Targeting self- And neoepitopes with a modular self-adjuvanting cancer vaccine

Abstract

Induction of a potent CD4 and CD8 T cell response against tumor-specific and tumor-associated antigens is critical for eliminating tumor cells. Recent vaccination strategies have been hampered by an inefficacious and low-amplitude immune response. In this article, we describe a self-adjuvanted chimeric protein vaccine platform to address these challenges, characterized by a multidomain construction incorporating (a) a cell-penetrating peptide allowing internalization of several multiantigenic MHC-restricted peptides within (b) the multiantigenic domain and (c) a TLR2/4 agonist domain. Functionality of the resulting chimeric protein is based on the combined effect of the above-mentioned 3 different domains for simultaneous activation of antigen-presenting cells and antigen cross-presentation, leading to an efficacious multiantigenic and multiallelic cellular immune response. Helper and cytotoxic T cell responses were observed against model-, neo-, and self-antigens and were highly potent in several murine tumor models. The safety and the immunogenicity of a human vaccine candidate designed for colorectal cancer treatment was demonstrated in a nonhuman primate model. This therapeutic vaccine approach, which we believe to be newly engineered, is promising for the treatment of poorly infiltrated tumors that do not respond to currently marketed immunotherapies.