Immunology and Infectious Disease Commons^™

Development Of A Pd-L1 Pet Imaging Biomarker, Caleb Jack Bridgwater

Posters-at-the-Capitol

Immunotherapy strategies are very promising treatments for cancer patients. Specifically, Immune checkpoint inhibitor therapy focusing on the PD-1/PD-L1 pathway shows long-lasting positive results in many cancer patients. Unfortunately, not all the patients can benefit from this highly effective treatment. Hence, there is a great need for predictive biomarkers. Immunohistochemical (IHC) staining has been used as a way of predicting patient response, yet shows many problems. For example, IHC utilizes an invasive biopsy and sample fixing, which creates an incomplete and delayed picture of the patient’s biochemistry and the tumor microenvironment, consequently ignoring metastases.

The purpose of this study is to …

Tumor Surveillance Using Liquid Biome In Pediatric High Grade Gliomas, Erin Bonner, Eshini Panditharatna, Madhuri Kambhampati, Stefaan Van Gool, Wilfried Stuecker, Roger J. Packer, Javad Nazarian

GW Research Days 2016 - 2020

Immunotherapy is currently being used to treat pediatric brain cancer, though its efficacy in treating patients with diffuse intrinsic pontine glioma (DIPG), the deadliest pediatric brain tumor, has not been evaluated. MRI is the gold standard for monitoring tumor response to therapy, but is limited by pseudoresponse and psuedoprogression: post-treatment, immune cells infiltrate the primary tumor causing transient tumor enlargement, which falsely resembles tumor progression on MRI. Thus, it is critical to develop more accurate approaches to monitor tumor response to immunotherapy. Here, we use a liquid biopsy platform we have already established to monitor tumor response to therapy, to …

Galectin - Method For Enhancing Specific Immunotherapies In Cancer Treatment, Peter G. Traber, William L. Redmond, Eliezer Zomer, Anatole Klyosov, Stephanie N. Linch

Technology Transfer - Patents

Methods and compositions of the invention relate to the enhancement of specific immunotherapies in cancer treatment. In particular, aspects of the invention relate to novel approaches to boost immune function using a complex carbohydrate pharmaceutical compound alone or in combination with other targeted immunotherapy to increase the efficacy of immunotherapy of cancer.

Immune Checkpoint Inhibitors In Neuroendocrine Tumors: A Single Institution Experience With Review Of Literature, Aman Chauhan, Millicent Horn, Gray Magee, Kurt Hodges, B. Mark Evers, Susanne Arnold, Lowell B. Anthony

Markey Cancer Center Faculty Publications

This unique case series and review of literature suggests that immune checkpoint inhibitors may have clinical activity in neuroendocrine tumors.

Objective: Summarize advances of immuno-oncology in neuroendocrine tumors with the help of a case series.

Design: Case series and review of literature.

Intervention or Exposure: The patients were treated with immune checkpoint inhibitors (pembrolizumab or nivolumab).

Main Outcome(s) and Measures(s): Life expectancy, quality of life, disease progression.

Results: Maximum durable response of 16 months in one of the patients so far. All patients showed improvement in quality of life before disease progression. Two out of four are still on therapy. …

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

Dissertations and 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 …

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

Dissertations and 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 …

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

Dissertations and 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 …

Characterization Of Murine Breast Cancer Cell Lines For Anti-Cancer Vaccine, Haven N. Frazier

Biological Sciences Undergraduate Honors Theses

Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer death among women in the United States (1). While treatments involving radiation and chemotherapy currently exist, disease must be detected early in order for the treatments to be somewhat effective, and there is no effective treatment after metastasis occurs (2). Additionally, current therapies do not mitigate tumor immunosuppression. Decreasing the tumor-associated immunosuppressive conditions while activating antitumor immunity could prevent recurrence and metastasis, possibly leading to an effective treatment for cancer (3). Tumor cell vaccines could possibly address this issue and have become a …

