ingest cdrApp 2018-06-13T20:31:52.218Z 51cd2fe2-3fd7-401f-a923-a97bc3db68a2 modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-06-13T21:58:26.992Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2018-06-13T21:58:38.316Z Adding technical metadata derived by FITS addDatastream MD_FULL_TEXT fedoraAdmin 2018-06-13T21:59:01.047Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-06-13T21:59:23.477Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-11T04:46:54.958Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-16T14:11:11.021Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-27T00:43:39.390Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-10-12T01:19:30.865Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-20T19:20:35.156Z Qi Liu Author UNC/NCSU Joint Department of Biomedical Engineering School of Medicine Immunotherapy for desmoplastic melanoma: nano-medicine approaches of vaccination and immune-modulation 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. Spring 2018 2018 Biomedical engineering immunotherapy, melanoma, nanomedicine, tumor microenvironment, vaccine eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biomedical Engineering Gu Zhen Thesis advisor Leaf Huang Thesis advisor Rihe Liu Thesis advisor Kristy Ainslie Thesis advisor Philip Smith Thesis advisor David Zaharoff Thesis advisor text Qi Liu Author UNC/NCSU Joint Department of Biomedical Engineering School of Medicine Immunotherapy for desmoplastic melanoma: nano-medicine approaches of vaccination and immune-modulation 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. Spring 2018 2018 Biomedical engineering immunotherapy, melanoma, nanomedicine, tumor microenvironment, vaccine eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biomedical Engineering Gu Zhen Thesis advisor Leaf Huang Thesis advisor Rihe Liu Thesis advisor Kristy Ainslie Thesis advisor Philip Smith Thesis advisor David Zaharoff Thesis advisor text Qi Liu Author UNC/NCSU Joint Department of Biomedical Engineering School of Medicine Immunotherapy for desmoplastic melanoma: nano-medicine approaches of vaccination and immune-modulation 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. Spring 2018 2018 Biomedical engineering immunotherapy, melanoma, nanomedicine, tumor microenvironment, vaccine eng Doctor of Philosophy Dissertation Biomedical Engineering Zhen Gu Thesis advisor Leaf Huang Thesis advisor Rihe Liu Thesis advisor Kristy Ainslie Thesis advisor Philip Smith Thesis advisor David Zaharoff Thesis advisor text University of North Carolina at Chapel Hill Degree granting institution Qi Liu Creator UNC/NCSU Joint Department of Biomedical Engineering School of Medicine Immunotherapy for desmoplastic melanoma: nano-medicine approaches of vaccination and immune-modulation 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. Biomedical engineering immunotherapy; melanoma; nanomedicine; tumor microenvironment; vaccine eng Doctor of Philosophy Dissertation Biomedical Engineering Zhen Gu Thesis advisor Leaf Huang Thesis advisor Rihe Liu Thesis advisor Kristy Ainslie Thesis advisor Philip Smith Thesis advisor David Zaharoff Thesis advisor text University of North Carolina at Chapel Hill Degree granting institution 2018 2018-05 Qi Liu Author UNC/NCSU Joint Department of Biomedical Engineering School of Medicine Immunotherapy for desmoplastic melanoma: nano-medicine approaches of vaccination and immune-modulation 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. Spring 2018 2018 Biomedical engineering immunotherapy, melanoma, nanomedicine, tumor microenvironment, vaccine eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biomedical Engineering Zhen Gu Thesis advisor Leaf Huang Thesis advisor Rihe Liu Thesis advisor Kristy Ainslie Thesis advisor Philip Smith Thesis advisor David Zaharoff Thesis advisor text Qi Liu Creator UNC/NCSU Joint Department of Biomedical Engineering School of Medicine 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. 2018-05 2018 Biomedical engineering immunotherapy; melanoma; nanomedicine; tumor microenvironment; vaccine eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Zhen Gu Thesis advisor Leaf Huang Thesis advisor Rihe Liu Thesis advisor Kristy Ainslie Thesis advisor Philip Smith Thesis advisor David Zaharoff Thesis advisor text Liu_unc_0153D_17708.pdf uuid:b204de03-8b3b-4cbb-b70f-2c43c4d8a79d 2020-06-13T00:00:00 2018-04-19T21:31:52Z proquest application/pdf 7027567