Integrative Cancer Immunogenomic Analysis Of Serial Melanoma Biopsies Reveals Correlates Of Response And Resistance To Sequential Ctla-4 And Pd-1 Blockade Treatment, Whijae Roh

Dissertations & Theses (Open Access)

Melanoma is the most malignant form of skin cancer. The five-year survival rate for metastatic melanoma is 19.9%. Although targeted therapy of BRAF and MEK inhibitors were developed for melanoma, resistance to therapy is inevitable. Immune checkpoint blockade, which reverses the suppression of the immune system, on the other hand, has shown a durable response in 20-30% of patients with metastatic melanoma. However, more predictive and robust biomarkers of response to this therapy are still needed, and resistance mechanisms remain incompletely understood. To address this, we examined a cohort of metastatic melanoma patients treated with sequential checkpoint blockade against cytotoxic …

Modeling Post Stroke Respiratory Dysfunction, Apneas And Cognitive Decline, Anthony Patrizz

Dissertations & Theses (Open Access)

Modeling Post Stroke Respiratory Dysfunction,

Apneas and Cognitive Decline

Anthony Patrizz, B.A.

Advisory Professor: Louise McCullough M.D., Ph.D.

Stroke is a major cause of mortality and the leading cause of long-term disability in the US. More than 60% of individuals suffering a first time stroke develop respiratory dysfunction, prolonging recovery and increasing mortality. Post-stroke cognitive decline is a major contributor to disability and nursing home placement, therefore the cognitive consequences of Stroke Induced Respiratory Dysfunction (SIRD) need to be explored if we hope to enhance functional recovery. The first step towards treatment of the negative consequences of SIRD is the …

Impact Of Kras/Nras Mutational Heterogeneity On Clinical Outcomes In Colorectal Cancer, Jonathan M. Loree

Dissertations & Theses (Open Access)

Introduction: Mutations in KRAS/NRAS (RAS) predict a lack of benefit from anti-EGFR agents in metastatic colorectal cancer (mCRC). As next generation sequencing (NGS) has advanced, we are discovering atypical and low allele frequency mutations. We aimed to evaluate how NGS can optimally define RAS mutant CRC and the role of relative mutant allele frequency (rMAF) as a biomarker.

Methods: Using institutional and public cohorts of mCRC patients with NGS results, we described the prevalence and clinical impact of atypical (not in current guidelines) and low rMAF RAS mutations (RAS MAF by the MAF of the mutated gene with …

Dynamic Assessment Of Nk Cell Interactions With Pediatric Tumor Cells To Predict Response To Immunotherapy, Arianexys Aquino Lopez

Dissertations & Theses (Open Access)

Due to Natural Killer (NK) cells’ capacity to target tumor cells without prior sensitization, adoptive NK cell therapy represents a promising immunotherapy approach for pediatric cancer patients. Our laboratory has developed an NK cell expansion protocol that generates large quantities of NK cells for therapeutic infusion. Given that NK cells are heterogeneous, with variable receptor expression and potential to target tumor cells, the purpose of my study was to determine whether subpopulations of NK cells with enhanced anti-tumor potential could be identified for increased potency of the NK cell infusion product. In addition, we previously showed that our expanded NK …

Memory Potential, Molecular Characterization, And Translational Applications Of The Novel Theo/Tceo T Cell Phenotype, Todd Bartkowiak, Todd Bartkowiak

Dissertations & Theses (Open Access)

T cells comprise a substantial arm of the immune system and are exquisitely adapted to combat pathogens and tumors. The inflammatory environment largely dictates the nature of T cell response. A hallmark of T cell-mediated immunity is formation of immunological memory; the ability to respond more potently to re-encounter with pathogens. The immune system is also capable of recognizing tumors as foreign, much like viral or bacterial pathogens. Tumors have evolved, though, to generate an immunosuppressive environment to avoid destruction. The field of immunotherapy seeks to overcome immune suppression, in part by targeting T cell co-receptors on the cell surface …

