Artificial Immunity Platforms for Cellular Immunotherapy [electronic resource].

9781085776455

Ann Arbor : ProQuest Dissertations & Theses, 2019.

1 online resource (184 p.)

Access is available to the Yale community.

Antigen presentation is at the cornerstone of adaptive immunity as it determines the specificity, direction and magnitude of effector immune responses. The ability to leverage the power and sensitivity of our immune system towards specific disease targets, therefore, hinges upon our command over antigen-presenting cells (APCs). To this end, Dendritic Cells (DCs), dubbed professional APCs, have been identified as desirable targets for cellular immunotherapies; however, significant hurdles in production and manipulation of DCs have resulted in disappointing clinical outcomes. Thus, there is pressing need for novel strategies to 1) efficiently generate therapeutic DCs, 2) impart disease-specific programming to trigger desired effector responses, and 3) monitor their clinical efficacy.First, in search of a method to produce clinically-relevant APCs, we investigated a cellular immunotherapy for T cell lymphoma (CTCL) shown to induce physiologic maturation of autologous DCs from patient blood, extracorporeal photopheresis (ECP). In the process of uncovering ECP’s mechanism, which has remained unelucidated for nearly 30 years, since its inception and wide adoption across over 350 medical centers, we discovered that platelets induce cross-presentation and DC differentiation in blood monocytes. Functional studies of these platelet-matured cells we call physiological DCs (phDCs) demonstrated robust activation of adaptive T cell immunity in murine and human experimental systems, suggesting translational potentials for effective DC immunotherapy. We then investigated the use of biodegradable nanoparticles (NPs) as a novel vaccination strategy for modulating the quality of DC-driven immune responses in cancer and autoimmune disease models. Specifically, our studies explored the significance of encapsulation strategy in the delivery of multiple bioactive agents for the induction and maintenance of immunogenic or tolerogenic responses. Our investigations discovered that NP encapsulation strategies direct the co-delivery and co-localization kinetics of payloads, thus, shaping the overall quality of induced vaccine responses. Through this work, we identified that NP-mediated immunomodulation requires careful consideration of the spatiotemporal distribution characteristics of the delivery formulation. Finally, we engineered a microfluidic device to assess DC-based immunotherapies by the quality of induced effector immune responses. Using an electrokinetic method of exerting force onto polarizable particles, dielectrophoresis (DEP), we developed a microfluidic chip that could discriminately quantify unactivated and activated T cells in a label-free, point-of-care manner. In this approach, T cells from patient peripheral blood samples can be quickly analyzed by their immunologic activation states. As the goal of DC-based immunotherapy is the activation of T cells that produce disease-specific effector response, we expect this DEP-enabled device to report on the efficacy of immunotherapy ahead of available clinical indications. Overall, this research has culminated in the generation of clinically-relevant, physiological DCs, demonstration of biophysical determinants for effective nanoparticle-mediated DC immunotherapy, and development of bioelectronic tools to assess immunologic activity. Our findings address critical challenges in the clinical implementation of DC-based cellular therapies.

Dissertations & Theses @ Yale University.

Books / Online / Dissertations & Theses

English

January 17, 2020

Thesis (Ph.D.)--Yale University, 2019.

Yale University. Chemical and Environmental Engineering.