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PhD Defense, Anh Pham Van Nguyen, Engineering Nanotheranostic Platforms for Efficient Monitoring of Tumor Response to Immunotherapy

Date/Time: 

Thursday, September 9, 2021 - 12:00pm

Location: 

N610 LSL or via Zoom

Details: 

Chair:  Ashish Kulkarni

Abstract

Modulating the immune functions to improve antitumor response has become a significant pillar in cancer treatment in recent years. By understanding the critical role of the immune system in eliminating neoplastic cells, several immunotherapeutic strategies have been developed to surmount carcinogenesis and immune escape mechanisms. Despite recent advancements in immune checkpoint inhibitors (ICIs), the success rates of such therapies vary among patients and cancer types. Conventional imaging techniques such as MRI, CT, and PET/CT scanning are routinely used to monitor the tumor response to the assigned therapy in clinics. However, they lack the sensitivity and specificity to validate the early response of the tumor correctly. This is due to the dependence on changes of tumor volume or metabolic profile of the tumors, which requires extended periods of time to evaluate the actual treatment outcomes. To address these challenges, imaging technology that allow detection of ongoing subcellular events in the tumor microenvironment are in high demand to provide more insights into biological processes, which subsequently can help early determine the actual responses to immunotherapies noninvasively.

This thesis focused on developing stimuli-responsive nanotheranostic platform, an integrative system of nanocarrier, therapy, and diagnostic tool, for early and accurate readouts of treatment efficacy directly in the tumor microenvironment. We first aimed to monitor in real-time the T-cell killing activity in both cell-based and preclinical studies 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 visualization of active granzyme B (GrzB), a potent hallmark of T cell cytotoxicity, as a direct way to monitor the initiation of the effective immune response following PD-1/PD-L1 perturbation. We further demonstrated that the nanoreporters enabled differentiation of highly responsive from poorly responsive tumors to the same treatment dosage much earlier than any significant gross changes in tumor volumes were observed.

In the follow-up study, we applied the nanoreporter technology to three-dimensional (3D) culture on a microfluidic chip for high-throughput screening of the efficacy of different ICIs and combination immunotherapy onto different tumor models. In this study, 3D organotypic spheroids were derived from explanted tumors to preserve the parental immune contexture, which provided a more relevant tumor microenvironment and, consequently, a more accurate functional biology study than 2D cell culture. Using organoid-on-chip, we were able to identify the kinetics of GrzB – caspase 3 (Casp3) apoptotic cascade of each ICI – tumor combination using a dual-probe nanoreporter that could detect GrzB and Casp3 concordantly. Such mechanistic and dynamic approach provided an early prediction of ICIs efficacy and unveiled molecular mechanisms underlying heterogeneous immune responses.

In our final study, we engineered a translatable MRI-based nanoreporter that could provide a practical prognosis tool in a clinically relevant setting. Previously developed fluorescence-based imaging tools allowed monitoring treatment response in vitro and in vivo, yet encountered restricted optical penetration depth in deep tissues. Here in this study, we synthesized and characterized a 19F-MRI reporter probe that could “switch on” and “switch off” in response to the presence of Casp3. To generate such an activatable probe, DOTA(Gd3+) complex was used to quench the 19F compound in close proximity via paramagnetic relaxation enhancement. This study aimed to provide preliminary proof-of-concept for a future translatable imaging tool that could aid in early identifying patients’ response to immunotherapies noninvasively.

 
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