Membrane Bound Il21 Promotes Natural Killer Cell Expansion Through Mir 124-3p Mediated Regulation, Anitha Somanchi

Dissertations & Theses (Open Access)

Natural Killer (NK) cells are cells of the innate immune system that act as first line of defense against viral infections and participate in tumor immune surveillance. NK cells do not cause graft versus host disease (GvHD), or require prior antigen exposure to exert anti-tumor activity, hence are an attractive choice for immunotherapy applications. Owing to small numbers of NK cells in peripheral blood (1-32%, with a 6% median), ex vivo expansion of NK cells is critical for NK cell adoptive immunotherapy, various expansion platforms have been explored over the decades. We developed a robust platform for ex vivo expansion …

High-Throughput Mapping Of The Biological Effects Of Particle Therapy, Lawrence Bronk

Dissertations & Theses (Open Access)

Radiation therapy is an essential tool in the cure of many cancer patients. Charged particle based radiation therapies are gaining momentum as the physical dose distributions of ions are superior to standard photons due their limited range. Additionally, charged particle radiation has been shown to have linear energy transfer (LET) specific relative biological effectiveness (RBE) when compared to photons. It is essential to employ accurate biophysical models for particle beams in order to maximize the therapeutic potential of particle therapy through the introduction of biologically optimized treatment planning. The development of such models requires the support of large amounts of …

Volumetric, Magnetic Resonance-Visible, And Radiation-Sensitive Detectors For Magnetic Resonance Image-Guided Radiation Therapy, Hannah J. Lee

Dissertations & Theses (Open Access)

VOLUMETRIC, MAGNETIC RESONANCE-VISIBLE, AND RADIATION-SENSITIVE DETECTORS FOR MAGNETIC RESONANCE IMAGE-GUIDED RADIATION THERAPY

Hannah Jungeun Lee

Advisory Professor: Geoffrey S. Ibbott, Ph.D.

Due to the superior soft-tissue contrast of magnetic resonance imaging (MRI) compared to conventional computed tomography (CT) and other on-board imaging techniques, several groups have integrated MRI and radiation treatment machine systems. The advent of MR image-guided radiation therapy (MR-IGRT) using systems, such as the 1.5 MRI – 7 MV linear accelerator (MR-Linac), now allow for improved soft-tissue on-board imaging for patient position and tumor target localization verification and the ability to assess functional biological tissue characteristics with MRI, …

Identifying The Immune Related Metabolic Properties Of Pancreatic Cancer Using Nuclear Magnetic Resonance Spectroscopy And Dynamic Magnetic Resonance Spectroscopic Imaging With Hyperpolarized Pyruvate, Joseph Weygand

Dissertations & Theses (Open Access)

Despite its relatively low incidence, pancreatic cancer was the fourth leading cause of cancer-related death in the US in 2015. This is due in part to pancreatic cancer’s natural resistance to both chemotherapy and radiotherapy. Immunotherapy presents an attractive potential treatment approach, but initial trials in mice have proved ineffective. Because cancer cells exhibit a significant increase in metabolic activity relative to normal tissue, an understanding of the metabolic function of tumors in systems with different levels of immunocompetence is a critical first step to develop an understanding of the immune-related metabolic properties of the tumor, which have potential application …

Managing Variant Discrepancy In Hereditary Cancer: Clinical Practice, Barriers, And Desired Resources, Ellen Zirkelbach

Dissertations & Theses (Open Access)

Variants are changes in the DNA whose phenotypic effects may or may not be definitively understood. Because variant interpretation is a complex process, sources sometimes disagree on the classification of a variant, which is called a variant discrepancy. This study aimed to determine the practice of genetic counselors regarding variant discrepancies and to identify the barriers to counseling a variant discrepancy in hereditary cancer genetic testing. This investigation was unique because it was the first to address variant discrepancies from a clinical point of view. An electronic survey was sent to genetic counselors in the NSGC Cancer Special Interest Group. …

