Heterologous, costimulation-assisted vaccinations drive potent cellular immune responses to cancer

Immunotherapy of cancer has emerged as an effective means for the treatment of solid cancer. The therapeutic efficacy of current therapies, however, is hampered by the low immunogenicity of the currently available vaccines that typically induce immune responses at or below the threshold of detection. Bacterial or viral vectors are able to overcome this limitation but require laborious vector design and are thus unsuitable for individually tailored vaccination approaches. We sought to develop a novel cancer vaccination that induces potent immune responses while preserving a maximum of flexibility with regard to the antigen of choice. Since co-stimulatory antibodies are potent stimulators of T cell expansion, we tested various combinations of agonistic costimulatory antibodies in combination with peptides and TLR agonists. We observed optimal CD8 T cell expansion when peptide vaccination was given in combination with the TLR3 agonist Poly I:C and CD40 agonistic antibodies. To enable short-term amplification of the cancer-specific immune response, we combined this costimulation-assisted vaccination with various primary immunizations. Surprisingly, the combination of the costimulation-based vaccination with a dendritic cell immunization led to massive amplification of CD8 T cell immune responses targeting either neoantigens or tumor-associated antigens. In therapeutic setting, the novel vaccination led to complete regression of subcutaneous tumor after vaccination against a single, high affinity antigen. Our results demonstrate that optimized prime-boost vaccinations are able to strongly amplify cancer-specific immune responses thus warranting their further evaluation for the immunotherapy of cancer patients. Corresponding author: Wirth, Thomas E-Mail: wirth.thomas@mh-hannover.de