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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
41

Augmentation of anti-myeloma engineered T cells by pharmacological or genetic interventions / Augmentation of anti-myeloma T cells

Afsahi, Arya January 2023 (has links)
Multiple myeloma is an aggressive plasma cell cancer that consistently acquires multi-drug resistance and relapses despite initial treatment successes. Patients may go through greater than 10-lines of therapy, highlighting the need for more effective treatment options. Immunotherapies are the latest evolution in targeted cancer treatments, and thus far have displayed impressive results in several hematological cancers, including multiple myeloma. T cells possess robust anti-tumor functions which can be harnessed and refined for the treatment of cancers. Genetic engineering of T cells to express a chimeric antigen receptor (CAR) confers antigen-specific tumor-targeting, and adoptive transfer of patient-derived CAR-engineered T (CAR T) cells has been efficacious in relapsed/refractory multiple myeloma. Despite the high efficacy, CAR T cell therapy for myeloma is associated with serious adverse events, which limits dose levels and patient eligibility. We have developed a novel synthetic antigen receptor platform, called the T cell antigen coupler (TAC) receptor, which has shown comparatively higher efficacy with a reduced pro-inflammatory profile compared with CAR T cells in pre-clinical models. The TAC receptor was purpose-built to co-opt the natural T cell activation machinery and lacks the costimulatory signaling typically incorporated in CAR designs. This thesis investigates strategies to augment TAC T cell function against for multiple myeloma through the evaluation of ancillary pharmacological and protein stimuli that would complement the anti-tumor functions of TAC T cells without modifying the TAC receptor design. In chapter 2, I investigated a strategy combining TAC T cells with the SMAC mimetic LCL161 to provide transient costimulatory effects. While LCL161 boosted TAC T cells survival and proliferation, the drug also enhanced susceptibility of TAC T cells to apoptosis and offered no advantage to the TAC T cells when challenged with myeloma. In chapter 3, I engineered TAC T cells to secrete IL-27 in an attempt to modulate the myeloma microenvironment and support T cell cytolytic function. IL-27 did not enhance the anti-tumor activity of TAC T cells but forced expression of IL-27 led to a reduction in the production of pro-inflammatory cytokines without altering cytotoxicity. In appendix I, I describe the process of optimizing CRISPR/Cas9 editing of primary TAC T cells. This methodology was required for much of the work in chapter 2. Ph.D. Thesis – Arya Afsahi McMaster University – Biochemistry and Biomedical Sciences v In appendix II, I describe an assessment of mRNA-engineering as a method to produce TAC T cells. This approach proved to be therapeutically futile and was not pursued beyond the work described herein. The work presented here highlights methods of combining TAC T cells with a clinically relevant SMAC mimetic, or the cytokine IL-27, and provides insights into the biological mechanisms that are affected by these approaches. / Thesis / Doctor of Philosophy (PhD)
42

How Do Hexokinases Inhibit Receptor-Mediated Apoptosis?

Schöninger, Axel, Wolf, Philipp, Edlich, Frank 13 June 2023 (has links)
The regulated cell death apoptosis enables redundant or compromised cells in ontogeny and homeostasis to remove themselves receptor-dependent after extrinsic signaling or after internal stress by BCL-2 proteins on the outer mitochondrial membrane (OMM). Mitochondrial BCL-2 proteins are also often needed for receptor-mediated signaling in apoptosis. Then, the truncated BH3-only protein BID (tBID) blocks retrotranslocation of the pro-apoptotic BCL-2 proteins BAX and BAK from the mitochondria into the cytosol. BAX and BAK in turn permeabilize the OMM. Although the BCL-2 proteins are controlled by a complex regulatory network, a specific mechanism for the inhibition of tBID remained unknown. Curiously, it was suggested that hexokinases, which channel glucose into the metabolism, have an intriguing function in the regulation of apoptosis. Recent analysis of transient hexokinase interactions with BAX revealed its participation in the inhibition of BAX and also BAK by retrotranslocation from mitochondria to the cytosol. In contrast to general apoptosis inhibition by anti-apoptotic BCL-2 proteins, hexokinase I and hexokinase 2 specifically inhibit tBID and thus the mitochondrial apoptosis pathway in response to death receptor signaling. Mitochondrial hexokinase localization and BH3 binding of cytosolic hexokinase domains are prerequisites for protection against receptor-mediated cell death, whereas glucose metabolism is not. This mechanism protects cells from apoptosis induced by cytotoxic T cells.
43