Role Of Modern Immunotherapy In Gastrointestinal Malignancies: A Review Of Current Clinical Progress, Zin W. Myint, Gaurav Goel

Markey Cancer Center Faculty Publications

Gastrointestinal (GI) cancers are a group of highly aggressive malignancies with a huge disease burden worldwide. There is clearly a significant unmet need for new drugs and therapies to further improve the treatment outcomes of GI malignancies. Immunotherapy is a novel treatment strategy that is emerging as an effective and promising treatment option against several types of cancers. CTLA-4 and PD-1 are critical immune checkpoint molecules that negatively regulate T cell activation via distinct mechanisms. Immune checkpoint blockade with antibodies directed against these pathways has already shown clinical efficacy that has led to their FDA approval in the treatment of …

Immune Modulating Functions By Soypeptide Lunasin In Cancer Immunotherapy, Chun-Yu Tung

Open Access Dissertations

Chemotherapy is currently the mainstay of treatment for most cancer patients. Despite its efficacy in eliminating cancer cells, a high percentage of chemotherapy patients eventually relapse or suffer progression of the disease. Immunosurveillance is capable of recognizing and eliminating continuously arising transformed mutant cells, and thus cancer immunotherapy is one of the emerging therapeutic strategies that harnesses the power of the immune system to eradicate chemotherapy-resistant cancerous cells. However, the adverse side effects of chemotherapy impede the therapeutic effects of immunotherapy. Our previous studies demonstrate that lymphoma patients are refractory to clinical immunotherapy because of chemotherapy-induced immune dysfunction. In addition, …

Targeting Histone Deacetylases In Melanoma And T-Cells To Improve Cancer Immunotherapy, Andressa Sodre De Castro Laino

USF Tampa Graduate Theses and Dissertations

Histone deacetylases (HDACs) are key mediators of gene expression and, thus, major regulators of cell function. As such, HDACs play a role in orchestrating tumor biology, and the use of small inhibitors targeting theses proteins is attractive for the field of cancer therapy. Indeed, several HDAC inhibitors have received FDA-approval for the treatment of malignancies, while a myriad of these compounds continue to be evaluated in clinical trials. Besides their direct impact on tumor growth, HDAC inhibitors have been shown to increase immunogenicity of cancer cells, facilitating generation of a productive immune response against tumors. Immunotherapeutic approaches take advantage of …

Antigen Specific Induced T Regulatory Cellular Therapy For Graft-Versus-Host Disease Following Allogeneic Bone Marrow Transplantation, Jessica Lauren Heinrichs

USF Tampa Graduate Theses and Dissertations

Allogeneic hematopoietic stem cell transplantation (allo-HCT) has been a successful cellular therapy for patients suffering from hematological malignancies for many decades; however, the beneficial effects of graft-versus-leukemia (GVL) are classically offset by graft-versus-host disease (GVHD). GVHD occurs when major and/or minor human leukocyte antigen (HLA) mismatches between donor and recipient cause rapid expansion and activation of donor effector T cells (Teffs) resulting in end organ damage to the recipient’s epithelial tissues. Given the lymphoproliferative nature of this disease, the standard treatment option is broad immunosuppression, which can result in primary disease relapse, steroid refractory GVHD, and/or opportunistic infection. A more …

Adipocyte-Induced Inflammation In Prostate Tumor Progression In Bone: Role Of Cxcr2 And Osteopontin, Aimalie Lynnette Hardaway

Wayne State University Dissertations

Abstract

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men. Evidence suggests that age and obesity, conditions associated with adipocyte accumulation in the bone marrow, are linked to increased risk of developing PCa and progressing to metastatic disease. Studies presented in this dissertation were based on the hypothesis that metastatic progression in bone is a result of a cooperative effort between bone marrow adipocytes, macrophages, osteoclasts, and PCa cells. We specifically focused on two adipocyte-supplied chemokines, CXCL1 and CXCL2, and bone marrow macrophage-secreted osteopontin as key drivers of pro-inflammatory environment in the bone marrow and important …

Development And Characterization Of An Autologous Whole Cell Breast Cancer Vaccine, Samantha Leigh Kurtz

Graduate Theses and Dissertations

Approximately 40,000 women will die from breast cancer in the United States in 2014. About 90% of these deaths will be due to metastases, rather than the primary tumor and majority of metastases are due to the recurrence and progression of non-metastatic disease. Current adjuvant treatments, such as chemotherapy and radiation, have severe side effects and may result in overtreatment and drug resistance.

