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Articles 1 - 20 of 20
Full-Text Articles in Cell and Developmental Biology
Early Development Of C3ar1-Targeting Chimeric Antigen Receptor T Cells For The Treatment Of Glioblastoma Multiforme, Cameron Fraser
Early Development Of C3ar1-Targeting Chimeric Antigen Receptor T Cells For The Treatment Of Glioblastoma Multiforme, Cameron Fraser
Electronic Theses, Projects, and Dissertations
Glioblastoma multiforme is the most aggressive type of glioma, demonstrating extremely low long-term survival despite modern therapies. Chimeric antigen receptor T cells have shown extreme levels of success in the treatment of B cell lymphomas through persistent anti-tumor activity. Prior research has demonstrated the therapeutic potential in targeting the C3a-C3aR1 pathway as it acts in an autocrine loop, maintaining the proliferation and survival of cancer stem cells within the tumor. Here, we reorient the treatment to target C3aR1 for the treatment of glioblastoma multiforme. In order to achieve this, Jurkat immortalized T cells will express various chimeric antigen receptor designs …
Kir-Based Inhibitory Cars Overcome Car-Nk Cell Trogocytosis-Mediated Fratricide And Tumor Escape, Ye Nmn Li
Kir-Based Inhibitory Cars Overcome Car-Nk Cell Trogocytosis-Mediated Fratricide And Tumor Escape, Ye Nmn Li
Dissertations & Theses (Open Access)
Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted the transfer of the CAR-cognate-antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their targets, (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen expressing NK cells (NKTROG+) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both …
Mirna-489 Induces Immunogenic Cell Death In Triple Negative Breast Cancer Cells, Ryan P. Titus
Mirna-489 Induces Immunogenic Cell Death In Triple Negative Breast Cancer Cells, Ryan P. Titus
Senior Theses
It has been well established that microRNAs (miRNAs) play an important role in the regulation of gene expression and consequently promoting or downregulating molecular pathways. When dysregulated, miRNAs have been found to serve as important biomarkers for cancer diagnosis and influence tumor initiation and progression. It has been previously established that miRNA-489 is a tumor suppressor microRNA, and it directly targets cell proliferative pathways like the HER2-SHP2-MAPK pathway. In this study, we focus on the role of miRNA-489, in the induction of immunogenic cell death (ICD) in triple-negative breast cancer cell lines. We first examined the effects of miRNA-489 on …
Visualization And Characterization Of The Immunological Synapse Between Chlorotoxin Chimeric Antigen (Cltx-Car) Redirected T Cells And Targeted Glioblastoma Tumors, Arianna Livi
CMC Senior Theses
Chimeric Antigen Receptor T (CAR-T) cells have demonstrated anti-tumor activity against aggressive and invasive cancers such as glioblastoma (GBM); however, clinical response rates remain low in clinical trial studies. Tumor heterogeneity and tumor microenvironment conditions pose significant challenges for treatment of GBM, thus continuous optimization of CAR-T cell therapies and identification of novel, widely expressed, and highly specific GBM antigens are vital to better patient outcomes. A newly developed CAR-T cell construct incorporating chlorotoxin (CLTX) as the targeting domain exhibited broad GBM-targeting capabilities and elicited potent cytotoxic effects during preclinical studies and is currently being tested in a phase I …
Targeting Ezh2 To Improve Outcomes Of Lung Squamous Cell Carcinoma, Tanner Ducote
Targeting Ezh2 To Improve Outcomes Of Lung Squamous Cell Carcinoma, Tanner Ducote
Theses and Dissertations--Toxicology and Cancer Biology
Only 20% of patients diagnosed with lung squamous cell carcinoma (LSCC) respond to immunotherapy. Anti-PD1 immunotherapy is most commonly prescribed to these patients; however, most will become refractory. It is important to understand the mechanisms underlying this problem to increase durability and survival. Building upon the work of other groups, our lab has demonstrated that the inhibition of the histone methyltransferase, EZH2, is crucial to maintaining an immunologically responsive microenvironment. Based on our data, we hypothesize that combining EZH2 inhibitors with anti-PD1 therapy will increase response and durability. To study non-small cell lung cancers (NSLC) our lab uses a variety …