Identification of Immunological Targets for Brain Cancer Immunotherapy

Wang, Zhenda January 2022 (has links)
Background Cancer immunotherapy has yielded many successes. Yet to some hard-to-treat brain tumors, such as glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), it still lacks substantial improvement. Neoantigens resulting from mutations in malignant cells are the key targets for employing adoptive cell therapies. A novel therapeutical strategy may be developed based on the identification of T cell receptors (TCRs) targeting specific neoantigens. Methods Previous work had been done to provide essential materials, including candidate neoantigen peptides, human leukocyte antigen (HLA) genotypes, and peripheral blood mononuclear cell (PBMCs) from patients and healthy donors (HDs). Autologous antigen-presenting cells (APCs) and T cells were isolated from PBMCs for in vitro assays. The activation of T cells against peptides was evaluated by the upregulation of 41BB utilizing flow cytometry (FACS). The cell populations with positive signals were sorted through FACS for TCR sequencing directly or after rapid cell expansion. Results T cells and APCs from 12 HDs were isolated. T cells from 10 HDs were analyzed after in vitro stimulation. T cells from HD30 showed reactions to several public neoantigens; while T cells from HD49 and HD53 showed reactions also to private neoantigens restricted in GBM patient C6. Conclusion The upregulation of 41BB indicated the activation of T cells and the existence of reactive TCRs against either public or private neoantigens in some HDs. Those reactive TCRs and their encoding sequences were the fundamentals of future works. Due to practical reasons, TCR sequencing cannot be done within this project. In future works, wildtype peptides will be included to further validate the results, ensuring identified TCRs recognize neoantigens specifically. Furthermore, the identified TCRs will be cloned and transferred to freshly isolated T cells to confirm their functionality. Keywords Cancer immunotherapy, brain cancer, neoantigen, MHC/HLA, TCR
44

Characterizing the role of the CD58-CD2 axis in anti-cancer immunity

Ho, Patricia January 2024 (has links)
Immune checkpoint blockade (ICB) therapies have transformed the treatment landscape for advanced melanoma, extending patient survival and improving quality of life for numerous patients with a disease that was once considered to be universally fatal. However, despite the success of ICB for many patients, over half are either resistant to initial therapy, or develop resistance over time after an initial response. The mechanisms underlying this therapy resistance remain unclear for the majority of patients. We have recently identified loss of the co-stimulatory and adhesion molecule CD58 on melanoma cells as a driver for cancer immune evasion and ICB resistance. In this thesis, we use in vitro co-culture models of patient-derived melanoma cells and tumor infiltrating lymphocytes as well as in vivo patient-derived xenograft models to demonstrate the necessity of CD58 interactions with its ligand CD2 on T cells for T cell activation, tumor infiltration, and effector cytotoxicity. Furthermore, using genome-wide genetic and protein screening approaches, we identify CMTM6 as a positive regulator of CD58, and uncover its role in mediating CD58’s regulation of inhibitory PD-L1 signaling by binding to both proteins and preventing their lysosomal degradation. Thus, CMTM6 co-regulates these co- inhibitory and co-stimulatory signals such that, in the absence of CD58, CMTM6 becomes available to bind and stabilize additional PD-L1, enhancing its inhibitory signals to T cells. Finally, we identify a potential role for CD58 on T cells as a marker of effector memory T cells with enhanced effector and progenitor function. The CD58-CD2 axis therefore serves a multi-faceted, underappreciated role in melanoma cancer immunity, and may serve as a therapeutic target for enhancing anti-tumor T cell responses.
45

Targeting T Cell Glycolysis to Mitigate Graft-versus-Host Disease

Ezhakunnel, Kevin 01 January 2021 (has links)
Hematological cancers account for nearly ten percent of cancer cases diagnosed annually in the United States. Patients who fail to respond to chemotherapy or radiotherapy must often undergo a bone marrow transplant to treat their malignancy. A significant complication following this procedure is Graft versus Host Disease (GvHD), which occurs when donor T cells mount an immune response against recipient tissues. Immunological research has highlighted the role of aberrant T cell metabolism, specifically a shift toward aerobic glycolysis, as a key driver behind the occurrence of this condition. The transcription factor FoxK1 has been revealed to be a key regulator of the cell's ability to induce aerobic glycolysis. Utilizing established GvHD murine models and novel CRISPR-Cas9 techniques, this study investigates how controlling this important pathway by FoxK1 may limit the damage inflicted by GvHD. Our studies reveal that depleting FoxK1 in donor T cells has a protective effect following transplants by promoting an immunosuppressive phenotype in donor T cells. These results suggest that FoxK1 may hold promise as a future cellular target for cellular therapies administered to transplant patients to prevent the occurrence of GvHD. Continued research is needed to ascertain the precise mechanisms that afford FoxK1 this protective role.
46

Targeting T Cell Metabolism to Ameliorate Graft-versus-Host Disease

Zikra, Karin 01 January 2021 (has links)
Hematopoietic stem cell transplantation (HSCT) is an important form of therapy for hematological genetic disorders and malignancies, particularly hematological cancers. However, common usage of this procedure is obstructed by graft-versus-host disease (GvHD), in which transplanted donor T cells wage an attack on recipient antigens, causing severe tissue damage and mortality. GvHD prognosis remains poor, and current treatment methods continue to be insufficient, especially for patients with more advanced and severe GvHD. T cells have been identified as the fundamental force behind GvHD, and their cellular metabolism is deemed vital to their fate and function, especially in pathogenic environments. A hallmark of T cell metabolism in GvHD microenvironments is aerobic glycolysis, which maximizes biomass accumulation and supports growth and proliferation. Lactate dehydrogenase A (LDHA) is an essential enzyme that sustains this pathway and may be a potential therapeutic target. Using murine and in-vitro GvHD models, this study investigates the ameliorative impacts of LDHA inhibition on the fate and function of T cells following HSCT. The results reveal that LDHA depletion leads to an immunosuppressive donor T cell characterization that minimizes recipient harm induced by GvHD. Future studies should focus on investigating LDHA inhibition in in-vivo models to introduce a paradigm shift in the development of clinically relevant therapeutics.
47

