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Combination therapy of injectable gelatin gel system encapsulating dendritic cell and oncolytic adenoviruses co-expressing IL-12 and GM-CSF

Title
Combination therapy of injectable gelatin gel system encapsulating dendritic cell and oncolytic adenoviruses co-expressing IL-12 and GM-CSF
Other Titles
IL-12와 GM-CSF 동시 발현 종양 선택적 살상 아데노바이러스와 수지상세포의 젤라틴 젤의 캡슐화를 통한 병합치료
Author
오정은
Alternative Author(s)
Jung-Eun Oh
Advisor(s)
윤채옥
Issue Date
2016-02
Publisher
한양대학교
Degree
Master
Abstract
Dendritic cell (DC) therapy is a promising strategy in cancer immunotherapy due to extremely low toxicity and induction of potent tumor-specific immunity. However, short activity of DC and immunosuppressive tumor microenvironment attenuates the therapeutic efficacy of DC cancer clinical trial. Expression of cytokines in the tumor tissues is a promising strategy to amend immunosuppressive tumor microenvironment and subsequently enhancing the therapeutic efficacy of DC. Oncolytic adenovirus (Ad) co-expressing interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) can induce potent antitumor effect through oncolytic Ad-mediated cell lysis and express therapeutic cytokines locally in the tumor tissues at a high level. Previously, this oncolytic Ad in combination with DC induced potent antitumor effect and antitumor immunity. However, this potent therapeutic efficacy by co-administration system required multiple administrations of both DC and oncolytic Ad due to rapid dissemination of these therapeutics at the tumor site. In this study, we investigated non-immunogenic gelatin-based hydrogel as a carrier for both oncolytic Ad and DC to elicit prolonged and potent antitumor effect at primary tumor with single administration. Enzymatic degradation of gelatin gel induces sustained release of both oncolytic Ad and DC to tumor site over a considerable time period. Ad released from the gel can infect local tumor cells and produce tumor-associated antigens through subsequent cancer-selective replication and cytolysis of tumor cells. Further, oncolytic Ad-mediated tumor-specific expression and amplification of therapeutic cytokines (IL-12 and GM-CSF) at the tumor tissue resulted in significantly improved downregulation of tumor-mediated immunosuppression, immune cell recruitment, and activation of both endogenous and exogenous DC in comparison with non-encapsulated oncolytic Ad and DC combination. Moreover, gel-encapsulated oncolytic Ad and DC system resulted in significantly enhanced tumor-specific immunity. Gel-encapsulated oncolytic Ad and DC significantly attenuated tumor-mediated thymic atrophy, which is associated with immunosuppression in the tumor microenvironment, in comparison to combination therapy without gel, suggesting that antitumor immunity was restored in the tumor tissue. Taken together, these results demonstrate that a gelatin gel encapsulation of oncolytic Ad and DC can be a promising candidate for future clinical immunotherapy.
URI
https://repository.hanyang.ac.kr/handle/20.500.11754/127195http://hanyang.dcollection.net/common/orgView/200000427954
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > BIOENGINEERING(생명공학과) > Theses (Master)
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