Triple synergy between cancer vaccine and checkpoint inhibitors in a pre-clinical tumor model

Authors

• WJ Becker
• PB Olkhanud
• HM Maengm JA Berzofsky

Abstract

Despite advances in checkpoint inhibitor (CPI) therapy for cancer, many cancers remain resistant. Tumors deemed ‘cold’ based on insufficient T cell infiltration into tumors show reduced potential for CPI therapy. Cancer vaccines may overcome this resistance by inducing the needed T cell immune response against the tumor to synergize with CPIs when the absence or low levels of anti-tumor T cells contributes to the primary resistance to CPIs. Here we used a mouse tumor model, TC1, expressing HPV16 E6 and E7 oncogenes, and administered a vaccine consisting of the E7 peptide combined with alpha-galactosylceramide (a potent NKT cell agonist) and GM-CSF as adjuvants. We show the synergy between the tumor-antigen specific vaccine and the combination of two CPIs, anti-TIGIT and anti-PD-L1. The synergistic effect of the triple combination provides more protection against tumor growth than either treatment alone or any pairwise combination and significantly improves survival in a CD8+ T cell-dependent manner. Depletion of CD4 T cells surprisingly improved the vaccine response, and depleting FoxP3+ Tregs via diphtheria toxin in FoxP3-GFPDTR mice revealed Tregs to be the causative agent inhibiting the response. The triple combination induces E7-specific T cells infiltrating the tumors by tetramer staining in young and aged mice, and aged mice show protection albeit less than their younger counterparts. These data show proof-of-concept for a novel combination of a vaccine designed to elicit de novo anti-tumor T cell responses that can be amplified by synergistic CPIs and Treg depletion that lead to greater survival.

Scientific Focus Area: Cancer Biology

This page was last updated on Monday, September 25, 2023