United Immunity Co. Ltd.

In therapeutic cancer vaccines, vaccine antigens must be efficiently delivered to the antigen-presenting cells (dendritic cells and macrophages) located in the lymphoid organs (lymph nodes and spleen) at the appropriate time to induce a potent antitumor immune response. Nanoparticle-based delivery systems in cancer immunotherapy are of great interest in recent year. We have developed a novel cancer vaccine that can use self-assembled polysaccharide nanogel of cholesteryl group-modified pullulan (CHP) as an antigen delivery system for clinical cancer immunotherapy for the first time. Additionally, we recently proposed a novel technology that uses CHP nanogels to regulate the function of tumor-associated macrophages, leading to an improvement in the tumor microenvironment. When combined with other immunotherapies, macrophage function modulation using CHP nanogels demonstrated a potent inhibitory effect against cancers resistant to immune checkpoint inhibition therapies. In this review, we discuss the applications of our unique drug nanodelivery system for CHP nanogels.

Immune checkpoint inhibitors and adoptive transfer of gene-engineered T cells have emerged as novel therapeutic modalities for hard-to-treat solid tumors; however, many patients are refractory to these immunotherapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. By comparing the tumor microenvironment of checkpoint inhibition-sensitive and -resistant murine solid tumors, we observed that the resistant tumors had low immunogenicity. We identified antigen presentation by CD11b+F4/80+ tumor-associated macrophages (TAMs) as a key factor correlated with immune resistance. In the resistant tumors, TAMs remained inactive and did not exert antigen-presenting activity. Targeted delivery of a long peptide antigen to TAMs by using a nano-sized hydrogel (nanogel) in the presence of a TLR agonist activated TAMs, induced their antigen-presenting activity, and thereby transformed the resistant tumors into tumors sensitive to adaptive immune responses such as adoptive transfer of tumor-specific T cell receptor-engineered T cells. These results indicate that the status and function of TAMs have a significant impact on tumor immune sensitivity and that manipulation of TAM functions would be an effective approach for improving the efficacy of immunotherapies.