Enhancing adoptive T-cell therapy with fucoidan-based IL-2 delivery microcapsules.

Adoptive cell therapy (ACT) with antigen-specific T cells is a promising treatment approach for solid cancers. Interleukin-2 (IL-2) has been utilized in boosting the efficacy of ACT. However, the clinical applications of IL-2 in combination with ACT is greatly limited by short exposure and high toxicities. Herein, a complex coacervate was designed to intratumorally deliver IL-2 in a sustained manner and protect against proteolysis. The complex coacervate consisted of fucoidan, a specific IL-2 binding glycosaminoglycan, and poly- l -lysine, a cationic counterpart (FPC 2 ). IL-2-laden FPC 2 exhibited a preferential bioactivity in ex vivo expansion of CD8 + T cells over Treg cells. Additionally, FPC 2 was embedded in pH modulating injectable gel (FPC 2 -IG) to endure the acidic tumor microenvironment. A single intratumoral administration of FPC 2 -IG-IL-2 increased expansion of tumor-infiltrating cytotoxic lymphocytes and reduced frequencies of myeloid populations. Notably, the activation and persistency of tumor-reactive T cells were observed only in the tumor site, not in the spleen, confirming a localized effect of FPC 2 -IG-IL-2. The immune-favorable tumor microenvironment induced by FPC 2 -IG-IL-2 enabled adoptively transferred TCR-engineered T cells to effectively eradicate tumors. FPC 2 -IG delivery system is a promising strategy for T-cell-based immunotherapies.