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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.
1

Chimeric Antigen Receptor T-Cell Therapy in Glioblastoma: Charging the T Cells to Fight

Land, Craig A., Musich, Phillip R., Haydar, Dalia, Krenciute, Giedre, Xie, Qian 01 December 2020 (has links)
Glioblastoma multiforme (GBM) is the most common malignant brain cancer that invades normal brain tissue and impedes surgical eradication, resulting in early local recurrence and high mortality. In addition, most therapeutic agents lack permeability across the blood brain barrier (BBB), further reducing the efficacy of chemotherapy. Thus, effective treatment against GBM requires tumor specific targets and efficient intracranial drug delivery. With the most recent advances in immunotherapy, genetically engineered T cells with chimeric antigen receptors (CARs) are becoming a promising approach for treating cancer. By transducing T lymphocytes with CAR constructs containing a tumor-associated antigen (TAA) recognition domain linked to the constant regions of a signaling T cell receptor, CAR T cells may recognize a predefined TAA with high specificity in a non-MHC restricted manner, and is independent of antigen processing. Active T cells can travel across the BBB, providing additional advantage for drug delivery and tumor targeting. Here we review the CAR design and technical innovations, the major targets that are in pre-clinical and clinical development with a focus on GBM, and multiple strategies developed to improve CAR T cell efficacy.
2

Characterizing the Response of TAC- and CAR-Engineered T cells Following Antigenic Stimulation

Lau, Vivian Wing Chong January 2018 (has links)
T lymphocytes engineered with chimeric antigen receptors (CARs) have shown remarkable success in the treatment of leukemias. Conventional CARs seek to recapitulate TCR and costimulatory signals through fusion of T cell signaling elements into a single receptor. The robust anti-tumor activity of CAR T cells is often accompanied by debilitating toxicities due to excessive T cell activation and cytokine production following infusion. Our lab has generated a novel chimeric receptor termed T cell antigen coupler (TAC), which is designed to engage native T cell signaling domains for cellular activation. In a murine xenograft model, we previously found that TAC T cells mediated rapid tumour regression in the absence of toxicities. Comparatively, CAR T cells elicited significant lethal toxicities to the mice due to reactivity against an unspecific antigen that resulted in excessive proliferation and cytokine production in vivo. Here, we report that TAC and CAR T cells have fundamentally different biology, both at rest, and during activation. TAC T cells were more sensitive to the context of stimulation compared to CAR T cells. Whereas TAC T cells can discriminate between antigen bound to a bead, or antigen present on a cell, CAR T cells do not make the same distinction and responds equally well to both. Compared to several different CAR constructs, TAC T cells are less prone to tonic signaling and T cell differentiation in the absence of antigen. These findings support that TAC T cells may pose a safety benefit as a cancer immunotherapy, due to its distinct biology from CAR T cells that enables them to require more stringent contexts for activation. / Thesis / Master of Science (MSc) / Cytotoxic T cells are also known as “resident killer” cells of the immune system, as they can seek and eliminate diseased or infected tissue, including cancer cells. However, cancer cells can evade elimination by T cells over time. Genetic engineering of T cells allows us to re-arm T cells against cancer cells. T cells isolated from a patient are genetically modified to recognize cancer cells specifically. So far, these modified T cells have been successful against several leukemias. However, the side effects of this treatment can be substantial and life-threatening, due to the massive reaction of the T cells against the cancer cells following infusion. We explore the biology of two different types of engineered T cells to better understand the interaction between T cell and tumour cell. Our results aim towards mitigating the side effects of T cell treatment, while investigating how we can improve its effectiveness for the future.
3

Investigating signaling and protein expression dynamics in T-cell activation and exhaustion