Since greater than 90% of patients are diagnosed between stages I-III and have minimal residual disease after treatment, there is an opportunity to treat patients with an autologous breast cancer vaccine. Autologous vaccines under development have a …

Autoantibodies To The Ny-Eso-1 Tumor Antigen In Metastatic Melanoma: Sialylation Of The Fc Region Of Immunoglobulin G Induces Differential Expression Signatures Of Inflammatory Molecules During Dendritic Cell Differentiation And Maturation, Martin Oaks, Nathaniel Rein, John O. Richards, James Shaffer

Journal of Patient-Centered Research and Reviews

Purpose: We tested the hypothesis that different glycoforms of antibodies from patients with metastatic melanoma have different functional effects on human dendritic cell differentiation and maturation.

Methods: Antibodies to the cancer antigen NY-ESO-1 were affinity-purified from patients with melanoma and further fractionated into different glycoforms by lectin chromatography. Sialic acid-rich and sialic acid-poor fractions of these immunoglobulin G antibodies (IgG) were added to dendritic cell cultures during both differentiation and maturation, and the resulting cellular messenger RNA (mRNA) and culture supernatants were tested by microarray and enzyme-linked immunoassay for molecules related to inflammatory pathways.

Results: We identified unique mRNA and …

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

University Scholar Projects

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed, …

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

Honors Scholar Theses

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed, …

Method For Enhancing Specific Immunotherapies In Cancer Treatment, Peter G. Traber, William L. Redmond, Eliezer Zomer, Anatole Klyosov, Stefanie N. Linch

Technology Transfer - Patents

Methods and compositions of the invention relate to the enhancement of specific immunotherapies in cancer treatment. In particular, aspects of the invention relate to novel approaches to boost immune function using a complex carbohydrate pharmaceutical compound alone or in combination with other targeted immunotherapy to increase the efficacy of immunotherapy of cancer.

Resistance Of Human Cytomegalovirus To Cyclopropavir Maps To A Base Pair Deletion In The Open Reading Frame Of Ul97, Brian G. Gentry, Laura E. Vollmer, Ellie D. Hall, Katherine Z. Borysko, Jiri Zemlicka, Jeremy P. Kamil, John C. Drach

Oncology Faculty Publications

Human cytomegalovirus (HCMV) is a widespread pathogen in the human population, affecting many immunologically immature and immunocompromised patients, and can result in severe complications, such as interstitial pneumonia and mental retardation. Current chemotherapies for the treatment of HCMV infections include ganciclovir (GCV), foscarnet, and cidofovir. However, the high incidences of adverse effects (neutropenia and nephrotoxicity) limit the use of these drugs. Cyclopropavir (CPV), a guanosine nucleoside analog, is 10-fold more active against HCMV than GCV (50% effective concentrations [EC₅₀s] = 0.46 and 4.1 μM, respectively). We hypothesize that the mechanism of action of CPV is similar to that …

Characterization Of Differentiation And Prognostic Biomarkers On Cd8+ Tumor-Infiltrating Lymphocytes In Metastatic Melanoma, Richard C. Wu

Dissertations and Theses (Open Access)

