With the US FDA’s approval of the first cancer vaccine for prostate cancer  and immune checkpoint blockade therapy against CTLA-4 for melanoma , the complex interaction between antitumor immune responses and tumor immune evasion is being intensely scrutinized. Despite a number of exciting preclinical studies and clinical research, most novel immunotherapies have demonstrated limited efficacy in early-phase clinical trials. The reason for this is multifactorial. First, novel agents have generally been tested in patients with treatment refractory, metastatic and large tumor burdens who failed multiple therapeutic regimens in the past. Second, cancer is an extremely heterogeneous disease, even within the same subtype. Single agent therapy, regardless of its type, will most likely be ineffective. Moreover, and probably most importantly, tumor cells have a large arsenal of adaptive capabilities that render targeted therapies ineffective.