Lawton, Matthew Luke 30 October 2024 (has links)
T lymphocytes are a key aspect of the adaptive immune system, allowing the body to mount effective and long-lasting immune responses. Generally, there are two major types of T cells: CD8+ T cells, which are cytotoxic, and CD4+ T cells, which have many subsets but a majority are “helper” T cells which secrete cytokines to bolster the immune response. For T cells to function appropriately and efficiently, many signaling cascades are activated and inhibited to modulate a T-cell’s function and differentiation. These signals can come from strength and duration of T cell receptor binding, cell-cell interactions with antigen presenting cells and surrounding tissue, as well as from the present cytokine milieu. These signals are dynamic, complex, and can affect many different downstream pathways, making a holistic systems-biology approach the ideal strategy to study signaling in T cells. T-cell activation is normally short (1-3 days), however in some contexts such as cancer or infection, T-cell activation can be chronic (days to weeks) and lead to dysfunction, known as T-cell exhaustion. T-cell exhaustion is a clinically important cell state whereby T cells lose their effector functions (cytotoxicity and secretion of cytokines), proliferative ability, and upregulate many coinhibitory receptors (e.g., PD-1, TIM-3, LAG-3). T-cell exhaustion has been well studied, with some transcriptional drivers (e.g., TOX) and changes in metabolism (e.g., mitochondrial dysfunction) already identified. However, much of what has been discovered about T-cell exhaustion has been done in CD8+ T cells due to their direct role in antigen removal via cytotoxicity. CD4+ T cells are shown to also become exhausted and play an equally important role in the immune response for proper and complete neutralization of the pathogen, and many aspects of CD4+ T-cell exhaustion remain unclear. Here, I report on my quantitative global proteomic and phosphoproteomic studies of T-cell activation in human primary T cells, ranging from healthy acute physiological responses (i.e., hours to days) to dysfunctional long term chronic activation (i.e., days to weeks). I developed an in vitro model of CD4+ T-cell exhaustion and analyzed these cells using a multi-omic approach and uncovered pathways and proteins underlying the progression and demarcation of this understudied cell type. I identified novel CD4+ T-cell exhaustion-associated cell surface markers (e.g., CD276 and FLT-1), transcription factors (e.g., ZEB2), and implicated p300 as playing a role in epigenetic regulation of key exhaustion-associated genes. In addition, I investigated artificial activation signaling in a chimeric antigen receptor (CAR) expressing T-cell model, allowing us to tease apart differences in signaling to better fine tune this potent clinical tool. We compared the basal states of three different CARs and found that changing just one signaling domain can lead to drastic changes in T cells even before introduction of antigen. The resulting systems-level understanding of signaling mechanisms in T cells provides a valuable resource for the advancement of fundamental T-cell biology, for reprogramming T-cell signaling for desired output, and for developing immunotherapies to modulate immune signaling for clinical utility. / 2025-10-29T00:00:00Z
4

CD19-targeting CAR T Cells for Treatment of B Cell Malignancies : From Bench to Bedside

Karlsson, Hannah January 2014 (has links)
Immunotherapy for cancer is a young research field progressing at high speed. The first chimera of an antibody and a signaling chain was designed by Zelig Eshhar and was later further developed to enhance existing T cell therapy by combining a single-chain fragment of an antibody with the CD3 zeta chain of the TCR complex. T cells expressing these chimeric antigen receptors (CARs) could recognize and specifically kill tumor cells. However the T cells, lacked in persistence and tumor rejection did not occur. Thus, the CAR constructs have been improved by providing the T cell with costimulatory signals promoting activation. The focus of this thesis has been to evaluate second and third generation αCD19-CAR T cells for the treatment of B cell leukemia and lymphoma. B cell tumors commonly upregulate anti-apoptotic proteins such as Bcl-2, which generates therapy resistance. In the first paper a second generation (2G) αCD19-CD28-CAR T cell was combined with the Bcl-2 family inhibitor ABT-737. ABT-737 sensitized tumor cells to CAR T cell therapy and may be an interesting clinical combination treatment. In paper II, the phenotype and function of a third generation (3G) αCD19-CD28-4-1BB-CAR T cell were evaluated. B cell-stimulated CAR T cells showed increased proliferation and an antigen-driven accumulation of CAR+ T cells. 3G CAR T cells had equal cytotoxic capacity, similar lineage, memory and exhaustion profile phenotype compared to 2G CARs. However, 3G CAR T cells proliferated better and had increased activation of intracellular signaling pathways compared to 2G CAR T cells. In paper III, αCD19-CD28-4-1BB-CAR T cells were used to stimulate immature dendritic cells leading to an upregulation of maturation markers on co-cultured dendritic cells. Hence, CAR T cells may not only directly kill the tumor cells, but may induce bystander immunity that indirectly aids tumor control. This thesis also include supplementary information about the development and implementation of protocols for GMP production of CAR T cell batches for a phase I/IIa clinical trial currently ongoing for patients with refractory B cell leukemia and lymphoma. So far, two patients have safely been treated on the lowest dose.
5

