BEMPEG in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in a wide variety of murine tumor models showed superior anti-tumor activity over infrequently dosed native IL-2 and systemically expanded anti-tumor CD8+ T cells while reducing Tregs in tumor tissue but not in the periphery. Here, CTLA4 is linked to neoplasm.