Nanoparticle-based modulation of CD4+ T cell effector and helper functions enhances adoptive immunotherapy

Adoptive cell therapies (ACT) hold promise for cancer immunotherapy, but optimization is still an ongoing process. Here the authors report CD4-targeted, nanoparticle-based artificial antigen-presenting cells that expand CD4(+) T cells capable of lysing tumor cell lysis in vitro, and CD8(+) T cells showing antitumor activity in a mouse melanoma model. Helper (CD4(+)) T cells perform direct therapeutic functions and augment responses of cells such as cytotoxic (CD8(+)) T cells against a wide variety of diseases and pathogens. Nevertheless, inefficient synthetic technologies for expansion of antigen-specific CD4(+) T cells hinders consistency and scalability of CD4(+) T cell-based therapies, and complicates mechanistic studies. Here we describe a nanoparticle platform for ex vivo CD4(+) T cell culture that mimics antigen presenting cells (APC) through display of major histocompatibility class II (MHC II) molecules. When combined with soluble co-stimulation signals, MHC II artificial APCs (aAPCs) expand cognate murine CD4(+) T cells, including rare endogenous subsets, to induce potent effector functions in vitro and in vivo. Moreover, MHC II aAPCs provide help signals that enhance antitumor function of aAPC-activated CD8(+) T cells in a mouse tumor model. Lastly, human leukocyte antigen class II-based aAPCs expand rare subsets of functional, antigen-specific human CD4(+) T cells. Overall, MHC II aAPCs provide a promising approach for harnessing targeted CD4(+) T cell responses.