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

Abstract

Abstract 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 (FPC2). IL‐2‐laden FPC2 exhibited a preferential bioactivity in ex vivo expansion of CD8+T cells over Treg cells. Additionally, FPC2 was embedded in pH modulating injectable gel (FPC2‐IG) to endure the acidic tumor microenvironment. A single intratumoral administration of FPC2‐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 FPC2‐IG‐IL‐2. The immune‐favorable tumor microenvironment induced by FPC2‐IG‐IL‐2 enabled adoptively transferred TCR‐engineered T cells to effectively eradicate tumors. FPC2‐IG delivery system is a promising strategy for T‐cell‐based immunotherapies.

Keywords

• adoptive T‐cell therapy
• complex coacervate
• fucoidan
• immunotherapy
• interleukin‐2