CD8⁺ cytotoxic T lymphocytes (CTL) frequently infiltrate tumors, yet most melanoma patients fail to undergo tumor regression. We studied the differentiation of the CD8⁺ tumor-infiltrating lymphocytes (TIL) from 44 metastatic melanoma patients using known T-cell differentiation markers. We also compared CD8⁺ TIL against the T cells from matched melanoma patients’ peripheral blood. We discovered a novel subset of CD8⁺ TIL co-expressing early-differentiation markers, CD27, CD28, and a late/senescent CTL differentiation marker, CD57. This CD8⁺CD57⁺ TIL expressed a cytolytic enzyme, granzyme B (GB), yet did not express another cytolytic pore-forming molecule, perforin (Perf). In …

Impact Of Cryoablation On Tumor Immunity, Jesse Veenstra

Wayne State University Dissertations

Background and Objectives: Percutaneous cryoablation is a minimally invasive procedure for tumor debulking, which has the potential to initiate or amplify tumor immunity through the release of tumor-associated antigens and endogenous danger signals. However, enhanced immunity is rarely observed in treated patients, suggesting the need for mechanistic analysis. The goal is to determine how cryoablation affects tumor specific immunity and if the response can be improved through exogenous TLR9 stimulation.

Methodology: We evaluated anti-Her2/neu immunity following cryoablation in wt BALB/c and tolerant NeuT mice inoculated with neu or Her2 expressing mammary tumors TUBO and D2F2/E2 respectively. Mice were treated with …

Histone Deacetylases As Targets For Melanoma Immunotherapy, David Michael Woods

USF Tampa Graduate Theses and Dissertations

Cancer represents the second leading cause of death in the United States. For many malignancies, currently available treatment options offer little long-lasting survival benefits to patients. However, recent studies have shown immunotherapeutic approaches to be an attractive strategy to cancer treatment. While many current immunotherapeutic strategies convey durable responses, such responses are only seen in a minority of patients. An increased understanding of the mechanisms governing tumor immunogenicity and the biology of immune responses is crucial to improving upon the efficacy of current and future cancer immunotherapies. Histone deacetylases (HDACs), enzymes classically associated with regulation of gene expression, have been …

Activation Of Amp-Activated Protein Kinase By 3,39-Diindolylmethane (Dim) Is Associated With Human Prostate Cancer Cell Death In Vitro And In Vivo, Di Chen, Sanjeev Banerjee, Qiuzhi C. Cui, Dejuan Kong, Fazlul H. Sarkar, Q. Ping Dou

Oncology Faculty Publications

There is a large body of scientific evidence suggesting that 3,39-Diindolylmethane (DIM), a compound derived from the digestion of indole-3-carbinol, which is abundant in cruciferous vegetables, harbors anti-tumor activity in vitro and in vivo. Accumulating evidence suggests that AMP-activated protein kinase (AMPK) plays an essential role in cellular energy homeostasis and tumor development and that targeting AMPK may be a promising therapeutic option for cancer treatment in the clinic. We previously reported that a formulated DIM (BR-DIM; hereafter referred as B-DIM) with higher bioavailability was able to induce apoptosis and inhibit cell growth, angiogenesis, and invasion of prostate cancer cells. …

Enhancing The Immune Response Through Ikkbeta-Induced Activation Of Nf-Kappab, Emily Hopewell

USF Tampa Graduate Theses and Dissertations

Nuclear factor-κB (NF-κB) is one of the main regulators of inflammatory and immune responses. It is a family of transcription factors composed of five members: RelA, RelB, cRel, NF-κB1 (p105/p50), and NF-κB2 (p100/p52). Homo- and hetero-dimers of family members are inhibited by inhibitor of &klappaB (IκB) family members and activated by IκB kinase (IKK) family members. The IKK family is comprised of IKKα, IKKΒ, and IKKγ. The focus of my dissertation delves into the role of NF-κB activation by IKKΒ in both an immunotherapy setting and its role in T cell mediated anti-tumor immune responses.

