Dissertation
Evaluating the complexity of the immune response to vidutolimod: a virus-like particle containing a TLR9 agonist
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2023
DOI: 10.25820/etd.006993
Abstract
Recent advances in cancer immunotherapy were recognized by the 2019 Nobel Prizes in Biomedicine, and show exciting new potential to greatly improve patient outcomes. However, many patients fail to mount a clinically meaningful anti-tumor immune response with current immunotherapies. In situ immunization is an immunotherapy strategy with the potential to overcome this limitation by altering the tumor microenvironment (TME) in a manner that allows for the generation of a tumor-specific immune response.
Vidutolimod, previously known as CMP-001, is a novel formulation of a class A TLR9 agonist encased in a virus-like particle (VLP). This drug is currently under study as an in situ immunization agent in the treatment of cancer. Murine studies have shown that in situ immunization with vidutolimod in the context of systemic anti-PD1 therapy, results in a T cell dependent anti-tumor immune response that is superior to either drug alone. Ongoing clinical trials with vidutolimod in the context of anti-PD1 therapy show promising results. Yet, what remains unclear is how vidutolimod impacts the TME to ultimately lead to this enhanced immune response. This works aims to address this knowledge gap, so vidutolimod-mediated in situ immunization can be optimized clinically.
Prior work has demonstrated two key events in the mechanism of action of vidutolimod: one, the immunostimulatory effects of vidutolimod are dependent on generation of an anti-Qβ antibody response which results in opsonization of vidutolimod by plasmacytoid dendritic cells (pDCs) and production of Type 1 Interferon and two, in situ immunization with vidutolimod induces a T cell dependent anti-tumor immune response.
In this thesis, peripheral blood mononuclear cells are used as a model to study the TME. We begin by developing human anti-Qβ antibodies for use in in vitro experiments. This manufacturing process is described in detail in Chapter 2.
Next, using this antibody, we utilize single cell RNA sequencing to elucidate the impact of human anti-Qβ-coated vidutolimod on the immune system. We show that anti-Qβ-coated vidutolimod induces production of Type 1 Interferon by pDCs. This in turn impacts on a variety of cell types, most notably monocytes. We further demonstrate that pDC-derived Type 1 Interferon in context with Fc gamma receptor (FcγR) signaling (induced by uptake of the anti-Qβ-coated vidutolimod immune complex) impacts monocytes in such a manner that enhances their T cell proliferative capacity. These studies are described in Chapter 3.
In Chapter 4, we explore mechanisms regulating the production of Type 1 Interferon by pDCs in response to anti-Qβ-coated vidutolimod. We show that monocytes exposed to high levels of anti-Qβ-coated vidutolimod immune complexes negatively regulate Type 1 Interferon production by pDCs. These findings mirror what occurs during a viral memory response.Lastly, in Chapter 5, we summarize the aforementioned findings and highlight parallels in the fields of autoimmunity and virus biology. Understanding the role of immune complexes in related fields will be crucial as we continue to investigate the immune response to anti-Qβ-coated vidutolimod.
Ultimately, this work highlights the diverse roles monocytes play in modulating the immune response to anti-Qβ-coated vidutolimod and downstream cellular immunity. This work advances our understanding of the mechanism of action of anti-Qβ-coated vidutolimod and has major implications for the continued efficacy of this drug in the clinic.
Details
- Title: Subtitle
- Evaluating the complexity of the immune response to vidutolimod: a virus-like particle containing a TLR9 agonist
- Creators
- Shakoora Sabree
- Contributors
- George J. Weiner (Advisor)Jon C. Houtman (Committee Member)Gail A. Bishop (Committee Member)Polly J. Ferguson (Committee Member)Prajwal Gurung (Committee Member)Kevin L. Legge (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Immunology)
- Date degree season
- Summer 2023
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006993
- Number of pages
- xiv, 103 pages
- Copyright
- Copyright 2023 Shakoora A Sabree
- Language
- English
- Date submitted
- 04/26/2023
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 75-86).
- Public Abstract (ETD)
- A major line of defense between a patient and the aberrant growth of cancerous cells is a healthy and fully functional immune system. The immune system is equipped with a variety of cells, such as T cells and natural killer cells, who specialize in producing toxic byproducts that kill tumor cells. Nevertheless, cancer has developed ways to grow in spite of these effector cells by expressing molecules that deactivate immune cells. Cancer immunotherapy is a field of that seeks to reactivate a patient’s immune system to better target cancer cells. This field is showing great promise in improving patient outcomes. However, many patients fail to achieve clinically meaningful responses with current immunotherapies.
In situ immunization is an immunotherapy strategy with the potential to greatly improve patient outcomes by enhancing the activation of specific immune cells that are often deactivated within a tumor. This is achieved by injecting immunostimulatory drugs directly into a patient’s tumor. Vidutolimod is a new in situ immunization agent currently under study. This body of work seeks to understand what happens to the immune response after vidutolimod is injected. To study this, immune cells from the blood are used as a model for what may occur within the tumor.
Ultimately, we show that vidutolimod activates two key immune cells: plasmacytoid dendritic cells and monocytes, that work together to activate T cells. This work advances our understanding of vidutolimod and yields important lessons for how to improve the clinical efficacy of this novel drug.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984454743302771
Metrics
2 File views/ downloads
29 Record Views