Utilizing nanotechnology to improve the activation of CD8 T cells for cancer immunotherapy
Embargo until
2020-05-01
Date
2018-03-15
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Publisher
Johns Hopkins University
Abstract
The immune system can be manipulated to recognize and eliminate cancerous cells. Many of these manipulations aim to increase the proliferation and activation of tumor-targeting cytotoxic CD8+ T cells through direct stimulation or attenuation of immuno-inhibitory checkpoint pathways. Here, I use nanotechnology to develop platforms that can enhance and/or target immuno-stimulatory properties by controlling the kinetics, costimulation, and nanoscale delivery of immunotherapies.
I first developed a nanoparticle that converts inhibitory signals in the tumor microenvironment to T cell stimulatory signals. By tethering checkpoint blockade and co-stimulatory molecules to a single platform, I made particles that physically link tumor cells and T cells while inhibiting checkpoint activity and activating T cells. These particles delayed or eliminated tumor growth in several murine models at doses 10-100x less than soluble inhibitory and co-stimulatory molecules and resulted in a systemic memory immune response while localizing the nanoparticles to the tumor microenvironment.
Next, I developed a modified type of artificial antigen presenting cell (aAPC) that boosts CD8+ T cell activation for adoptive cell transfer. T cell signaling components were separated onto distinct superparamagnetic nanoparticles and activation was induced by clustering the particles with a magnetic field. This platform streamlined the application of various combinations of co-stimulatory molecules together with a single antigen-specific receptor to increase the expansion of antigen-specific T cells and extend their persistence in vivo.
Finally, I developed more effective biodegradable aAPC by modifying the particle material and through combination with checkpoint blockade. Biodegradable aAPC synergized with anti-PD-1 checkpoint blockade to delay the growth of established murine melanoma. A new type of polymeric aAPC also activated antigen-specific CD8+ T cells at doses 100x less than previous particle formulations.
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Keywords
cancer immunotherapy, nanotechnology, CD8 T cells