Guiding immunotherapy combinations: Who gets what?

Although PD-1 and CTLA-4 inhibitors have proven successful in a range of malignancies, there are subsets of patients that do not respond to these agents due to upregulation of adaptive and innate resistance mechanisms by the tumor and its surrounding microenvironment. As new immunotherapeutic strategies are developed, there is a need for rational implementation of novel immunotherapy combinations that target complementary mechanisms of immunotherapy resistance intrinsic to each patient and tumor type. In this short review, we cover mechanisms by which tumors evade the immune system, as well as summarize available clinical data on emerging therapeutic agents that target these defense mechanisms. Rational implementation of combination immunotherapy targeting patient- and malignancy-specific immune evasion mechanisms may thus lead to enhanced response rates and allow immunotherapy to be effective even in tumors that are historically considered poorly responsive to immunotherapy.