Targeted co-delivery of Trp-2 polypeptide and monophosphoryl lipid A by pH-sensitive poly (β-amino ester) nano-vaccines for melanoma

Abstract

Dendritic cell (DC)-targeted vaccines based on nanotechnology are a promising strategy to efficiently induce potent immune responses. We synthesized and manufactured a mannose-modified poly (β-amino ester) (PBAE) nano-vaccines with easily tuneable and pH-sensitive characteristics to co-deliver the tumor-associated antigen polypeptide Trp-2 and the TLR4 agonist monophosphoryl lipid A (MPLA). To reduce immunosuppression in the tumor microenvironment, an immune checkpoint inhibitor, PD-L1 antagonist, was administrated along with PBAE nano-vaccines to delay melanoma development. We found that mannosylated Trp-2 and MPLA-loaded PBAE nano-vaccines can target and mature DCs, consequently boosting antigen-specific cytotoxic T lymphocyte activity against melanoma. The prophylactic study indicates that combination therapy with PD-L1 antagonist further enhanced anti-tumor efficacy by 3.7-fold and prolonged median survival time by 1.6-fold more than free Trp-2/MPLA inoculation. DC-targeting PBAE polymers have a great potential as a nanotechnology platform to design vaccines and achieve synergistic anti-tumor effects with immune checkpoint therapy.

Keywords: Cancer immunotherapy; Immune checkpoint therapy; Nano-vaccine; Poly (β-amino ester); Polypeptide antigen.