Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice

SignificanceSeveral immunotherapies are approved for treating cancer patients, including aCTLA-4 (anti–cytotoxic T-lymphocyte–associated protein 4; ipilimumab) and anti–PD-1 (anti-programmed cell death protein 1; nivolumab; pembrolizumab), but the best clinical results are coming from combination immunotherapy. Our research demonstrates that aOX40 (anti-CD134)/aCTLA-4 immunotherapy can lead to a potentially tumor-promoting Th2-cytokine milieu (IL-4, IL-5, IL-13) when relying on endogenous antigen presentation. However, aOX40/aCTLA-4 treatment combined with a tumor antigen-specific vaccine, DEC-205 (anti–dendritic and epithelial cells, 205 kDa)–HER2 (human epidermal growth factor receptor 2), promoted robust tumor infiltration by effector CD8 T cells and restored Th1 polarization of CD4 T cells, leading to improved overall survival in a mammary carcinoma model. This study has direct relevance for the design of combination therapy trials in patients.