Development of Biomaterials for Chimeric Antigen Receptor (CAR) T Cell Therapy

Thesis (Ph.D.)--University of Washington, 2018Chimeric antigen receptor (CAR) T cell therapy has emerged as an effective new cancer treatment that genetically reprograms a patient’s T cells to recognize an epitope specifically expressed on the surface of cancer cells and trigger cytotoxic action against those cancer cells. This therapy has been especially effective in the treatment of CD19+ hematologic malignancies. However, the manufacturing of these autologous cell therapies requires laborious processing steps that present multiple challenges and opportunities for innovation, described in Chapter 1. The current manufacturing system requires extensive use of biologic reagents including antibody-coated magnetic beads for manipulation and expansion, and retroviruses for genetic modification of ex vivo cultured T cells. In this work, three classes of synthetic biomaterials are developed to improve and study the ex vivo expansion and genetic modification of primary human T cells. In Chapter 2, we describe the development of cell-templated supported lipid bilayers as a platform for studying the effect of activation particle design on polyclonal T cell expansion and differentiation. Chapter 3 describes work towards identifying synthetic peptide and aptamer targeting ligands for T cell activation through library screening techniques. In Chapters 4 and 5, we report the use of cationic polymers of defined architecture for non-viral gene delivery to T cells and study the underlying barriers to improved gene delivery in T cells. The major findings from this work are summarized in Chapter 6 where we also make recommendations for future applications and directions of this work