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http://hdl.handle.net/11375/26629
Title: | Local sustained delivery of antibody therapeutics from injectable hydrogels for the treatment of glioblastoma |
Authors: | Huynh, Vincent |
Advisor: | Wylie, Ryan |
Department: | Chemical Biology |
Publication Date: | 2021 |
Abstract: | Modern production techniques and new therapeutic targets have resulted in the development of different antibody-based treatment modalities, increasing the repertoire of viable drug candidates. The clinical success of immune checkpoint inhibitors (ICIs) has generated great interest in antibody-based drugs as cancer immunotherapeutics. The lack of treatment options for glioblastoma, the most malignant glioma, has expedited the investigation of antibody immunotherapeutics for glioblastoma. However, glioblastoma’s low tumor mutational burden (TMB) and immunosuppressive tumor immune microenvironment (TIME) render ICI monotherapies ineffective. Furthermore, physiological barriers (blood-brain barrier) impede drug localization, requiring high systemic doses that result in severe immunological side effects. To address these limitations, we demonstrate the benefit of: (1) local sustained release of antibody immunotherapeutics to increase the duration and magnitude of anti-cancer response and, (2) combination therapies to further promote immune cell mediated killing of glioblastoma. With the goal of creating an implant for the local infusion of immunotherapeutics (LIIT), herein, I describe the development of an injectable hydrogel that incorporates an affinity based drug delivery system (DDS). Using well known affinity interactions, a three component DDS referred to as competitive affinity release (CAR) released a bioactive antibody for >100d. CAR was then modified to a new system called displacement affinity release (DAR), for the delivery of minimally modified antibody. An in situ gelling, injectable, low-fouling poly(carboxybetaine) hydrogel was fabricated for the localization of the DDS. The DDS hydrogel combination was used to deliver a dual antigen T cell engager (DATE) targeting CD133 positive glioblastoma cells in 3D embedded spheroid cultures and a patient derived xenograft model. Controlled release of CD133 targeting DATE increased survival benefit within the xenograft model. Within the 3D embedded spheroid model, the combination therapy of DATE with an αPD-1 ICI increased and sustained cytotoxic effects. Here I developed a platform technology for the local infusion of immunotherapeutics (LIIT), amenable to any antibody cancer immunotherapeutics. This project demonstrates how local infusion with immunostimulatory drugs can increase the magnitude and duration of anti-cancer immunotherapy in glioblastoma where physiological barriers impede drug accumulation. |
URI: | http://hdl.handle.net/11375/26629 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Huynh_Vincent_finalsubmission202106_PhD.pdf | 7.95 MB | Adobe PDF | View/Open |
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