{"id":{"repo_id":"ottawa-retro","oai_identifier":"oai:ruor.uottawa.ca:10393/45824"},"canonical_url":"https://search.dev.ndltd.org/etd/ottawa-retro/oai:ruor.uottawa.ca:10393/45824","repository":{"repo_id":"ottawa-retro","name":"University of Ottawa","base_url":"https://ruor.uottawa.ca/server/oai/request"},"display":{"title":"Smac Mimetic and Combination Immunotherapy for the Treatment of Urothelial Cell Carcinoma","abstract":"The inhibitors of apoptosis (IAP) proteins regulate cell death signaling cascades. Smac mimetic (SM) compounds are antagonists of these proteins and are being evaluated for their anti-cancer efficacy and immunomodulatory effects. Here, I adopted an orthotopic murine model of urothelial carcinoma (MB49) resistant to prominent immune-stimulating therapies BCG mycobacterium and PD-1/PD-L1 checkpoint blockade. I found treatment with a monovalent SM, LCL161, generated T lymphocyte-dependent cures of MB49, retaining potent anti-tumour immune memory and significantly improving overall survival benefit. Separately, I report SM treatment modulates multiple components comprising the cellular adaptive immune response. Specifically, I found SM promoting the expansion of antigen-presenting cells (APCs) in vitro and enabling T lymphocyte priming in vivo. I evaluated SM in combination with concurrent immune checkpoint blockade. The combination of SM with a monoclonal antibody targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4, 9h10 clone) potentiated anticancer immunity, curing all tested subjects of MB49. I verified Fc receptor-dependent intratumoural regulatory T cell depletion as a required mechanism for enhancing survival probability with the combination of SM and anti-CTLA-4. The further evaluation of mechanisms responsible for SMs stimulating immunity will promote their clinical application for cancer therapy.","abstract_html":"The inhibitors of apoptosis (IAP) proteins regulate cell death signaling cascades. Smac mimetic (SM) compounds are antagonists of these proteins and are being evaluated for their anti-cancer efficacy and immunomodulatory effects. Here, I adopted an orthotopic murine model of urothelial carcinoma (MB49) resistant to prominent immune-stimulating therapies BCG mycobacterium and PD-1/PD-L1 checkpoint blockade. I found treatment with a monovalent SM, LCL161, generated T lymphocyte-dependent cures of MB49, retaining potent anti-tumour immune memory and significantly improving overall survival benefit. Separately, I report SM treatment modulates multiple components comprising the cellular adaptive immune response. Specifically, I found SM promoting the expansion of antigen-presenting cells (APCs) in vitro and enabling T lymphocyte priming in vivo. I evaluated SM in combination with concurrent immune checkpoint blockade. The combination of SM with a monoclonal antibody targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4, 9h10 clone) potentiated anticancer immunity, curing all tested subjects of MB49. I verified Fc receptor-dependent intratumoural regulatory T cell depletion as a required mechanism for enhancing survival probability with the combination of SM and anti-CTLA-4. The further evaluation of mechanisms responsible for SMs stimulating immunity will promote their clinical application for cancer therapy.","abstract_has_math":false,"creators":["Sanda, Tarun"],"institution":"Université d'Ottawa / University of Ottawa","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Korneluk, Robert"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-01-11T18:07:03Z","date_published":"2024-01-11T18:07:03Z","updated_at":"2026-07-24T03:39:27Z","subjects":[],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["http://dx.doi.org/10.20381/ruor-30028"],"render_values":[{"text":"http://dx.doi.org/10.20381/ruor-30028","href":"http://dx.doi.org/10.20381/ruor-30028","code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/10393/45824","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Korneluk, Robert"]},{"key":"dc:creator","label":"Author","values":["Sanda, Tarun"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2024-01-11T18:07:03Z","2024-01-11"]},{"key":"dc:publisher","label":"Institution","values":["Université d'Ottawa / University of Ottawa"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10393/45824","http://dx.doi.org/10.20381/ruor-30028"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The inhibitors of apoptosis (IAP) proteins regulate cell death signaling cascades. Smac mimetic (SM) compounds are antagonists of these proteins and are being evaluated for their anti-cancer efficacy and immunomodulatory effects. Here, I adopted an orthotopic murine model of urothelial carcinoma (MB49) resistant to prominent immune-stimulating therapies BCG mycobacterium and PD-1/PD-L1 checkpoint blockade. I found treatment with a monovalent SM, LCL161, generated T lymphocyte-dependent cures of MB49, retaining potent anti-tumour immune memory and significantly improving overall survival benefit. Separately, I report SM treatment modulates multiple components comprising the cellular adaptive immune response. Specifically, I found SM promoting the expansion of antigen-presenting cells (APCs) in vitro and enabling T lymphocyte priming in vivo. I evaluated SM in combination with concurrent immune checkpoint blockade. The combination of SM with a monoclonal antibody targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4, 9h10 clone) potentiated anticancer immunity, curing all tested subjects of MB49. I verified Fc receptor-dependent intratumoural regulatory T cell depletion as a required mechanism for enhancing survival probability with the combination of SM and anti-CTLA-4. The further evaluation of mechanisms responsible for SMs stimulating immunity will promote their clinical application for cancer therapy."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Smac Mimetic and Combination Immunotherapy for the Treatment of Urothelial Cell Carcinoma"]}]}],"canonical_facts":{"dc:contributor":["Korneluk, Robert"],"dc:creator":["Sanda, Tarun"],"dc:date":["2024-01-11T18:07:03Z","2024-01-11"],"dc:description":["The inhibitors of apoptosis (IAP) proteins regulate cell death signaling cascades. Smac mimetic (SM) compounds are antagonists of these proteins and are being evaluated for their anti-cancer efficacy and immunomodulatory effects. Here, I adopted an orthotopic murine model of urothelial carcinoma (MB49) resistant to prominent immune-stimulating therapies BCG mycobacterium and PD-1/PD-L1 checkpoint blockade. I found treatment with a monovalent SM, LCL161, generated T lymphocyte-dependent cures of MB49, retaining potent anti-tumour immune memory and significantly improving overall survival benefit. Separately, I report SM treatment modulates multiple components comprising the cellular adaptive immune response. Specifically, I found SM promoting the expansion of antigen-presenting cells (APCs) in vitro and enabling T lymphocyte priming in vivo. I evaluated SM in combination with concurrent immune checkpoint blockade. The combination of SM with a monoclonal antibody targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4, 9h10 clone) potentiated anticancer immunity, curing all tested subjects of MB49. I verified Fc receptor-dependent intratumoural regulatory T cell depletion as a required mechanism for enhancing survival probability with the combination of SM and anti-CTLA-4. The further evaluation of mechanisms responsible for SMs stimulating immunity will promote their clinical application for cancer therapy."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10393/45824","http://dx.doi.org/10.20381/ruor-30028"],"dc:language":["en"],"dc:publisher":["Université d'Ottawa / University of Ottawa"],"dc:title":["Smac Mimetic and Combination Immunotherapy for the Treatment of Urothelial Cell Carcinoma"],"dc:type":["Thesis"]},"updated_at":"2026-07-24T03:39:27Z"}