The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia
The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia
Dissertations & Theses (Open Access)
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …
Determining The Role Of Dendritic Cells During Response To Treatment With Paclitaxel/Anti-Tim-3, Alycia Gardner
Determining The Role Of Dendritic Cells During Response To Treatment With Paclitaxel/Anti-Tim-3, Alycia Gardner
USF Tampa Graduate Theses and Dissertations
Intratumoral CD103+ dendritic cells (cDC1) are required for anti-tumor immune responses. In tumors that are poorly responsive to immunotherapeutic approaches targeting T cells, targeting cDC1 represents an alternative approach that may be useful in improving patient response rates. As such, it is critical to understand cDC1 function within tumors, and what may be preventing optimal function of cDC1. TIM-3 is a receptor that is highly expressed by cDC1 in murine and human mammary tumors, and TIM-3 blocking antibodies are currently being evaluated in clinical trials for a number of solid and hematological malignancies. In order to best design combinatorial therapeutic …
Elucidating The Role Of The Tyrosine Phosphatase, Shp-2, In Regulation Of Pd-L1 Expression In Non-Small Lung Cancer Using Both Biochemical Analyses And Real-World Genomic Information, Keller Toral
Theses and Dissertations--Pharmacy
Immune checkpoint inhibitors (ICIs), especially those that target programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1), have been shown to provide substantial clinical benefit in many patients with non-small cell lung cancer (NSCLC). While these therapeutic agents can be highly effective in the correct context, the biological systems that malignant cells draft from normal activities of the cell are poorly characterized. Tumor cell-specific expression of PD-L1 is likely important for clinical benefit from PD-1 and PD-L1 inhibitors. It is known that PD-L1 is inappropriately expressed in many cancers harboring mutations in the RAS family of genes. …
Investigating The Antitumor Effects Of A Dsrna-Nanoparticle Complex In An In Vitro Ovarian Cancer Model, Aaron Lewis
Investigating The Antitumor Effects Of A Dsrna-Nanoparticle Complex In An In Vitro Ovarian Cancer Model, Aaron Lewis
Theses and Dissertations (Comprehensive)
An estimated 1 in 70 women will be diagnosed with ovarian cancer in their lifetime. Despite advanced detection and treatment methods, it remains a silent killer with an expected survival rate of 50%. A developing method in cancer treatment is the use of compounds that stimulate the immune system to aid in the body's fight against the disease. This project focused on the use of the potent immune stimulant double-stranded RNA (dsRNA), commercially available as polyinosinic:polycytidylic acid, poly(I:C), to induce cytotoxicity in two ovarian cancer cell lines; SKOV-3 and OVCAR-3. Some challenges exist with the delivery of dsRNA due to …
Micrornas Associated With Melanoma Inflammation And Response To Pd-1 Inhibition, Robert Szczepaniak Sloane
Micrornas Associated With Melanoma Inflammation And Response To Pd-1 Inhibition, Robert Szczepaniak Sloane
Dissertations & Theses (Open Access)
Melanoma is an aggressive malignancy of melanocytes with historically poor outcomes. Melanoma therapy has improved markedly over the past decade with advances in molecularly targeted agents and immunotherapies. Immune checkpoint inhibitors achieve T-cell mediated anti-tumor efficacy by blocking engagement of inhibitory checkpoints on T-cells to overcome immunosuppressive signals from tumor cells and the broader microenvironment. Despite these advances, there are a significant proportion of patients who do not benefit from existing immunotherapy strategies making it a priority to identify and target the mechanisms that confer resistance to therapy. We demonstrate that microRNAs are accurate markers of microenvironment composition with prognostic …
Exploiting The Immunomodulatory Potentials Of Inkt Cells In Sepsis And Cancer., Joshua Choi
Exploiting The Immunomodulatory Potentials Of Inkt Cells In Sepsis And Cancer., Joshua Choi
Electronic Thesis and Dissertation Repository
