Exploiting the Antitumor Immune Response Using IL-12 Armed Oncolytic MG1 Virus In An Infected Cell Vaccine
Despite improvements in chemotherapy and radical surgical debulking, peritoneal carcinomatosis (PC) remains among the most common causes of death for abdominal cancers. Immunotherapies have demonstrated efficacy in selected solid malignancies but their potential in PC is poorly explored. Here I repo...
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Université d'Ottawa / University of Ottawa
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ndltd-uottawa.ca-oai-ruor.uottawa.ca-10393-355992018-12-22T05:28:14Z Exploiting the Antitumor Immune Response Using IL-12 Armed Oncolytic MG1 Virus In An Infected Cell Vaccine Alkayyal, Almohanad Bell, John Auer, Rebecca Oncolytic virus Cancer vaccines Interleukin-12 Despite improvements in chemotherapy and radical surgical debulking, peritoneal carcinomatosis (PC) remains among the most common causes of death for abdominal cancers. Immunotherapies have demonstrated efficacy in selected solid malignancies but their potential in PC is poorly explored. Here I report that intraperitoneal injection of an infected cell vaccine (ICV), consisting of autologous tumor cells infected ex-vivo with an oncolytic Maraba MG1 virus expressing interleukin-12 (IL-12), promotes the migration of activated natural killer (NK) cells to the peritoneal cavity in response to the secretion of interferon gamma-induced protein-10 (IP-10) from dendritic cells. This recruitment of cytotoxic, IFNγ-secreting NK cells is associated with a dramatic reduction in tumor burden and improved survival in a colon cancer model of PC. Even in mice with bulky PC (tumors >8 mm), a complete radiological response was demonstrated within 8-14 weeks, associated with 100% long-term survival. Importantly, these results were recapitulated in human lymphocytes exposed to human tumor cell lines infected with MG1-IL12. Finally, I demonstrate that MG1-IL12-ICV generates an effective CD4 and CD8 T cell response in mice following prophylactic immunization associated with the maturation of peritoneal dendritic cells and enrichment of tumor-specific peritoneal T cells. The research presented in this thesis suggests that an MG1-IL12-ICV is a promising therapy that could provide benefit to the thousands of patients diagnosed with PC each year. 2016-12-14T13:55:56Z 2018-12-08T10:00:10Z 2016 Thesis http://hdl.handle.net/10393/35599 http://dx.doi.org/10.20381/ruor-557 en application/pdf Université d'Ottawa / University of Ottawa |
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Oncolytic virus Cancer vaccines Interleukin-12 |
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Oncolytic virus Cancer vaccines Interleukin-12 Alkayyal, Almohanad Exploiting the Antitumor Immune Response Using IL-12 Armed Oncolytic MG1 Virus In An Infected Cell Vaccine |
description |
Despite improvements in chemotherapy and radical surgical debulking, peritoneal carcinomatosis (PC) remains among the most common causes of death for abdominal cancers. Immunotherapies have demonstrated efficacy in selected solid malignancies but their potential in PC is poorly explored. Here I report that intraperitoneal injection of an infected cell vaccine (ICV), consisting of autologous tumor cells infected ex-vivo with an oncolytic Maraba MG1 virus expressing interleukin-12 (IL-12), promotes the migration of activated natural killer (NK) cells to the peritoneal cavity in response to the secretion of interferon gamma-induced protein-10 (IP-10) from dendritic cells. This recruitment of cytotoxic, IFNγ-secreting NK cells is associated with a dramatic reduction in tumor burden and improved survival in a colon cancer model of PC. Even in mice with bulky PC (tumors >8 mm), a complete radiological response was demonstrated within 8-14 weeks, associated with 100% long-term survival. Importantly, these results were recapitulated in human lymphocytes exposed to human tumor cell lines infected with MG1-IL12. Finally, I demonstrate that MG1-IL12-ICV generates an effective CD4 and CD8 T cell response in mice following prophylactic immunization associated with the maturation of peritoneal dendritic cells and enrichment of tumor-specific peritoneal T cells. The research presented in this thesis suggests that an MG1-IL12-ICV is a promising therapy that could provide benefit to the thousands of patients diagnosed with PC each year. |
author2 |
Bell, John |
author_facet |
Bell, John Alkayyal, Almohanad |
author |
Alkayyal, Almohanad |
author_sort |
Alkayyal, Almohanad |
title |
Exploiting the Antitumor Immune Response Using IL-12 Armed Oncolytic MG1 Virus In An Infected Cell Vaccine |
title_short |
Exploiting the Antitumor Immune Response Using IL-12 Armed Oncolytic MG1 Virus In An Infected Cell Vaccine |
title_full |
Exploiting the Antitumor Immune Response Using IL-12 Armed Oncolytic MG1 Virus In An Infected Cell Vaccine |
title_fullStr |
Exploiting the Antitumor Immune Response Using IL-12 Armed Oncolytic MG1 Virus In An Infected Cell Vaccine |
title_full_unstemmed |
Exploiting the Antitumor Immune Response Using IL-12 Armed Oncolytic MG1 Virus In An Infected Cell Vaccine |
title_sort |
exploiting the antitumor immune response using il-12 armed oncolytic mg1 virus in an infected cell vaccine |
publisher |
Université d'Ottawa / University of Ottawa |
publishDate |
2016 |
url |
http://hdl.handle.net/10393/35599 http://dx.doi.org/10.20381/ruor-557 |
work_keys_str_mv |
AT alkayyalalmohanad exploitingtheantitumorimmuneresponseusingil12armedoncolyticmg1virusinaninfectedcellvaccine |
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1718805273064243200 |