These findings add to the accumulating evidence that the enhanced anti-tumor activity of combination anti-CTLA-4 and anti-PD-1 is mediated not only through additive effects, but also through mechanisms distinct from the monotherapies.22,26,98 While anti-CTLA-4 and anti-PD-1 combination ICT outperforms monotherapy in patients with metastatic melanoma, immune-related adverse events are problematic.99–102 We found that neoAg SLP vaccines combined with either anti-CTLA-4 or anti-PD-1 drove anti-tumor responses against Y1.7LI or MC38 that were equal to or better than combination ICT. This evidence concerns the gene CTLA4 and metastatic melanoma.