Invariant natural killer T (iNKT) cells are a unique unconventional T cell subset that recognize glycolipids presented by CD1d expressing cells. The prototypical glycolipid agonist of iNKT cells, α-Galactosylceramide (α-GalCer), can induce the rapid release of an arsenal of cytotoxic effector molecules and enormous amounts of immunomodulatory cytokines as early as two hours after activation. In addition to α-GalCer, various glycolipid agonists are available that allow for specific, in vivo targeting of iNKT cells, and can exert divergent T-helper (TH)1 and/or TH2 immune responses. Therefore, the type of response instigated by iNKT cells can profoundly influence …
Putative Roles Of Cd200 In The Leukemogenesis And Immune Evasion Of Leukemia Stem Cells, Shelley Herbrich
Putative Roles Of Cd200 In The Leukemogenesis And Immune Evasion Of Leukemia Stem Cells, Shelley Herbrich
Dissertations & Theses (Open Access)
Acute myeloid leukemia (AML) stem cells (LSC) are capable of surviving current standard chemotherapy and are the likely source of deadly, relapsed disease. While stem cell transplant serves as proof-of-principle that AML LSCs can be eliminated by the immune system, the translation of existing immunotherapies to AML have been met with limited success. Consequently, understanding and exploiting the unique immune mechanisms of AML LSCs is critical. To identify novel immunotherapeutic targets, we sourced multiple large, publicly available datasets and identified CD200 as a potential stem-cell specific immune checkpoint in AML. We hypothesized that CD200 was a stem-cell specific mechanism of …
Identification Of Imiquimod As A Potential Combination For Anti-Cd47 Antibodies In Cancer Therapy, Nicole Brittaney Pang
Identification Of Imiquimod As A Potential Combination For Anti-Cd47 Antibodies In Cancer Therapy, Nicole Brittaney Pang
Scripps Senior Theses
The avenues of targeted immunotherapy offers a promise of less toxic treatment options for those battling different forms of cancer. Specifically, the process of hijacking a patient’s own immune system to fight cancer from within versus using external treatments like chemotherapy which is extremely damaging to the patient. One such avenue includes the usage of monoclonal antibodies as an effective modality for immunotherapy. Cluster of Differentiation 47 (CD47), also known as the ‘don’t eat me signal’, aids in cell proliferation and evasion of phagocytosis and has been found to be a target for stopping tumorigenesis. Previous research has been successful …
Delivery Of Small Molecule And Rna Using Synthetic Polymeric Micelles And Multifunctional Exosomes For The Treatment Of Type 1 Diabetes, Yang Peng
Theses & Dissertations
Type 1 diabetes is one of the most challenging chronic autoimmune diseases. The destruction and dysfunction of insulin-secreting β cells are the results of inflammatory infiltration and the synergistic effect of multiple immune cells. The aim of this dissertation is to develop novel and reliable therapeutic approaches to advance the treatment of T1D: including chemical modification of a broad-spectrum immunosuppressant, co-application of small molecule based immune intervention and siRNA based β cell preservative therapy, and administration of a PI3K-δ/γ dual inhibitor to specifically target immune cells, utilizing synthetic polymeric micelles or natural produced multi-functional exosomes derived from human bone marrow …
T Cell Immunity In Pancreatic Cancer Is Undermined By Dendritic Cell Dysfunction, Samarth Hegde
T Cell Immunity In Pancreatic Cancer Is Undermined By Dendritic Cell Dysfunction, Samarth Hegde
Arts & Sciences Electronic Theses and Dissertations
Pancreatic cancer carries a dismal prognosis, and desperately needs viable therapeutic interventions beyond chemo-radiation. T cell-dependent immunotherapies have shown great promise in several tumor types, but have not been effective for the vast majority of pancreatic cancer patients. This is, in part, due to our limited understanding of how antigenicity of pancreatic lesions is recognized, and how adaptive immunity is overcome in this disease. We sought to study tumor-immune interactions and identify mechanisms for this immune-failure using several spontaneous and unperturbed mouse models of pancreatic adenocarcinoma. We found that early pancreatic lesions fail to elicit tumor-limiting CD4+ TH1 and CD8+ …
Cross-Presentation Is A Source Of Tumor Antigens For Multiple Myeloma Immunotherapy, Alexander A. Perakis
