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Design of Immuno-Nanoparticles to Alter the Tumor Immune Microenvironment

Lorkowski, Morgan
http://orcid.org/0000-0003-4373-8200
http://rave.ohiolink.edu/etdc/view?acc_num=case1638957330620722

Abstract Details

2022, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Cancer is a direct result of the immune system’s failure to identify and eliminate mutated cells early in their development. Cancer immunotherapy aims to retrain the body’s natural defense mechanism to recognize malignant cells, to remove cancerous tissue and to remember their signature to prevent future disease recurrence. While clinically approved immunotherapies produce remarkable results in specific patient subsets, treatment success relies heavily on the composition of immune cells within the tumor, which can vary drastically between patients and between tumor landscapes. Many aggressive, treatment-resistant cancers possess a highly immunosuppressive tumor microenvironment, containing large numbers of dysfunctional innate immune cells that shield cancer cells from detection. When properly activated, dendritic cells and macrophages act as essential antigen-presenting cells (APCs) to drive maturation of naïve T cells. However, clinically approved immunotherapies focus largely on adaptive T cell-mediated activity and fail to address inadequate antigen presentation necessary for proper T cell stimulation. To overcome local immunosuppression, proinflammatory agents can reprogram dysfunctional APCs into operational immune cells that can bridge the innate and adaptive arms of the immune system to generate an effective antitumor response. Nanoparticles present a versatile, engineerable approach to improve the safety and delivery of potent immunomodulatory agents. The objective of this dissertation is to design systemically administered immunomodulatory nanoparticles to alter the innate immune compartment of hard-to-treat cancers. We chose systemic administration as this route allows for seamless access to the APC-rich perivascular region of the tumor. In the following chapters, we show that systemically administered nanoparticles drive proinflammatory cytokine secretion and stimulate innate immune cell recruitment in orthotopic models of immunosuppressive pancreatic, brain and breast cancer. Future studies stand to augment existing immunotherapies in order to generate and perpetuate robust antitumor activity and prevent potential metastasis and recurrence.
Efstathios Karathanasis (Advisor)
Li Wang (Committee Member)
Jeffrey Capadona (Committee Member)
Zheng-Rong Lu (Committee Chair)
152 p.
Biomedical Engineering
Nanoparticles; immunotherapy; cancer

Recommended Citations

Citations

  • Lorkowski, M. (2022). Design of Immuno-Nanoparticles to Alter the Tumor Immune Microenvironment [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1638957330620722

    APA Style (7th edition)

  • Lorkowski, Morgan. Design of Immuno-Nanoparticles to Alter the Tumor Immune Microenvironment. 2022. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1638957330620722.

    MLA Style (8th edition)

  • Lorkowski, Morgan. "Design of Immuno-Nanoparticles to Alter the Tumor Immune Microenvironment." Doctoral dissertation, Case Western Reserve University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=case1638957330620722

    Chicago Manual of Style (17th edition)

case1638957330620722
176
© 2021, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.