P-Pev: micelle-like complexes transformed from tumor extracellular vesicles by PEG-PE for personalized therapeutic tumor vaccine.

The clinical benefits of personalized therapeutic tumor vaccines are mainly challenged by the need to identify immunogenic neoantigens promptly, given the rapid pace of tumor mutations. An increasing body of literature addresses the potential of tumor-derived extracellular vesicles (TEVs) as an anti-tumor "cell-free" vaccine due to their substantial presence of neoantigens. However, their immunosuppression and limited presentation efficiency of dendritic cells (DCs) restrict their further application. Here, we have developed a novel tumor-personalized vaccine, termed P-Pev, based on remodeled TEVs by polymeric surfactant polyethylene glycol-phosphatidyleolamine (PEG-PE) and adjuvant monophosphoryl lipid A (MPLA). Our results show that PEG-PE transforms TEVs into micelle-like complexes by disrupting the original structure, facilitating antigens delivery to the cytoplasm, and cross-presentation by DCs. P-Pev particularly prevents the immunosuppressive impacts of TEVs on the ability of DCs to prime CD8 T cells and eliminates the potency of TEVs to promote lung metastasis through their membrane-bound PD-L1. Finally, the P-Pev effectively induces neoantigen-specific cytotoxic T lymphocytes (CTLs) responses and exhibits excellent therapeutic effects in various murine tumor models. Also, the P-Pev induces neoantigen-specific antibodies, suggesting the involvement of humoral immunity in its anti-tumor effects. More importantly, it has been shown that P-Pev prepared by mutated tumor cells can retard these mutated tumor cell-established syngeneic tumors better than P-Pev prepared by original tumor cells, indicating the feasibility that leverages TEVs to prepare personalized tumor vaccines, and it is synergistically enhanced by PD-1 mAb combination. Collectively, we present a general strategy that offers a streamlined, cost-effective, and time-consuming approach to preparing personalized therapeutic tumor vaccines.