Cross-Presentation Is A Source Of Tumor Antigens For Multiple Myeloma Immunotherapy, Alexander A. Perakis
Dissertations & Theses (Open Access)
Cross-presentation is an essential bridge between the innate and adaptive arms of the immune system where antigen presenting cells (APCs) prime cytotoxic T cell responses. We have recently identified cross-presentation as a mechanism by which solid tumors present exogenous antigens. We therefore hypothesized that multiple myeloma would be capable of cross-presentation as these cells are derived from B cells, known APCs. We explored the capacity of multiple myeloma to cross-present PR1, a human leukocyte antigen (HLA)-A2 nonameric peptide that is derived from neutrophil elastase (NE) and proteinase 3 (P3), and the ability to treat multiple myeloma using PR1-targeting immunotherapies. Here …
Influences Of Antroquinonol And 4-Acetylantroquinonol B On Inflammatory Tumorigenesis In The Mcf-7 Breast Cancer Cell Line With Or Without Tnf-Α Stimulation, Ting-Chun Lin
Masters Theses
Breast cancer (BC) is one of the most common cancers among women worldwide that ~25% of new cancer cases diagnosed every year would be BC; moreover, ~15% of cancer deaths per year caused by BC makes it the leading cause of cancer death among women worldwide. To date, though the cause of a large proportion of BC are still unclear, recent studies have revealed that a supportive breast tissue microenvironment is critical for the development and progression of BC, especially the communication with immune cells within breast tissue. Therefore, breast inflammatory microenvironment is currently received a substantial attention in the …
Tumors Interrupt Irf8-Mediated Dendritic Cell Development To Overcome Immune Surveillance, Melissa Ann Meyer
Tumors Interrupt Irf8-Mediated Dendritic Cell Development To Overcome Immune Surveillance, Melissa Ann Meyer
Arts & Sciences Electronic Theses and Dissertations
Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, which expands immune suppressive granulocytes and monocytes to create a protective tumor niche shielding even antigenic tumors. As myeloid cells and immune-stimulatory conventional dendritic cells (cDCs) are derived from the same progenitors, it is logical that tumor-induced myelopoiesis might also impact cDC development. The cDC subset cDC1 is marked by CD141 in humans and CD103 or CD8α in mice. cDC1s act by cross presenting antigen and activating CD8+ T cells. Given these functions, CD103+ cDC1s can support anti-tumor CD8+ T cell responses. However, CD103+ cDC1 numbers are …
Immunotherapy Of Cancer: Reprogramming Tumor/Immune Cellular Crosstalk To Improve Anti-Tumor Efficacy, Kyle K. Payne
Immunotherapy Of Cancer: Reprogramming Tumor/Immune Cellular Crosstalk To Improve Anti-Tumor Efficacy, Kyle K. Payne
Theses and Dissertations
Immunotherapy of cancer has been shown to be promising in prolonging patient survival. However, complete elimination of cancer and life-long relapse-free survival remain to be major challenge for anti-cancer therapeutics. We have previously reported that ex vivo reprogramming of tumor-sensitized immune cells by bryostatin 1/ionomycin (B/I) and the gamma-chain (γ-c) cytokines IL-2, IL-7, and IL-15 resulted in the generation of memory T cells as well as CD25+ NKT cells and CD25+ NK cells. Adoptive cellular therapy (ACT) utilizing these reprogrammed immune cells protected FVBN202 mice from tumor challenge, and overcame the suppressive functions of myeloid-derived suppressor cells (MDSCs). We then …
T-Cell Treatments For Solid And Hematological Tumors, Drew C. Deniger
T-Cell Treatments For Solid And Hematological Tumors, Drew C. Deniger
Dissertations & Theses (Open Access)
Cell-based therapies have demonstrated potency and efficacy as cancer treatment modalities. T cells can be dichotomized by their T cell receptor (TCR) complexes where alpha/beta T cells (95% of T cells) and gamma/delta T cells (+T cells proliferated to clinically significant numbers and ROR1+ tumor cells were effectively targeted and killed by both ROR1-specific CAR+ T cell populations, although ROR1RCD137 were superior to ROR1RCD28 in clearance of leukemia xenografts in vivo. The second specific aim focused on generating bi-specific CD19-specific CAR+ gamma/delta T cells with polyclonal TCRgamma/delta repertoire on CD19+ artificial antigen presenting cells (aAPC). …