Immune checkpoint blockade antibodies are setting a new standard of care for cancer patients. It is therefore important to assess any new immune-based therapies in the context of immune checkpoint blockade. Here， we evaluate the impact of combining a synthetic consensus TERT DNA vaccine that has improved capacity to break tolerance with immune checkpoint inhibitors. We observed that blockade of CTLA-4 or， to a lesser extent， PD-1 synergized with TERT vaccine， generating more robust anti-tumor activity compared to checkpoint alone or vaccine alone. Despite this anti-tumor synergy， none of these immune checkpoint therapies showed improvement in TERT antigen-specific immune responses in tumor-bearing mic... More
Immune checkpoint blockade antibodies are setting a new standard of care for cancer patients. It is therefore important to assess any new immune-based therapies in the context of immune checkpoint blockade. Here， we evaluate the impact of combining a synthetic consensus TERT DNA vaccine that has improved capacity to break tolerance with immune checkpoint inhibitors. We observed that blockade of CTLA-4 or， to a lesser extent， PD-1 synergized with TERT vaccine， generating more robust anti-tumor activity compared to checkpoint alone or vaccine alone. Despite this anti-tumor synergy， none of these immune checkpoint therapies showed improvement in TERT antigen-specific immune responses in tumor-bearing mice. αCTLA-4 therapy enhanced the frequency of T-bet/CD44 effector CD8 T cells within the tumor and decreased the frequency of regulatory T cells within the tumor， but not in peripheral blood. CTLA-4 blockade synergized more than Treg depletion with TERT DNA vaccine， suggesting that the effect of CTLA-4 blockade is more likely due to the expansion of effector T cells in the tumor rather than a reduction in the frequency of Tregs. These results suggest that immune checkpoint inhibitors function to alter the immune regulatory environment to synergize with DNA vaccines， rather than boosting antigen-specific responses at the site of vaccination.
