Optimal long peptide for flagellin-adjuvanted HPV E7 cancer vaccine to enhance tumor suppression in combination with anti-PD-1

BACKGROUND: Therapeutic cancer vaccines, which induce or amplify tumor-specific T cell responses, are a critical component of multiple combination cancer immunotherapy regimens. Innovative neoantigen identification continually prompts the development of vaccine platforms. However, vaccine monotherapy is not sufficient to eradicate tumors. Thus, therapeutic strategies combining cancer vaccines and treatment with other immune modulators have been expl, ored. Previously, we showed that flagellin has an excellent adjuvant activity to induce effective immune responses to co-administered peptide epitopes through TLR5 stimulation in mouse TC-1 tumor models and flagellin-expressing bacteria modulate the tumor microenvironment (TME) toward enhanced immunogenicity. METHODS: Given that short- and long-peptides undergo different fates of internalization, processing, and MHC-restricted presentation by professional antigen-presenting cells (APCs), we compared the antitumor activity of flagellin-adjuvanted peptide vaccines by employing the E7 CD8 epitope short peptide (E7-SP(49-57)) and E7 long peptides (E7-LP20(43-62 )and E7-LP35(43-77)). Because combinations take center stage in immune checkpoint inhibitor (ICI) therapy, we evaluated the best E7 peptide vaccine component for combination with anti-PD-1 in the mouse TC-1 model. RESULTS: Flagellin adjuvanted E7-LP35 vaccine (FlaB-LP35Vax) showed significantly higher antitumor activity than flagellin adjuvanted E7-SP vaccine (FlaB-SPVax) and flagellin adjuvanted E7-LP20 vaccine (FlaB-LP20Vax) in a mouse TC-1 tumor model. Coadministration of flagellin was essential for E7-mediated tumor suppression. PD-1 blockade enhanced the therapeutic efficacy of FlaB-LP35Vax but not FlaB-SPVax. Taken together, E7-LP35 is an optimal tumor antigen for flagellin-adjuvanted E7 cancer vaccines, and the combination of FlaB-LP35Vax with anti-PD-1 antibody treatment induced long-term antitumor immune responses. CONCLUSIONS: This result suggests that cooperation between CD4(+) and CD8(+ )cell-mediated immune responses is essential for the success of combination therapy with cancer vaccines and ICIs.