Immunotherapy for desmoplastic melanoma: nano-medicine approaches of vaccination and immune-modulation Public Deposited

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  • March 20, 2019
Creator
  • Liu, Qi
    • Affiliation: School of Medicine, UNC/NCSU Joint Department of Biomedical Engineering
Abstract
  • Melanoma, the most lethal skin cancer, has an incremental incidence, few durable therapies, and a low survival rate of less than 10 % for late-stage patients in clinics. In desmoplastic melanoma, a rare histological variant of melanoma, the highly fibrotic morphology as well as the immune-suppressive tumor microenvironment led to distinct clinical behavior when compared with other melanoma subtypes, thus hindering treatment efficacy. To overcome these therapeutic hurdles, herein in this dissertation work I developed multiple innovative strategies based on targeted nano-delivery systems. These strategies include the effective delivery of therapeutic vaccination, immune-modulating chemo-drugs and active compounds, gene therapy, and a combination of chemo-immune initiated/guided treatment. A total of five aims were sequentially designed, including 1) nano-vaccination. The tumor-specific antigen peptides were efficiently delivered to antigen-presenting cells along with immune-stimulating adjuvant. This therapeutic vaccine inhibited aggressive tumor growth. 2) nano-sunitinib. The FDA approved drug sunitinib was targeted delivered to the tumor with improved anti-tumor efficacy, furthermore, it largely remodeled immune suppressive microenvironment and facilitated vaccination efficacy. 3) nano-fraxinellone. The active compound fraxinellone was nano-delivered to the tumor microenvironment, inhibiting the transition of tumor associated fibroblasts and skewed TGF-β/IFN- γ balancing toward pro-inflammatory settings. 4) nano-wnt5a trap. Key molecular wnt5a secreted by tumor cells in inducing dendritic cell tolerance and tumor fibrosis was locally trapped, thus significantly tuned immune recognition and surveillance of cancer progression. 5) nano-delivery of mitoxantrone and celastrol. Two drugs were screened out with highest anti-tumor and anti-fibrosis potentials and worked synergistically in inducing immunogenic tumor cell death and long-term memory immune responses. Using animal models of desmoplastic melanoma, our nanomedicine designs significantly elicited an overall anti-tumor immunity with increased efficacy, safety profiles, and prolonged host survival, suggesting their high translatability to the clinic. This dissertation research work further sheds light on a deeper understanding of cancer type-specific microenvironment and immune modulators, as well as future mechanism studies in designing immunotherapy for desmoplastic melanoma.
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Advisor
  • Gu, Zhen
  • Zaharoff, David
  • Smith, Philip
  • Ainslie, Kristy
  • Liu, Rihe
  • Huang, Leaf
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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