Nanoimmunotherapy: Combining Immunotherapy and Nanomedicine to Develop Enhanced Therapeutics for the Treatment of Solid Tumors Open Access
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Adoptive cell therapy has demonstrated significant clinical benefit for patients with blood cancers, however their promise has yet to be fulfilled in the context of solid tumors. There are multiple factors contributing to the challenges facing adoptive immunotherapies for solid tumors, including the innate tumor microenvironment, which contains an abundance of suppressive cell types, as well as produces immunosuppressive cytokines such as IL10 and TGFβ. In this dissertation, I address the limitations of existing therapeutics and develop nanoimmunotherapy treatment modalities that are applicable to a range of solid tumors. The term “nanoimmunotherapy” refers to an emerging niche field that combines the multifunctional capabilities of nanoparticles with immune-based therapies. Specifically, in this body of work, I use nanoimmunotherapy techniques to develop enhanced therapeutics that can (1) resist endogenous immunosuppression, (2) rapidly and effectively home to tumor sites, and/or (3) include an accessory mode of tumor-killing, in order to achieve maximal therapeutic efficacy against solid tumors. In Chapter 3, I focus on genetic engineering strategies to develop improved therapies; specifically, NK cell therapeutics (established from allogenic umbilical cord donors) were generated to be resistant to potent TGFβ-mediated immunosuppression and contain novel “switch” receptors, capable of converting the suppressive pathway into a means of activating NK cells and enhancing anti-tumor activity in vitro and in vivo. In Chapters 4 and 5, I focus on nano-engineering strategies, centered around the concept of an immune effector-nanoparticle biohybrid construct. This biohybrid strategy is something that is customizable across multiple platforms, as demonstrated by studies with different immune components (T cells vs. NK cells) and different nanoparticle components (PBNP vs. IONP), and it represents a generalizable therapeutic modality that can be specifically tailored to suit the unique challenges that different tumors produce, and draws upon proficiencies of both the innate and adaptive immune systems in order to achieve a maximal therapeutic effect. Taken together, the strategies described in this dissertation encompass novel examples of nanoimmunotherapy, and highlight the potential of combinatorial therapies, such as these, to be applied in the clinic for the treatment of challenging solid tumor malignancies.