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Author ORCID Identifier
https://orcid.org/0000-0002-2069-9352
AccessType
Campus-Only Access for Five (5) Years
Document Type
dissertation
Degree Name
Doctor of Philosophy (PhD)
Degree Program
Chemical Engineering
Year Degree Awarded
2023
Month Degree Awarded
May
First Advisor
Ashish Kulkarni
Subject Categories
Biotechnology | Chemical Engineering
Abstract
The immune system plays a crucial role in fighting malignant cells, and modulation of immune function to improve anti-tumor response has become a significant focus in cancer treatment. Immune checkpoint inhibitor (ICI) treatments have been approved by the US FDA for several advanced-stage cancers. However, the response rates to these therapies vary among patients and cancer types, and existing clinical imaging tools lack the ability to differentiate responders from non-responders early on, which leads to prolonged suffering, severe toxicity from ineffective therapies, and high treatment costs. To address these challenges, this dissertation focuses on developing stimulirepsonsive nanoreporter platforms for earlier and more accurate readouts of disease progression and immunotherapeutic outcomes directly at the tumor microenvironment. We first aimed to monitor in real-time the T-cell killing activity using a two-in-one nanoreporter system that co-delivered anti PD-L1 checkpoint inhibitor and an activatable fluorescence probe to the tumor site. This study facilitated direct visualization of granzyme B (GrzB), a potent hallmark of T cell cytotoxicity that later contributed to tumor cell death, as a direct way to monitor initiation of effective immune response following PD-1/PD-L1 viii perturbation. This platform ushered a promising imaging tool for noninvasive and early evaluation of immunotherapy efficacy. We further advanced the nanoreporter technology to three-dimensional (3D) culture on microfluidic chip for high-throughput screening the efficacy of different ICIs onto different tumor models. Dual-probe nanoreporters that could detect GrzB and caspase- 3 (Casp3) concordantly were developed to identify the kinetics of GrzB-Casp3 apoptotic cascade of each ICI-tumor combination, providing early prediction of ICIs efficacy and unveiling molecular mechanisms underlying heterogeneous immune responses. This strategy can potentially assist in designing optimal treatment options, improving precision and personalized medicine with early prediction of clinical outcomes. Finally, we engineered a translatable MRI-based nanoreporter that could become a practical prognosis tool in clinically relevant setting. The synthesized 19F-MRI reporter probe could “switch on” and “switch off” in response to the presence of Casp3 due to paramagnetic relaxation enhancement effect. This study aimed to provide preliminary proof-of-concept for future translatable imaging tool that could aid in early identifying patients’ response to therapies noninvasively. Overall, findings in this dissertation serve as guidance to develop forefront monitoring tools of immunotherapy responses in different settings, from in vitro, in vivo to translational context. These technologies could potentially provide valuable information for an optimized and personalized medicine.
DOI
https://doi.org/10.7275/35220748
Recommended Citation
Nguyen, Anh, "ENGINEERING NANOTHERANOSTIC PLATFORMS FOR EFFICIENT MONITORING OF RESPONSE TO IMMUNOTHERAPY" (2023). Doctoral Dissertations. 2838.
https://doi.org/10.7275/35220748
https://scholarworks.umass.edu/dissertations_2/2838