Nanoscale artificial antigen presenting cells for cancer immunotherapy

Abstract

Exciting developments in cancer nanomedicine include the engineering of nanocarriers to deliver drugs locally to tumors, increasing efficacy and reducing off-target toxicity associated with chemotherapies. Despite nanocarrier advances, metastatic cancer remains challenging to treat due to barriers that prevent nanoparticles from gaining access to remote, dispersed, and poorly vascularized metastatic tumors. Instead of relying on nanoparticles to directly destroy every tumor cell, immunotherapeutic approaches target immune cells to train them to recognize and destroy tumor cells, which, due to the amplification and specificity of an adaptive immune response, may be a more effective approach to treating metastatic cancer. One novel technology for cancer immunotherapy is the artificial antigen presenting cell (aAPC), a micro- or nanoparticle-based system that mimics an antigen presenting cell by presenting important signal proteins to T cells to activate them against cancer. Signal 1 molecules target the T cell receptor and facilitate antigen recognition by T cells, signal 2 molecules provide costimulation essential for T cell activation, and signal 3 consists of secreted cues that further stimulate T cells. Classic microscale aAPCs present signal 1 and 2 molecules on their surface, and biodegradable polymeric aAPCs offer the additional capability of releasing signal 3 cytokines and costimulatory molecules that modulate the T cell response. Although particles of approximately 5-10 μm in diameter may be considered the optimal size of an aAPC for ex vivo cellular expansion, nanoscale aAPCs have demonstrated superior in vivo pharmacokinetic properties and are more suitable for systemic injection. As sufficient surface contact between T cells and aAPCs is essential for activation, nano-aAPCs with microscale contact surface areas have been created through engineering approaches such as shape manipulation and nanoparticle clustering. These design strategies have demonstrated greatly enhanced efficacy of nano-aAPCs, endowing nano-aAPCs with the potential to be among the next generation of cancer nanomedicines.

Keywords: Cancer; Immunoengineering; Nanomedicine; Polymer; aAPC.

Figure 1

Strategies for aAPC design. A) A classic micro-aAPC with surface-bound signal 1 (anti-CD3, MHC multimer, etc.) and signal 2 (anti-CD28, anti-4-1BB, etc.) molecules. B) Newer aAPC systems are constructed from biodegradable materials capable of releasing costimulatory and signal 3 cytokines (IL-12, IFN-α/β, etc.). C) Nano-aAPCs are less efficient T cell activators, but may outperform micro-aAPCs in vivo due to their transport properties. D) Recent findings suggest that ellipsoidal nano-aAPCs activate T cells more efficiently compared to spherical nano-aAPCs due to increased contact surface area. E) Magnetic field-induced clustering of paramagnetic nano-aAPCs has been shown to increase T cell induction and expansion.

Figure 2

Ellipsoidal and magnetically clustered nano-aAPC enhance antigen-specific T cell activation and expansion in vivo. A) Ellipsoidal nanoparticles were created by mechanical stretching. (Scale bar is 500 nm). B) Fluorescent ellipsoidal nano-aAPCs circulate with a longer half-life in the bloodstream compared to spherical nano-APCs. C) Ellipsoidal nano-aAPCs led to a statistically significant increase in the percentage of antigen-specific T cells in vivo compared to spherical nano-aAPCs. Reproduced with permission from Small (48). D) Schematic of magnetic field-induced clustering of TCRs bound to paramagnetic nanoparticles. E) T cells stimulated with nano-aAPCs in a magnetic field and adoptively transferred were present at higher frequencies seven days post-injection compared to controls. F) Treatment with magnetically enhanced T cells led to increased survival when T cells and particles were adoptively transferred on Day 10. Reproduced with permission from ACS Nano <http://pubs.acs.org/doi/10.1021/nn405520d> (52), further permissions related to the material excerpted should be directed to the ACS.