Development of Lipid-like Nanoparticles for mRNA Delivery

Luo, Xiao, Luo January 2017 (has links)
No description available.
48

Enhancing monocyte effector functions in antibody therapy against cancer

Fatehchand, Kavin, Fatehchand 18 September 2018 (has links)
No description available.
49

INVESTIGATING MECHANISMS OF CANCER VACCINE-INDUCED TUMOR IMMUNITY AND AUTOIMMUNITY

Bernard, Dannie 10 1900 (has links)
<p><strong>INTRODUCTION: </strong>Pre-clinical and clinical data strongly support the feasibility of employing immunotherapy as a strategy to treat cancer.</p> <p><strong>METHODS: </strong>Using the B16F10 murine melanoma model, we have been investigating mechanisms of T cell-mediated antitumor immunity following immunization with dopachrome tautomerase (DCT), a melanoma-associated antigen.</p> <p><strong>RESULTS: </strong>In <strong>Chapter 2</strong>, we uncovered an interesting dichotomy whereby DCT-specific CD4<sup>+</sup> T cell-mediated tumor protection and autoimmunity are dependent on IL-4/STAT-6 and IFN-g/STAT-4, respectively. Our data also revealed that this phenomenon is extrinsic of CD4<sup>+</sup> T cell polarization.</p> <p>To gain further insight into the targets recognized by CD4<sup>+</sup> T cells, we conducted in <strong>Chapter 3</strong> extensive CD4<sup>+</sup> T cell epitope mapping experiments using overlapping peptide libraries. Interestingly, while we were able to identify “helper” epitopes within DCT that were required for maximal CD8<sup>+</sup> T cell expansion, we were unable to identify “effector” epitopes responsible for tumor rejection. Further examination of the requirements for the generation of CD4<sup>+</sup> T cell effector epitopes showed that post-translational modifications of the protein were involved.</p> <p>In <strong>Chapter 4</strong>, we investigated the modest efficacy afforded by DCT immunization in the context of established B16F10 melanomas. Using intratumoral transcriptional analysis, we demonstrated that the vaccine rapidly promoted an IFN-g-dependent immunosuppressive state inside the tumor. Concurrent treatment with the immunomodulatory antibodies anti-4-1BB and anti-PD-1 effectively counteracted this tumor immunosuppression, resulting in complete regression of tumors and long-term survival in 70% of the mice.</p> <p><strong>CONCLUSIONS: </strong>The research described in this thesis sheds new light into the mechanisms by which vaccine-mediated CD4<sup>+</sup> T cell responses participate to tumor rejection and autoimmunity. Moreover, our findings indicate that cancer vaccine-induced tumor immunosuppression significantly limits tumor regression, emphasizing the requirement of combinatorial approaches for successful cancer immunotherapy. Overall, our research offers new insight for future vaccine development.</p> / Doctor of Philosophy (Medical Science)
50

The utilization of activated B cell for cell carrier for viral vectored antigen delivery in the acceleration of CD8 T cell recall response

Zhang, Liang 10 1900 (has links)
<p>Cancer vaccine therapy aims at harnessing effective antigen specific immune responses to treat tumor. In particular, CD8+ T cells have the unique capacity to recognize and destroy tumor cell throughout the body. One potential approach to elicit high numbers of effector CD8+ T cells to control tumor growth is through repeated vaccination, a strategy called prime-boost vaccination. However, booster immunization is relatively inefficient during primary immune response because pre-activated effector T cells tend to impair robust antigen presentation. This phenomenon has been interpreted as a negative feedback mechanism where recently activated CD8+ T cells clear the antigen-bearing dendritic cells (DCs) and prevent memory T cells from the access of the boosting antigen. Interestingly, however, using in vitro activated B cell as a viral vector delivery system, we can boost T cell responses with the minimum viral input at a very short interval between immunizations. This B cell carrier is capable of delivering different viral vectors expressing different antigens, displaying a potential for broad application. The mechanisms behind B cell carrier-mediated efficient secondary responses are three fold: 1. Without the engagement of MHC molecules and antigen presentation, B cell carrying viral vector can bypass the killing by pre-existing effector T cells 2. B cells can delivery viruses to B cell follicles, a place separated from effector T cells, and mediate memory T cell expansion. 3. B cells can deliver antigen to both spleen and lymph node and induce antigen specific T cell expansion in multiple lymphoid organs. Our studies provide a novel boosting platform to accelerate CTL responses that has important clinical implications.</p> / Master of Science (MSc)

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