Please use this identifier to cite or link to this item:
http://hdl.handle.net/11375/26629
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Wylie, Ryan | - |
dc.contributor.author | Huynh, Vincent | - |
dc.date.accessioned | 2021-06-22T20:08:17Z | - |
dc.date.available | 2021-06-22T20:08:17Z | - |
dc.date.issued | 2021 | - |
dc.identifier.uri | http://hdl.handle.net/11375/26629 | - |
dc.description.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. | en_US |
dc.language.iso | en | en_US |
dc.title | Local sustained delivery of antibody therapeutics from injectable hydrogels for the treatment of glioblastoma | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Chemical Biology | en_US |
dc.description.degreetype | Dissertation | en_US |
dc.description.degree | Doctor of Philosophy (PhD) | en_US |
dc.description.layabstract | Drugs that enable the immune system to recognize cancer have the potential to produce numerous anti-cancer treatments, revolutionizing the field cancer research. However, many of these drugs are clinically ineffective because of toxic side effects from high doses required to achieve therapeutic concentrations. Additionally, physiological transport barriers in cancers, especially brain cancer, impede drug distribution, and make it more difficult to reach therapeutic levels. Delivering drugs to the correct location and for an optimal amount of time will improve drug efficacy. Drug loaded implants mostly composed of water, known as hydrogels, can be injected at the disease site for the slow infusion of drug into the area. This would simultaneously decrease the need for frequent drug administrations and decrease toxic side effects. Here, we present the development and testing of a medical implant that delivers drugs that redirect the immune system to recognize and kill brain tumors. The chemical properties of the implant were optimized for safe injection into the brain and for long term drug infusion. By extending the time of drug exposure using the implant, drug effectiveness was increased in mice bearing human brain cancer. Additionally, we showed the development of an in vitro model for brain cancer where anti-cancer effects of the drug loaded implant can be easily observed for applications in drug screening. This thesis, therefore, demonstrates how implantable materials can increase the effectiveness of anti-cancer drugs through efficient drug delivery. | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Huynh_Vincent_finalsubmission202106_PhD.pdf | 7.95 MB | Adobe PDF | View/Open |
Items in MacSphere are protected by copyright, with all rights reserved, unless otherwise indicated.