Accumulating evidence indicates that bead-based artificial antigen-presenting cells (aAPCs) are a powerful tool to induce
antigen-specific T cell responses in vitro and in vivo. To date, most conventional aAPCs have been generated by coupling an
antigen signal (signal 1) and one or two costimulatory signals, such as anti-CD28 with anti-LFA1 or anti-4-1BB (signal 2), onto the surfaces of cell-sized or nanoscale magnetic beads or
polyester latex beads. The development of a biodegradable scaffold and the combined use of multiple costimulatory signals as well as third signals for putative clinical applications is the next step in the development of this technology. Here, a novel biodegradable aAPC platform for active immunotherapy was developed by co-encapsulating
IL-2 and anti-CTLA-4 inside cell-sized polylactic-co-
glycolic acid microparticles (PLGA-MPs) while co-coupling an H-2Kb/TRP2-Ig dimer and anti-CD28 onto the surface.
Cytokines (activating signal) and
antibodies (anti-inhibition signal) were efficiently co-encapsulated in PLGA-MP-based aAPCs and co-released without interfering with each other. The targeted, sustained co-release of
IL-2 and anti-CTLA-4 achieved markedly enhanced, synergistic effects in activating and expanding
tumor antigen-specific T cells both in vitro and in vivo, as well as in inhibiting
tumor growth in a mouse
melanoma model, as compared with conventional two-signal aAPCs and
IL-2 or anti-CTLA-4 single-released aAPCs. These data revealed the feasibility and importance of the paracrine release of multiple costimulatory molecules and
cytokines from biodegradable aAPCs and thus provide a proof of principle for the future use of polymeric aAPCs for active immunotherapy of
tumors and
infectious diseases.