Belnoue and Mayol et al. designed a DC-targeting chimeric protein vaccine consisting of a cell-penetrating peptide to enhance internalization, a multi-antigenic domain to introduce MHC-restricted peptides, and a TLR2/4 agonist domain to act as a self-adjuvant. The vaccine induced effector and memory CD4+ and CD8+ T cell responses to multiple epitopes, increased tumor infiltration, remodeled the TME, and enhanced tumor control in various murine models. Antibodies to the vaccine developed but did not impact T cell responses. A vaccine candidate for use in humans showed safety and immunogenicity in a non-human primate.
Induction of a potent CD4 and CD8 T-cell response against tumor-specific and tumor-associated antigen is critical for eliminating tumor cells. Recent vaccination strategies have been hampered by an inefficacious and low amplitude immune response. Here we describe a self-adjuvanted chimeric protein vaccine platform to address these challenges, characterized by a multidomain construction incorporating (i) a cell penetrating peptide (CPP) allowing internalization of several multiantigenic Major Histocompatibility Complex (MHC)-restricted peptides within (ii) the multiantigenic domain (Mad) and (iii) a TLR2/4 agonist domain (TLRag). Functionality of the resulting chimeric protein is based on the combined effect of the above-mentioned three 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 non-human primate model. This newly engineered therapeutic vaccine approach is promising for the treatment of poorly infiltrated tumors that do not respond to currently marketed immunotherapies.