A central focus of immunotherapy …

Regulation Of Natural Killer Cells: Ship-1, 2b4, And Immunomodulation By Lenalidomide, Nicole Renee Fortenbery

USF Tampa Graduate Theses and Dissertations

Natural Killer cells (NK) are critical components of the innate immune system. Often referred to by their morphology, these large granular lymphocytes (LGLs) are bone marrow-derived lymphocytes and can be found throughout the body. NK cells reside in the liver, lymph nodes, spleen, thymus, and mucosal-associated lymphoid tissues (MALT). Importantly, NK cells also circulate throughout the blood where they function as surveyors of the body and are armed to eliminate malignant, infected, damaged, or foreign cells.

NK cells function by a dual receptor system. That is, NK receptors are broadly categorized as inhibitory or activating. It is a fine balance, …

Modulation Of Anti-Tumor Immune Response By Tgf-Β-Inducible Early Gene 1 (Tieg1), Andi Cani

Wayne State University Theses

Cancer immunotherapy has had limited clinical efficacy partly because regulatory T cells (Treg) suppress the immune response to tumor-associated antigens. Inducible regulatory T cells (iTreg), which are converted from naïve CD4 T cells by TGF-β, an abundant cytokine in the tumor microenvironment, may contribute to this immune suppression. Induction of Foxp3 by TGF-β is mediated by the transcription factor TIEG1 and abrogation of this protein prevents Foxp3 expression. We are testing the hypothesis that blockade of TIEG1 to prevent iTreg conversion will enhance immune response in DNA vaccination to the tumor associated antigen Her-2. Wild type and TIEG1 knockout mice …

Therapeutic Peptide-Based Vaccination Strategies Against Hpv-Induced Cancers, Kelly Barrios Marrugo

USF Tampa Graduate Theses and Dissertations

There is an urgent need for the development of an effective therapeutic vaccine against cancer caused by human papilloma virus (HPV). We focused on HPV-induced malignancies because of their high worldwide prevalence (e.g., cervical carcinoma and head & neck cancer). A successful therapeutic vaccine could prevent the 250 000 deaths/year worldwide and the 2.25 billion dollars that

are expended in related care in the US.

We used an HPV-induced mouse cancer model to test vaccines

composed of a CD8 T cell peptide epitope administered with potent adjuvants designed to generate vast numbers of high avidity cytotoxic T lymphocytes specific for …

Lenalidomide Targets The T-Cell Co-Stimulatory Pathway To Mediate Immune Modulation, Jessica Marie Mcdaniel

USF Tampa Graduate Theses and Dissertations

T-cells are lymphocytes that make up part of the adaptive arm of the immune system, and are essential for efficient protection from and eradication of viruses and pathogens. T-cells not only play an important role in protection from external agents, but also regulate and prevent activation towards self-peptides and detect and remove erratically growing cells. Alterations in T-cell activation and suppression contribute to auto-immunity, immunocompromised disorders, and cancer progression.

The immune system, and T-cells in particular, provides daily surveillance, recognition and destruction of aberrant cells. Although the immune system is proficient at suppressing malignant progression, tumor cells acquire various methods …

Hiv-1 Tat Protein Promotes Neuronal Dysfunction Through Disruption Of Micrornas, J Robert Chang, Ruma Mukerjee, Asen Bagashev, Luis Del Valle, Tinatin Chabrashvili, Brian J. Hawkins, Johnny J. He, Bassel E. Sawaya

School of Medicine Faculty Publications

Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release …

Determination Of The Optimal Form Of A Dna Vaccine To Induce An Effective Immune Response Against A Murine B-Cell Lymphoma, Deepti Aurora

All-Inclusive List of Electronic Theses and Dissertations

Tumor vaccines are a promising alternative to chemotherapy for the treatment of cancer. To be effective and safe, a cancer vaccine should specifically target antigens expressed only on tumor cells. The B-cell tumor-derived Ig receptor may be considered a model tumor antigen for cancer vaccine development. Specifically the immunoglobulin idiotype (ld) encoded by the variable region genes (VH and VL) provides a target antigen. Promising results have been obtained in clinical studies of ld vaccination using ld proteins. However, ld protein is laborious and time-consuming to produce. Gene-based vaccines, on the other hand, are inexpensive and offer ease of manipulation …