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Therapeutic Nanotechnology and Immunoengineering for Cellular Therapy in Autoimmune Diabetes and Cancer

  • Author(s): Chang, Ryan
  • Advisor(s): Desai, Tejal A
  • et al.
Abstract

Cellular therapy has gained impressive momentum in recent years as has the promise to become the third pillar of biomedical therapeutics after small molecule and biologic drugs. Cells have capabilities that are significantly superior to traditional small molecule and biologics that are essential to tackling some of the most difficult to treat diseases. Only cells are able to sense their environments, engage in complex signal processing, and ultimately respond through motility, release of molecules, or engagement of other cell types to elicit a therapeutic response. Indeed, we have already witness exciting advances such as the use of chimeric antigen receptor engineered T cells to kill tumor cells, or the replacement of dysfunctional endogenous cells with stem cells to recapitulate a lost native biological function.

It is becoming increasingly clear that there is a role for biomaterials to play within the paradigm of cellular therapy to facilitate and augment its efficacy. The delivery of cellular products into patients is fundamentally different from the administration of small molecule or biologic drugs, and may require the use of biomaterials for support to ensure optimal viability and function. In addition, material and device engineering may help overcome some challenges in protecting cellular therapeutic products from hazardous host environments, such as the immune response. Finally, materials may be engineered to interact with endogenous or exogenous cells to precisely instruct their fate and function. Here, we illustrate three projects that combine engineered biomaterials with cells as novel strategies to help us understand and overcome challenges in diabetes and in cancer therapy.

First, we demonstrate the fabrication and use of nanoengineered thin film polymer materials to encapsulate of stem cells for the treatment of diabetes. Through the engineer of nanopores in to encapsulation devices, we show the ability to exclude immune cells and prevent priming of the host immune system. Remarkably, encapsulated stem cell derived beta cells are viable up to 6 months and exhibit glucose sensitive insulin secretion in vivo.

Next, we illustrate the utility of a novel polymer scaffold to facilitate transplantation of islets into previously non-viable sites. In this study, we fabricated highly defined template patterns into polymer scaffolds to optimize islet cluster loading. We show the insulin secretion ability of islets loaded in scaffolds in well preserved. Finally, the islet-scaffold construct transplanted into the epidydimal fat pad successfully controlled blood glucose in diabetic mouse model.

In our final project, we synthesized nanoparticle tumor vaccines inspired by oncolytic viruses to treat solid tumors. Polymeric nanoparticles were loaded with a cocktail of immune adjuvants and a tumor antigen peptide. We demonstrate that these particles can efficiently present antigens to antigen presenting cells to instruct antigen specific T cell activation. Moreover, the polymeric nanoparticle vaccine successfully prevented the outgrowth of tumors in a syngeneic melanoma tumor model.

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