Nanoparticle-based Photothermal Therapy for Potentiating CAR T Cell Therapy against Solid Tumors
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Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies, but its efficacy in solid tumors remains limited by poor T cell infiltration, antigen heterogeneity, and immunosuppressive cues within the tumor microenvironment (TME). This dissertation investigates a nano-immunotherapeutic strategy that integrates Prussian blue nanoparticle-mediated photothermal therapy (PBNP-PTT) with CAR T cell treatment to overcome these barriers. To address this gap, I evaluate the biological and therapeutic impact of PBNP-PTT in combination with CAR T cells across in vitro and in vivo neuroblastoma models. In Chapter Two, I show that PTT upregulates thermally stable, tumor-associated antigens suitable for CAR targeting. In Chapter Three, I demonstrate that PTT pre-treatment augments CAR T cell cytotoxicity in vitro, resulting in synergistic tumor killing. Chapter Four transitions to an immunocompetent mouse model, where the combination of PBNP-PTT and B7-H3 CAR T cells significantly improves tumor clearance and survival. Finally, Chapter Five provides evidence that PTT disrupts stromal architecture and remodels the TME, facilitating enhanced infiltration and activity of both CAR T cells and endogenous immune cells. Together, these findings establish proof-of-concept for PBNP-PTT as a potent adjuvant to CAR T cell therapy in solid tumors, offering a novel approach to sensitize tumors, reprogram the TME, and improve therapeutic outcomes.
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