Detecting And Evaluating Therapy Induced Changes In Radiomics Features Measured From Non-Small Cell Lung Cancer To Predict Patient Outcomes, Xenia J. Fave

Dissertations & Theses (Open Access)

The purpose of this study was to investigate whether radiomics features measured from weekly 4-dimensional computed tomography (4DCT) images of non-small cell lung cancers (NSCLC) change during treatment and if those changes are prognostic for patient outcomes or dependent on treatment modality. Radiomics features are quantitative metrics designed to evaluate tumor heterogeneity from routine medical imaging. Features that are prognostic for patient outcome could be used to monitor tumor response and identify high-risk patients for adaptive treatment. This would be especially valuable for NSCLC due to the high prevalence and mortality of this disease.

A novel process was designed to …

Genesurance Counseling: Patient Perspectives, Chelsea Wagner

Dissertations & Theses (Open Access)

Genetic counselors (GCs) have recently reported an increase in the discussion of insurance-related, or “genesurance,” topics during genetic counseling sessions. Despite increasing frequency, little knowledge exists about genesurance conversations and patient expectations. This study aimed to assess patient expectations of GCs in genesurance discussions and evaluate if health insurance literacy impacted these expectations. A 38-item survey, including a validated tool to assess health insurance literacy (HIL) was administered prior to patients receiving prenatal or cancer genetic counseling at three participating institutions. A total of 360 responses were analyzed. Key variables were compared using chi-square analysis and multivariable logistic regression was …

Developing Novel Approaches To Improve Response To T Cell Based Cancer Immunotherapy, Rina M. Mbofung

Dissertations & Theses (Open Access)

Recently, T cell based immunotherapies have moved to the forefront of cancer immunotherapy with the success of Adoptive T cell therapy (ACT) and Immune checkpoint blockade.ACT, where patients are treated with tumour infiltrating T cells (TILs), conferred a clinical response rate of ~50%. Treatment with anti-CTLA4 and anti –PD1 therapy, conferred response rates of up to 50%, greatly improving the overall survival of patients with advanced melanoma amongst other cancer types. Despite the encouraging outcomes, there are relatively low response rates coupled with the delay of weeks to months before tumour shrinkage can be appreciated. Thus, understanding what tumour intrinsic …

Parp Inhibitor Upregulates Pd-L1 Expression And Enhances Cancer-Associated Immunosuppression, Shiping Jiao

Dissertations & Theses (Open Access)

With recent approvals for therapeutic antibodies that block CTLA4, PD-1 and PD-L1, immune checkpoints have emerged as new targets in cancer therapy. In addition, there is accumulating evidence highlighting the role of cancer-associated immunity in patient response to cytotoxic anticancer agents. Inhibitors of poly (ADP-ribose) polymerase (PARP) have shown substantial cytotoxic effects against tumors with defects in DNA damage responses. However, whether a crosstalk between PARP inhibition and immune checkpoints exists remains unclear. Here, it has been shown that PARP inhibitors (PARPis) upregulate PD-L1 expression in multiple cancer cell lines, human xenograft tumors, and syngeneic mouse tumors. Mechanistically, PARPi inactivates …

The Utilization Of Prenatal Microarray: A Survey Of Current Genetic Counseling Practices And Barriers, Leslie N. Durham, Leslie Durham

Dissertations & Theses (Open Access)

Chromosomal microarray (CMA) assesses chromosome copy number variants (CNVs) missed by standard karyotyping. The American College of Obstetricians and Gynecologists (ACOG) recommends CMA for all patients with fetuses with an ultrasound anomaly and suggests that it be made available to all women undergoing invasive testing. In order to assess prenatal genetic counselors’ (GCs) practices regarding the utilization of CMA we conducted a survey of their current practices, attitudes, and perceived barriers. Of the 192 respondents, 183 (95%) have incorporated CMA into clinical practice with the majority (64%) believing that the benefits of CMA outweigh the harms. However, only half (52%) …