Programming cells in situ
The potential of cell therapies to provide effective new treatments for human diseases afflicting hundreds of millions worldwide is widely appreciated; however the ex vivo manipulation of cells central to current approaches imposes a large economic and regulatory burden, and the vast majority of transplanted cells die and don't engraft. This thesis demonstrates a powerful new technology to effectively program cells in situ using material systems that first recruit host cells and that serve as a residence for subsequent cell programming and cell dispersement to the target site for therapy. The utility of this approach was addressed in the prototypical context of cancer vaccines, in which antigen-presenting cells (dendritic cells; DCs) are the target host cell population.
The current understanding of immunological regulation opens the possibility that materials can now be designed to purposely mimic aspects of bacterial infection to create a desirable immune response. Poly(lactide-co-glycolide) (PLG) matrices were fabricated to deliver a pulse of the inflammatory cytokine, GM-CSF, to first recruit and locally expand host DCs. The material then presented and enhanced DC uptake of oligonucleotides mimicking bacterial DNA in order to program the recruited DCs, and to disperse the DCs to the lymph nodes to prime a T-cell immune response. This system quantitatively controlled DC trafficking and activation, and led to high lymph node homing of programmed DCs. As a cancer vaccine, these infection-mimics were able to generate specific and protective anti-tumor immunity in correlation with its ability to control DC mobilization and programming in situ. Importantly, these vaccine systems performed equivalent to current cellular based vaccines, but require none of the cell isolations, cellular transplantation or ex vivo cell manipulations that are essential to current cancer vaccines.
The specific systems developed in this thesis will be useful in vivo models to study DC biology and the ability of these infection mimics to modulate immunity may revolutionize therapies in the vaccine and autoimmune fields. More broadly, this thesis provides a template for the design of future cell therapies that may precisely control cell trafficking and function in situ, producing a powerful alternative to conventional therapies.