MEMP PhD Thesis Defense: Michelle Dion

Engineered Biomaterials for Brain Tumor Immunotherapy

Brain tumor therapy remains limited by an immunosuppressive, monotherapy-resistant tumor microenvironment and by a paucity of technologies capable of controlling therapy delivery kinetics to the tumor. In this thesis, we develop cell- and tissue-responsive biomaterial-based approaches for the delivery of combination chemoimmunotherapy to primary brain tumors.  We first describe the design of hydrogel-drug complexes that can adhere to brain tissue in situand sustain the release of multiple therapeutic payloads concurrently. We next describe how this system can be used to synchronize the delivery of an in situ vaccine strategy, consisting of cyclic dinucleotide nanoparticles, doxorubicin chemotherapy, and immune checkpoint blockade antibody anti-PD-1, to induce long-term survival (>80%) and immune memory in multiple orthotopic syngeneic glioblastoma mouse models following a single dose with minimal side effects. We further detail mechanistic studies that reveal that tumor rejection was a consequence of the therapy’s potent reprogramming of the tumor microenvironment, driven by two key phases: the initial rapid expression of inflammatory cytokines and tumor sensitization with antigen exposure during chemoimmunotherapy release, followed by the recruitment and sustained activation of antigen-presenting and effector cells facilitated by the hydrogel’s multiweek delivery period. Finally, in a genetically engineered mouse model, we characterize the therapy’s impact on antigen presentation dynamics and the tumor immunopeptidome, which may enable the development of complimentary antigen-directed approaches to further improve outcomes. Overall, our work presents tissue adhesive hydrogel-drug complexes as a strong proof-of-concept drug delivery technology and points to therapeutic release synchronized with biological responses as a key consideration for realizing robust immune activation without provoking toxicity in the treatment of brain tumors.

Thesis Supervisor:
Natalie Artzi, PhD
Associate Professor of Medicine, Harvard Medical School
Principal Research Scientist, Institute for Medical Engineering and Science, MIT
Core Faculty, Wyss Institute for Biological Engineering, Harvard University

Thesis Committee Chair:
Elazer R. Edelman, MD, PhD
Edward J. Poitras Professor in Medical Engineering and Science, MIT
Professor of Medicine, Harvard Medical School

Thesis Readers:
Samir Mitragotri, PhD
Hiller Professor of Bioengineering at the John A. Paulson School of Engineering and Applied Sciences, Harvard University
Core Faculty, Wyss Institute for Biological Engineering, Harvard University

Khalid Shah, PhD
Professor of Medicine, Harvard Medical School
Vice Chair of Research, Department of Neurosurgery, Brigham & Women’s Hospital

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Topic: Michelle Dion MEMP PhD Thesis Defense
Time: Friday, January 17, 2025, 11:00 AM Eastern Time (US and Canada)

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