Exploitation du potentiel thérapeutique des cellules Natural Killer pour traiter les cancers

Lemieux, William 12 1900 (has links)
Malgré le succès de l’utilisation des lymphocytes T modifiées par des récepteur antigéniques chimériques (CAR) contre les leucémies, celles-ci présentent des limites comme leur risque de CRS et leur inefficacité dans les tumeurs solides. Plusieurs autres immunothérapies cellulaires ont été proposées pour pallier à ces inconvénients. Les cellules natural killer (NK) ont plusieurs propriétés qui en font une alternative avantageuse aux cellules T dans les immunothérapies. Cependant, les cellules NK restent difficiles à modifier avec les outils actuels et leur efficacité reste limitée par les mécanismes immunosuppresseurs des tumeurs. Nous avons réussi à augmenter l’efficacité de transduction avec une nouvelle glycoprotéine, le BaEVRless. Nous avons aussi démontré que cette enveloppe ne provoque pas de modification du phénotype ou de l’activité intrinsèque des cellules NK. Dans un modèle de leucémie, nous avons déterminé que l’utilisation du BaEVRless permet la production de cellules CAR-NK fonctionnelles. Les cellules NK peuvent aussi être transduites efficacement par des constructions lentivirales portant les séquences codant pour deux constructions CAR simultanément. Nous avons aussi démontré que l’édition génomique des NK par la technologie Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR) est possible en utilisant une livraison non-virale. Avec cette méthode, nous avons pu réduire l’expression de NKG2A. Les cellules NK avec une expresssion réduite de NKG2A étaient résistantes à l’inhibition par HLA-E, exprimé sur des lignées de cancer du sein et du colon. Cet effet a été confirmé in vivo dans un modèle préclinique xenogénique. Ces résultats montrent deux stratégies qui pourraient permettre d’améliorer les immunothérapies à base de cellules NK. / Despite the overwhelming success of chimeric antigen receptor (CAR)-modified T lymphocytes against leukemias, some limitations have been observed, such as the risk of developing CRS and the lack of efficiency in solid tumor settings. Many other cell-based immunotherapies have been explored to circumvent those caveats. Natural killer (NK) cells present many advantageous properties that could make them a very promising alternative to T cells in immunotherapies. However, NK cells have some caveats, mainly they are hard to modify using conventional tools and they are sensitive to many inhibitory signals expressed by cancer cells. We managed to greatly improve the efficiency of transduction using a novel viral glycoprotein, BaEVRless. In the process, we determined that this novel enveloppe glycoprotein did not modify the phenotype or intrinsic activity of the transduced NK cells. In a leukemia model, we also showed that the BaEVRless can be used to generate functionnal CAR-NK cells. Moreover, the NK cells can be transduced with larger lentiviral constructions bearing two simultaneous CAR-coding sequences. We also demonstrated that Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR) modification of NK cells using a non-viral approach was possible. Using this approach, we generated NK cells with lower NKG2A expression, that were resistant to the inhibitory effects of HLA-E. This affect was seen in a breast cancer model and a colon cancer model. The in vitro results were confirmed in an in vivo preclinical xenogeneic model. Together, those results represent two improvements applicable to NK cell-based immunotherapies.

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