغرافية
| العنوان: |
Improving NK and T Cell Immunotherapies for Hematologic Malignancies |
| المؤلفون: |
Wong, Derek Perseus |
| بيانات النشر: |
Case Western Reserve University School of Graduate Studies / OhioLINK, 2023. |
| سنة النشر: |
2023 |
| المجموعة: |
Ohiolink ETDs |
| Original Material: |
http://rave.ohiolink.edu/etdc/view?acc_num=case1680822253188102Test |
| مصطلحات موضوعية: |
Biology, Biomedical Research, Immunology, Medicine, Molecular Biology, Oncology, immunotherapy, CAR-T cell therapy, BAFF, hematologic malignancies, B cell cancers, mantle cell lymphoma, non-Hodgkin lymphoma, multiple myeloma, acute lymphoblastic leukemia, NK cells, Cdk5, p35, cytotoxicity, TGF-beta, immunosuppression |
| الوصف: |
Advancements in therapy have improved remission and prolonged survival for patients with B cell malignancies. Unfortunately, for many challenging cancer subtypes such as mantle cell lymphoma, most patients will still relapse and die from the cancer. Chimeric antigen receptor (CAR)-T cell therapy uses genetically modified T cells expressing CAR protein to recognize and kill cancers expressing a specific antigen, such as CD19. Although CD19 CAR-T therapy has been very effective against relapsed/refractory B cell cancers, antigen escape and relapse still occur in up to 40% of patients treated with CD19 CAR-T. This work describes the creation and validation of a novel, BAFF ligand-based CAR that aims to prevent antigen escape by being able to bind multiple BAFF receptors expressed by the cancer cell, rather than one antigen alone. Using cytotoxicity assays, we demonstrate the functionality and specificity of BAFF CAR-T cells in killing several types of B cell malignancies, and we further confirm their efficacy in several mouse models of cancer. These results have helped bring BAFF CAR-T therapy to Phase I clinical trials, and we hope they prove efficacious for patients with relapsed/refractory B cell malignancies.Meanwhile, interest has rapidly increased in natural killer (NK) cell-based immunotherapies. NK cells have important roles in cancer immunosurveillance and offer advantages over T cells in clinical safety and time-to-treatment. However, NK therapies face challenges in efficacy and persistence, often due to the presence of TGF-β, a powerful immunosuppressive cytokine that is frequently elevated in cancer patients and a primary cause of NK cell dysfunction. In this work, we characterize an undiscovered role of cyclin dependent kinase 5 (Cdk5) and its coactivator p35 in NK cell cytotoxicity. Using genetic tools to modulate Cdk5/p35 kinase activity in human NK cells, as well as using NK cells from p35 knockout mice, we show that Cdk5/p35 negatively regulates NK cytotoxicity. Furthermore, we show that TGF-β induces p35 expression in NK cells, while p35 knockdown or expression of dominant negative Cdk5 resists TGF-β-mediated inhibition of NK cytotoxicity. Further understanding of these mechanisms may reveal novel strategies to enhance NK-based immunotherapies and overcome their dysfunction in cancer patients. |
| Original Identifier: |
oai:etd.ohiolink.edu:case1680822253188102 |
| نوع الوثيقة: |
text |
| اللغة: |
English |
| الإتاحة: |
http://rave.ohiolink.edu/etdc/view?acc_num=case1680822253188102Test |
| حقوق: |
This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| رقم الانضمام: |
edsndl.OhioLink.oai.etd.ohiolink.edu.case1680822253188102 |
| قاعدة البيانات: |
Networked Digital Library of Theses & Dissertations |
